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Sample records for aromatase inhibitor therapy

  1. Update on Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Seifert-Klauss V

    2015-01-01

    Full Text Available Aromatase inhibitors (AI block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.br Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS may be avoided. For premenopausal diseases which are said to be positively affected by

  2. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients. PMID:27178335

  3. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.

  4. Molecular Docking of Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Virapong Prachayasittikul

    2011-04-01

    Full Text Available Aromatase is an enzyme that plays a critical role in the development of estrogen receptor positive breast cancer. As aromatase catalyzes the aromatization of androstenedione to estrone, a naturally occurring estrogen, it is a promising drug target for therapeutic management. The undesirable effects found in aromatase inhibitors (AIs that are in clinical use necessitate the discovery of novel AIs with higher selectivity, less toxicity and improving potency. In this study, we elucidate the binding mode of all three generations of AI drugs to the crystal structure of aromatase by means of molecular docking. It was demonstrated that the docking protocol could reliably reproduce the interaction of aromatase with its substrate with an RMSD of 1.350 Å. The docking study revealed that polar (D309, T310, S478 and M374, aromatic (F134, F221 and W224 and non-polar (A306, A307, V370, L372 and L477 residues were important for interacting with the AIs. The insights gained from the study herein have great potential for the design of novel AIs.

  5. Aromatase inhibitors and anti-synthetase syndrome.

    Science.gov (United States)

    Mascella, Fabio; Gianni, Lorenzo; Affatato, Alessandra; Fantini, Manuela

    2016-09-01

    Adjuvant therapy in postmenopausal women with endocrine-responsive breast cancer (BC) is actually centered on the use of anti-aromatase inhibitors (AI). Several reports, however, are emerging in literature associating the use of this drugs to rheumatic disorders. This case report describes the first case of anti-synthetase syndrome diagnosis after treatment with anti-estrogen agents in a patient with pre-existing rheumatoid arthritis. PMID:27225465

  6. Natural Products as Aromatase Inhibitors

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purpos...

  7. Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214191

  8. Committee Opinion No. 663 Summary: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214185

  9. Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis

    Directory of Open Access Journals (Sweden)

    Mustata Gabriela

    2011-06-01

    Full Text Available Abstract Background The present study compares antiepileptic drugs and aromatase (CYP19 inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs are needed, especially since every individual responds differently to given treatment options. Methods Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits. Results The pharmacophore model returned 73% (19 out of 26 of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62 of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses. Conclusions This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity

  10. Aromatase inhibitors in the treatment of endometriosis.

    Science.gov (United States)

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  11. Aromatase inhibitors in the treatment of endometriosis

    Science.gov (United States)

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  12. Which patients benefit most from adjuvant aromatase inhibitors?

    DEFF Research Database (Denmark)

    Viale, G; Regan, M M; Dell'Orto, P;

    2011-01-01

    On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which...

  13. Complementary or alternative medicine as possible determinant of decreased persistence to aromatase inhibitor therapy among older women with non-metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Laetitia Huiart

    Full Text Available PURPOSE: Aromatase inhibitor therapy (AI significantly improves survival in breast cancer patients. Little is known about adherence and persistence to aromatase inhibitors and about the causes of treatment discontinuation among older women. METHODS: We constituted a cohort of women over 65 receiving a first AI therapy for breast cancer between 2006 and 2008, and followed them until June 2011. Women were selected in the population-based French National Health Insurance databases, and data was collected on the basis of pharmacy refills, medical records and face-to-face interviews. Non-persistence to treatment was defined as the first treatment discontinuation lasting more than 3 consecutive months. Time to treatment discontinuation was studied using survival analysis techniques. RESULTS: Overall among the 382 selected women, non-persistence to treatment went from 8.7% (95%CI: 6.2-12.1 at 1 year, to 15.6% (95%CI: 12.2-19.8 at 2 years, 20.8% (95%CI: 16.7-25.6 at 3 years, and 24.7% (95%CI: 19.5-31.0 at 4 years. In the multivariate analysis on a sub-sample of 233 women with available data, women using complementary or alternative medicine (CAM (HR = 3.2; 95%CI: 1.5-6.9 or suffering from comorbidities (HR = 2.2; 95%CI: 1.0-4.8 were more likely to discontinue their treatment, whereas women with polypharmacy (HR = 0.4; 95%CI: 0.2-0.91 were less likely to discontinue. In addition, 13% of the women with positive hormonal receptor status did not fill any prescription for anti-hormonal therapy. CONCLUSION: AI therapy is discontinued prematurely in a substantial portion of older patients. Some patients may use CAM not as a complementary treatment, but as an alternative to conventional medicine. Improving patient-physician communication on the use of CAM may improve hormonal therapy adherence.

  14. Aromatase inhibitors in men: effects and therapeutic options

    Directory of Open Access Journals (Sweden)

    de Jong Frank H

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended.

  15. Bilateral De Quervain Syndrome after Aromatase Inhibitor Administration: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Konstantinos Papadimitriou

    2012-01-01

    Full Text Available Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs, and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of the relevant literature.

  16. Aromatase inhibitor strategies in metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Heather L McArthur

    2009-07-01

    Full Text Available Heather L McArthur, Patrick G MorrisBreast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: Despite ongoing therapeutic innovations, metastatic breast cancer (MBC remains a treatable but incurable disease. In the developed world, a diagnosis of MBC without a preceding diagnosis of early stage disease is a rare event. However, approximately one-third of women with early stage breast cancer ultimately experience a distant recurrence. Because the majority of breast cancers express estrogen and/or progesterone receptors and are accordingly considered hormone-sensitive, therapeutic strategies that interfere with hormone-mediated tumorigenesis have been a cornerstone of the breast cancer management paradigm for decades. Historically, the selective estrogen receptor modulator tamoxifen has been the most extensively studied and widely used hormone maneuver in breast cancer. However, a recent therapeutic innovation, namely the successful development of third-generation aromatase inhibitors (AIs, has had a dramatic impact on the treatment paradigm for women with hormone-sensitive MBC. Because of the demonstrated efficacy in postmenopausal breast cancer patients, the generally favorable side-effect profile, and the convenience of oral administration, AIs are now in widespread clinical use. Currently, there are three clinically available third-generation AIs: two reversible, nonsteroidal AIs, letrozole and anastrozole; and one irreversible, steroidal AI, exemestane. All three agents are at least as efficacious as tamoxifen as monotherapy for postmenopausal women with hormone-sensitive MBC. Current clinical research aims to improve upon existing strategies by evaluating AIs in combination with systemic chemotherapy regimens and/or novel targeted agents. It is hoped that these therapeutic innovations will lead to ongoing improvements in quality of life parameters and ideally survival for women

  17. The effect of aromatase inhibitors on bone metabolism

    DEFF Research Database (Denmark)

    Folkestad, Lars; Bjarnason, Nina H; Bjerregaard, Jon Kroll;

    2009-01-01

    Aromatase inhibitors increase the disease-free survival in patients with receptor-positive breast cancer. Aromatase is a cytochrome P450 enzyme complex catalysing the conversion of androgens to oestrogens. These properties cause a significant increase in bone loss. In this MiniReview, we present ...... in comparison with tamoxifen. We conclude that treatment with aromatase inhibitors leads to an increased bone loss and thus an increase in the risk of fractures in women with breast cancer.......Aromatase inhibitors increase the disease-free survival in patients with receptor-positive breast cancer. Aromatase is a cytochrome P450 enzyme complex catalysing the conversion of androgens to oestrogens. These properties cause a significant increase in bone loss. In this MiniReview, we present...... data from the aromatase inhibitor studies and the studies designed to investigate aromatase inhibitor effect on bone metabolism. At the cellular level, oestrogen has profound effects on both osteoblasts and osteoclasts. Oestrogen decreases the osteoblastic production of resorptive cytokines...

  18. Aromatase inhibitors in the treatment of deep endometriosis

    Directory of Open Access Journals (Sweden)

    Simone Ferrero

    2009-09-01

    Full Text Available Recent case reports and pilot studies suggested that aromatase inhibitors might be effective in treating pain symptoms related to the presence of endometriosis. We present the case of a 32-year-old woman who suffered dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia caused by rectovaginal endometriosis. Pain symptoms recurred after treatment with the oral contraceptive pill; the patient refused surgery. Therefore a double-drug regimen including letrozole (2.5 mg/day and norethisterone acetate (2.5 mg/day was offered to the patient. The scheduled length of treatment was six months. This double-drug regimen determined a quick and significant improvement in all pain symptoms. During treatment, the patient complained mild arthralgia. After the interruption of treatment, pain symptoms quickly recurred and at 6-month follow-up their intensity was similar to baseline values. Operative laparoscopy was performed, the presence of rectovaginal endometriosis was confirmed and all visible endometriotic lesions were excised. Aromatase inhibitors might be offered when pain symptoms caused by endometriosis persist during the administration of other hormonal therapies and the patient refuses surgery. However, women must be informed that these drugs determine only a temporary relief of pain symptoms and might cause adverse effects (such as arthralgia.

  19. Aromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sri Lakshmi Hyndavi Yeruva

    2015-01-01

    Full Text Available Aromatase inhibitors (AIs are most commonly used for breast cancer patients with hormone receptor positive disease. Although the side effect profile of aromatase inhibitors is well known, including common side effects like arthralgia, bone pain, arthritis, hot flashes, and more serious problems like osteoporosis, we present a case of an uncommon side effect of these medications. We report the case of a postmenopausal woman on adjuvant hormonal therapy with anastrozole after completing definitive therapy for stage IIIB estrogen receptor-positive breast cancer, who was referred to hematology service for evaluation of persistent erythrocytosis. Primary and known secondary causes of polycythemia were ruled out. On further evaluation, we found that her erythrocytosis began after initiation of anastrozole and resolved after it was discontinued. We discuss the pathophysiology of aromatase inhibitor-induced erythrocytosis and reference of similar cases reported in the literature.

  20. Aromatase inhibitors in stimulated IVF cycles

    Directory of Open Access Journals (Sweden)

    Tournaye Herman

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels

  1. Potential role of aromatase inhibitors in the treatment of endometriosis

    Directory of Open Access Journals (Sweden)

    Abu Hashim H

    2014-07-01

    Full Text Available Hatem Abu HashimDepartment of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, EgyptAbstract: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis

  2. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    NARCIS (Netherlands)

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C.

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that wer

  3. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study

    International Nuclear Information System (INIS)

    In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI) is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms. We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+) breast cancer. A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly. The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia. Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication

  4. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    OpenAIRE

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line tr...

  5. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormone-sensitive early breast cancer: a case study

    Directory of Open Access Journals (Sweden)

    Bryce J

    2012-03-01

    Full Text Available Jane Bryce1, Martina Bauer2, Peyman Hadji21National Cancer Institute, Naples, Italy; 2Philipps University of Marburg, Marburg, GermanyBackground: In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms.Purpose: We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+ breast cancer.Methods and sample: A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly.Results: The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia.Conclusions: Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication.Keywords: adherence, anastrozole, aromatase inhibitor, arthralgia, breast cancer, letrozole

  6. Aromatase inhibitor-associated bone loss and its management with bisphosphonates in patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Bauer M

    2012-06-01

    Full Text Available M Bauer,1 J Bryce,2 P Hadji11University of Marburg, Marburg, Germany; 2National Cancer Institute, Naples, ItalyAbstract: Postmenopausal women have an increased risk of osteopenia and osteoporosis due to loss of the bone-protective effects of estrogen. Disease-related processes may also contribute to the risk of bone loss in postmenopausal women with breast cancer. One of the most common and severe safety issues associated with cancer therapy for patients with breast cancer is bone loss and the associated increase in risk of fractures. This paper reviews the recent literature pertaining to aromatase inhibitor (AI-associated bone loss, and discusses suggested management and preventative approaches that may help patients remain on therapy to derive maximum clinical benefit. A case study is presented to illustrate the discussion. We observed that AIs are in widespread use for women with hormone receptor-positive breast cancer and are now recommended as adjuvant therapy, either as primary therapy or sequential to tamoxifen, for postmenopausal women. AIs target the estrogen biosynthetic pathway and deprive tumor cells of the growth-promoting effects of estrogen, and AI therapies provide benefits to patients in terms of improved disease-free survival. However, there is a concern regarding the increased risk of bone loss with prolonged AI therapy, which can be managed in many cases with the use of bisphosphonates and other interventions (eg, calcium, vitamin D supplementation, exercise.Keywords: aromatase inhibitors, bisphosphonates, bone loss, breast cancer, estrogen

  7. Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer.

    Science.gov (United States)

    Yadav, Mange Ram; Barmade, Mahesh A; Tamboli, Riyaj S; Murumkar, Prashant R

    2015-11-13

    Breast cancer, an emerging disease among the women population, occurs due to overexpression of estrogens. The enzyme aromatase plays a key rate limiting role in the biosynthesis of estrogens. Certain clinical advantages of the use of exemestane, a steroidal aromatase inhibitor over non-steroidal aromatase inhibitors have drawn the attention of researchers for the development of novel steroidal aromatase inhibitors.The current review is a humble attempt to compile the reports by various researchers till date on the synthesis of steroidal aromatase inhibitors. It has been tried to encompass the structural modifications carried out by various researchers in the steroid ring system by taking up the functional group modifications on rings A, B, ring A/B junction, ring-D, ring modifications, bridged derivatives and heterocyclic ring-fused derivatives in a systematic way.

  8. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

    OpenAIRE

    Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

    2016-01-01

    Background mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. Methods In this study we utilized two AI-resistant breast cancer cell lines...

  9. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    OpenAIRE

    Schiff, Rachel; Chamness, Gary C.; Brown, Powel H.

    2003-01-01

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new s...

  10. Use of Network Inference to Unravel the Mechanisms of Action and Specificity of Aromatase Inhibitors

    Science.gov (United States)

    The vertebrate hypothalamus-pituitary-gonadal (HPG) axis is controlled through various feedback mechanisms in order to maintain a dynamic homeostasis during changing environmental conditions, including exposure to chemical stressors. In this study, three aromatase inhibitors, fad...

  11. A feasibility study of a Nordic walking intervention for women experiencing aromatase inhibitor associated arthralgia

    OpenAIRE

    Fields, Jo

    2015-01-01

    Background: Women taking AIs (Aromatase Inhibitors) as treatment for breast cancer commonly experience joint pain and stiffness (aromatase inhibitor associated arthralgia; AIAA) which can lead to early discontinuation of treatment. Exercise is often recommended and there is preliminary evidence it might prove helpful. Nordic Walking is a popular form of exercise in women with breast cancer, and based on a biopsychosocial model, could provide additional benefits over normal walking alone. Ther...

  12. Postmenopausal Breast Cancer, Aromatase Inhibitors, and Bone Health: What the Surgeon Should Know.

    Science.gov (United States)

    Baatjes, K J; Apffelstaedt, J P; Kotze, M J; Conradie, M

    2016-09-01

    Breast cancer, as the most common malignancy in women, remains a major public health issue despite countless advances across decades. Endocrine therapy is the cornerstone of treatment of the hormone-sensitive subtype of breast cancer. The use of aromatase inhibitors (AIs) in the postmenopausal women has extended the survival beyond that of Tamoxifen, but harbors a subset of side effects, most notably accelerated bone loss. This, however, does not occur in all women undergoing treatment. It is vital to identify susceptible patients early, to limit such events, employ early treatment thereof, or alter drug therapy. International trials on AIs, predominantly performed in North American and European females, provide little information on what to expect in women in developing countries. Here, surgeons often prescribe and manage endocrine therapy. The prescribing surgeon should be aware of the adverse effect of the endocrine therapy and be able to attend to side effects. This review highlights clinical and biochemical factors associated with decrease in bone mineral density in an, as yet, unidentified subgroup of postmenopausal women. In the era of personalized medical care, appropriate management of bone health by surgeons based on these factors becomes increasingly important. PMID:27189076

  13. A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS) | Division of Cancer Prevention

    Science.gov (United States)

    E1Z11 is a study to determine whether certain genetic information can predict which breast cancer patients will discontinue treatment with AIs due to the development of musculoskeletal symptoms (MSS). Women with stage 1-111 breast cancer who are prescribed the aromatase inhibitor anastrozole as treatment may join. |

  14. Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

    Science.gov (United States)

    The paper reports on the effects of a model aromatase inhibitor, fadrozole, on molecular and biochemical endpoints within the fathead minnow reproductive axis. Unlike previous studies, this work incorporated extensive time-course characterization over the course of an 8 d exposu...

  15. Combined down-regulation by aromatase inhibitor and GnRH-agonist in IVF patients with endometriomas-A pilot study

    DEFF Research Database (Denmark)

    Lossl, Kristine; Løssl, Kristine; Loft, Anne;

    2009-01-01

    OBJECTIVE: The key enzyme in the biosynthesis of estradiol, aromatase, has been demonstrated within endometriosis. Combined administration of aromatase inhibitor and GnRH-agonist may efficiently suppress estrogen biosynthesis through a combined pituitary, ovarian, peripheral and "in situ" action...

  16. Aromatase inhibitors induced autoimmune disorders in patients with breast cancer: A review

    Directory of Open Access Journals (Sweden)

    George Zarkavelis

    2016-09-01

    Full Text Available Subacute cutaneous lupus erythematosus (SCLE is characterized by particular cutaneous manifestations such as non-scaring plaques mainly in sunlight exposed parts of the body along with specific serum autoantibodies (i.e. antinuclear antibodies (ANA, Ro/SSa, La/SSb. It is considered either idiopathic or drug induced. The role of chemotherapeutic agents in causing SCLE has been investigated with the taxanes being the most common anticancer agents. However, recent data emerging point toward antiestrogen therapies as a causative factor not only for SCLE but also for a variety of autoimmune disorders. This is a report of a case of a 42 year old woman who developed clinical manifestations of SCLE after letrozole treatment in whom remission of the cutaneous manifestations was noticed upon discontinuation of the drug. In addition, an extensive review of the English literature has been performed regarding the association of antiestrogen therapy with autoimmune disorders. In conclusion, Oncologists should be aware of the potential development of autoimmune reactions in breast cancer patients treated with aromatase inhibitors.

  17. Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review

    Directory of Open Access Journals (Sweden)

    Venturini Pier L

    2011-06-01

    Full Text Available Abstract This systematic review aims to assess the efficacy of aromatase inhibitors (AIs in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin

  18. Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast cancer: a case series

    Science.gov (United States)

    Zagouri, F; Sergentanis, T N; Koutoulidis, V; Sparber, C; Steger, G G; Dubsky, P; Zografos, G C; Psaltopoulou, T; Gnant, M; Dimopoulos, M-A; Bartsch, R

    2013-01-01

    Background: Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. Methods: In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. Results: Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted. Conclusion: Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients. PMID:23722469

  19. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Abhinav Iyengar

    2013-01-01

    Full Text Available A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no spontaneous erythroid colonies were demonstrated. Erythrocytosis is common reason for referral to a hematologist. The myeloproliferative disorder, polycythemia vera, and the rare congenital polycythemias represent primary erythrocytosis. Common secondary causes include smoking, obstructive sleep apnea, and other pulmonary diseases. Erythrocytosis is well described with certain classes of drugs, including androgens. We hypothesize that exemestane contributed to the development of erythrocytosis in our patient. To our knowledge, erythrocytosis has not been previously described in association with aromatase inhibitors. These drugs prevent the conversion of androstenedione and testosterone to estrogen; thus the physiologic mechanisms may be similar to those responsible for erythrocytosis seen with exogenous androgens. These mechanisms are not well understood, but may include altered iron metabolism by a reduction in hepcidin levels.

  20. Patient adherence to aromatase inhibitor treatment in the adjuvant setting

    OpenAIRE

    Verma, S.; Madarnas, Y.; Sehdev, S.; Martin, G; Bajcar, J.

    2011-01-01

    Improvements in adjuvant systemic therapy and detection of early disease have resulted in a decline of breast cancer death rates across all patient age groups in Canada. Non-adherence to adjuvant hormonal therapy in the setting of early breast cancer may significantly affect patient outcome. Factors associated with medication adherence are complex and may be patient-related, therapy-related, and health care provider–related. To date, there is a gap in the literature concerning a comprehensive...

  1. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Bin; Hoshino, Juma; Jermihov, Katie; Marler, Laura; Pezzuto, John M.; Mesecar, Andrew D.; Cushman, Mark (Hawaii); (Purdue); (UIC)

    2012-07-11

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC{sub 50} 0.59 {mu}M) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC{sub 50} 70 nM) and 84 (IC{sub 50} 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC{sub 50} of 80 {mu}M. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC{sub 50} 1.7 {mu}M and 0.27 {mu}M, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  2. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

    International Nuclear Information System (INIS)

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 μM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 μM and 0.27 μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  3. Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.

    Science.gov (United States)

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A; Cushman, Mark

    2016-01-14

    A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment. PMID:26704594

  4. Aromatase Inhibitors for Endometriosis-Associated Infertility; Do We Have Sufficient Evidence?

    Science.gov (United States)

    Abu Hashim, Hatem

    2016-01-01

    Orally active aromatase inhibitors (AIs) have gained attention for treatment of infertile women with endometriosis in whom aromatase p450 is aberrantly expressed. This review aimed to critically appraise and summarize the available evidence concerning the use of AIs for management of endometriosis-associated infertility. PubMed was searched to May 2015 with the following key words: endometriosis, infertility and aromatase. Priority was given for randomized controlled trials (RCTs) followed by other study designs. Main outcome measures were as follows: rates of clinical pregnancy, miscarriage and live birth as well as endocrine outcomes. Eighty-two abstracts were screened and six original articles were included. A RCT demonstrated that post-operative letrozole treatment did not improve spontaneous pregnancy rate. Another RCT reported no superiority of letrozole superovulation over clomiphene citrate (each combined with intrauterine insemination) in minimalmild endometriosis and previous laparoscopic treatment. Anastrozole significantly inhibited the growth of endometriotic cells and their estrogen production in culture. In assisted reproductive technology (ART) cycles, dual suppression (Agonist/anastrozole) was tested in a pilot study with a pregnancy rate of 45% however, high pregnancy loss (30%) occurred. A retrospective study showed that letrozole may improve endometrial receptivity in endometriotic patients undergoing in vitro fertilization (IVF). An opposite view from an in vitro study showed lower estradiol production and aromatase expression in cultured granulosa cells from endometriotic women undergoing IVF and marked reduction under letrozole. In conclusion, current evidence is limited. More trials are warranted to enhance our knowledge and provide a clear and unequivocal evidence to guide our clinical management of infertile women with endometriosis using AIs. PMID:27695608

  5. Synthesis and PET studies of [11C-cyano]letrozole (Femara), an aromatase inhibitor drug

    International Nuclear Information System (INIS)

    Introduction: Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (Ki=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods: Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [11C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [11C-cyano]letrozole fraction in arterial plasma were also measured. Results: [11C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16±2.21 Ci/μmol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84. Conclusion: [11C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [11C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity and saturability in brain regions such as

  6. Long-term safety of aromatase inhibitors in the treatment of breast cancer

    Directory of Open Access Journals (Sweden)

    Jean-Marc A Nabholtz

    2008-03-01

    Full Text Available Jean-Marc A NabholtzBreast Cancer Research Institute La Prandie, Valojoulx, FranceAbstract: Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI, anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.Keywords: breast cancer, aromatase inhibitors, adjuvant, safety profile

  7. Arthralgia during aromatase inhibitor treatment in early breast cancer patients: prevalence, impact, and recognition by healthcare providers

    NARCIS (Netherlands)

    Boonstra, A.; Zadelhoff, J. van; Timmer-Bonte, J.N.H.; Ottevanger, P.B.; Beurskens, C.H.G.; Laarhoven, H.W.M. van

    2013-01-01

    BACKGROUND: : Many breast cancer patients experience arthralgia symptoms during aromatase inhibitor (AI) treatment, which leads to poor compliance and a lower quality of life. OBJECTIVE: : The research questions of this study were as follows: (1) What is the incidence of arthralgia during AI treatme

  8. Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

    Science.gov (United States)

    Flågeng, M Hauglid; Haugan Moi, L L; Dixon, J M; Geisler, J; Lien, E A; Miller, W R; Lønning, P E; Mellgren, G

    2009-01-01

    Background: Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity. Methods: We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13–16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole. Results: mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) was correlated (P=0.002), and both co-activators increased during treatment in the patient group as a whole (P=0.008 and P=0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P=0.002 and P=0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P=0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P=0.016), but in particular among responders (15 out of 21; P=0.008). Conclusion: Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo. PMID:19755984

  9. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    Science.gov (United States)

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  10. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

    Directory of Open Access Journals (Sweden)

    Stefano Gonnelli

    2008-11-01

    Full Text Available Stefano Gonnelli1, Roberto Petrioli21Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy (Dir. R. Nuti.; 2Department of Human Pathology and Oncology, Medical Oncology Section, University of Siena, Italy (Dir. G. FranciniAbstract: The third-generation aromatase inhibitors (AIs, letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD and lipid profile could be recommended for post-menopausal women candidate to AIs.Keywords: breast cancer, aromatase inhibitors, bone loss, lipids, cardiovascular risk

  11. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

    Directory of Open Access Journals (Sweden)

    Stefano Gonnelli

    2008-12-01

    Full Text Available Stefano Gonnelli1, Roberto Petrioli21Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy (Dir. R. Nuti.; 2Department of Human Pathology and Oncology, Medical Oncology Section, University of Siena, Italy (Dir. G. FranciniAbstract: The third-generation aromatase inhibitors (AIs, letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD and lipid profile could be recommended for post-menopausal women candidate to AIs.Keywords: breast cancer, aromatase inhibitors, bone loss, lipids, cardiovascular risk

  12. Paradoxal metabolic flare detected by 18F-fluorodeoxyglucose positron emission tomography in a patient with metastatic breast cancer treated with aromatase inhibitor and biphosphonate

    International Nuclear Information System (INIS)

    Patients with estrogen-receptor-positive advanced breast cancer are treated with endocrine therapy. The majority of breast cancer localizations show 18F-fluorodeoxyglucose (FDG) uptake at positron emission tomography (PET) examination. In these patients, the metabolic flare after therapy is common and was proposed as an index of therapy efficacy. Nevertheless, prolonged persistence of flare can lead to misinterpretation. We describe a case of a patient with invasive ductal breast cancer with bone metastases at bone scintigraphy and FDG PET scan and with expression of estrogen receptors. Initially, the patient underwent endocrine therapy in addition to a biphosfonate. Owing to progression observed in a bone scan, Tamoxifen was substituted with aromatase inhibitors. Successive bone scan examinations showed stabilization with a marked clinical improvement. A second FDG PET was performed 28 months after the first examination and showed a metabolic flare phenomenon with concomitant partial calcification of osteolitic lesions. This is an unusual case of prolonged metabolic flare

  13. In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

    DEFF Research Database (Denmark)

    Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B;

    2009-01-01

    whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved...... of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate...... TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. CONCLUSION: TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2...

  14. Molecular characterization of aromatase

    OpenAIRE

    Hong, Yanyan; Li, Hongzhi; Yuan, Yate-Ching; Chen, Shiuan

    2009-01-01

    Aromatase is an estrogen synthetase. Estrogens are female sex hormones involved in the development and growth of breast tumors. It has been of significant interest to elucidate the structure-function relationship of aromatase since its inhibitors have shown great promise in fighting breast cancer. Aromatase belongs to the cytochrome P450 family, and forms an electron-transfer complex with its partner, NADPH-cytochrome P450 reductase. Because of the membrane-bound character and heme-binding in...

  15. Masculinization of female golden rabbitfish Siganus guttatus using an aromatase inhibitor treatment during sex differentiation.

    Science.gov (United States)

    Komatsu, Toru; Nakamura, Shigeo; Nakamura, Masaru

    2006-08-01

    To elucidate the involvement of endogenous estrogen (estradiol-17beta; E2) and the decisive factor (somatic or germinal element) in the ovarian differentiation of tropical marine teleosts, the effect of the aromatase inhibitor (AI) fadrozole on gonadal sex differentiation in the golden rabbitfish Siganus guttatus (Bloch) was examined for different dosages and periods of treatment. Fadrozole interrupted ovarian cavity formation at a dose of 500 microg g(-1) diet, while there was little effect at 10 or 100 microg g(-1). The gonads from both the 30-day and 90-day administration (500 microg g(-1) diet) groups were significantly biased toward testes (P=0.002 and <0.0001, respectively), which suggests strongly that E2 is involved in early ovarian differentiation and that its suppression is an indispensable condition for testicular differentiation in S. guttatus. The results from the two different AI treatment periods imply that the initial feminization of somatic gonadal elements determines subsequent ovarian differentiation, including oogenesis: a conclusion supported by the considerable time lag between ovarian cavity formation and subsequent oogenesis during normal ovarian differentiation in S. guttatus.

  16. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis

    Science.gov (United States)

    Zhao, Xihe; Liu, Lei; Li, Kai; Li, Wusheng; Zhao, Li; Zou, Huawei

    2015-01-01

    The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV) side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR) of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49–2.78), letrozole and anastrozole was 1.80 (95% CI =0.40–3.92), and letrozole and exemestane was 1.46 (95% CI =0.34–3.4). OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence. PMID:26491345

  17. Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation

    International Nuclear Information System (INIS)

    Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14α-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC5 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC5 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered

  18. Evaluation of the quality and accuracy of information regarding aromatase inhibitors available on the internet.

    Science.gov (United States)

    Beaton, Ceri; Codd, Rhodri J; Holland, Phillip A; Gateley, Christopher A

    2008-01-01

    The internet is commonly used by patients to access medical information, particularly where new treatments become available and are highlighted in the press. There is however, no regulation of the quality or accuracy of the information presented on web sites. The aim of this study was to evaluate the quality and accuracy of the information concerning the aromatase inhibitors (AIs). The three most popular search engines: Google, Yahoo, and MSN were utilized. The top ten "hits" for the generic and proprietary names of each AIs: anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara) were evaluated using a 12-point score by a single assessor. The accuracy of the information provided was compared with the National Institute for Health and Clinical Excellence guidelines. The mean score for the 180 web sites was only 6.13 out of 12 (0-11). If we consider a score of 9 or more out of 12 (> or =75%) for a web site to represent good quality information, then 51 (28%) of pages scored well. Google was slightly better than Yahoo and MSN; with the highest percentage of web sites scoring well. In evaluating hits according to type of web sites, 50 (28%) were charity web sites and 30 (17%) were drug company web sites and both groups scored significantly higher than the overall mean (charity p = 0.014, drug company p = 0.001). Only 2 of 180 hits gave accurate statistical evidence regarding the benefits of AIs over tamoxifen. We have found that the quality and accuracy of information concerning AIs provided on the Internet is poor and patients using it are unlikely to find accurate information. It is therefore our duty as healthcare providers to guide patients, so as to avoid them from being overwhelmed by irrelevant and conflicting information. PMID:18537915

  19. Reduced estradiol synthesis by letrozole, an aromatase inhibitor, is protective against development of pentylenetetrazole-induced kindling in mice.

    Science.gov (United States)

    Rashid, Davood; Panda, B P; Vohora, Divya

    2015-11-01

    Neurosteroids, such as testosterone and their metabolites, are known to modulate neuronal excitability. The enzymes regulating the metabolism of these neurosteroids, thus, may be targeted as a noval strategy for the development of new antiepileptic drugs. The present work targeted two such enzymes i,e aromatase and 5α-reductase in order to explore the potential of letrozole (an aromatase inhibitor) on pentylenetetrazole (PTZ)-induced kindling in mice and the ability of finasteride (a 5α-reductase inhibitor) to modulate any such effects. PTZ (30 mg/kg, i.p.), when administered once every two days (for a total of 24 doses) induced kindling in Swiss albino mice. Letrozole (1 mg/kg, p.o.), administered prior to PTZ, significantly reduced the % incidence of kindling, delayed mean onset time of seizures and reduced seizure severity score. Letrozole reduced the levels of plasma 17β-estradiol after induction of kindling. The concurrent administration of finasteride and letrozole produced effects similar to letrozole on PTZ-kindling and on estradiol levels. This implies that the ability of letrozole to redirect the synthesis of dihydrotestosterone (DHT) and 5α-androstanediol from testosterone doesn't appear to play a significant role in the protective effects of letrozole against PTZ kindling. Letrozole, however, increased the levels of 5α-DHT in mice plasma. The aromatase inhibitors, thus, may be exploited for inhibiting the synthesis of proconvulsant (17β-estradiol) and/or redirecting the synthesis of anticonvulsant (DHT and 5α-androstanediol) neurosteroids.

  20. Synthesis and PET studies of [11C-cyano]letrozole (Femara®), an aromatase inhibitor drug

    Science.gov (United States)

    Kil, Kun-Eek; Biegon, Anat; Ding, Yu-Shin; Fischer, Andre; Ferrieri, Richard A.; Kim, Sung Won; Pareto, Deborah; Schueller, Michael J.; Fowler, Joanna S.

    2011-01-01

    Introduction Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone to estrone and estradiol respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole, Femara®) is a high affinity aromatase inhibitor (Ki=11.5 nM) which has FDA approval for breast cancer treatment. Here we report the synthesis of carbon-11 labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile, 3) were prepared in two-step syntheses from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via the tetrakis(triphenylphosphine)palladium(0) catalyzed coupling of [11C]cyanide with the bromo-precursor (3). PET studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. The free fraction of letrozole in the plasma, log D, and the [11C-cyano]letrozole fraction in the arterial plasma were also measured. Results [11C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79–80%, with a radiochemical purity greater than 98% and a specific activity of 4.16±2.21 Ci/μmol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance followed by slow clearance of carbon-11 from the brain with no difference between brain regions. The brain kinetics was not affected by co-injection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9% and log D was 1.84. Conclusion [11C-cyano]Letrozole is readily synthesized via a palladium catalyzed coupling reaction with [11C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase as revealed by the absence of regional specificity and saturability in brain regions, such as amygdala, which are known to contain

  1. Uso de inibidores da aromatase no tratamento do câncer de mama e osteoporose = The use of aromatase inhibitors for breast cancer treatment and osteoporosis

    Directory of Open Access Journals (Sweden)

    Cassol, Lina Barbosa

    2005-01-01

    Conclusão: Estratégias diagnósticas, preventivas e, eventualmente, terapêuticas de osteoporose devem ser empregadas precocemente em pacientes com câncer de mama tratadas com inibidores da aromatase

  2. Serum estradiol should be monitored not only during the peri-menopausal period but also the post-menopausal period at the time of aromatase inhibitor administration

    Directory of Open Access Journals (Sweden)

    Zembutsu Hitoshi

    2009-11-01

    Full Text Available Abstract Background Aromatase inhibitor (AI therapy is being extensively used as postoperative adjuvant therapy in patients with hormone receptor-positive postmenopausal breast cancer. On the other hand, it has been reported that ovarian function was restored when AI was administered to patients who had undergone chemical menopause with chemotherapy or tamoxifen. However, there have been no reports of comprehensive monitoring of estradiol (E2 in breast cancer patients with ordinary menopause who were being administered AI. Patients and Methods Beginning in March 2008, regular monitoring of the serum levels of E2, luteinizing hormone (LH and follicle-stimulating hormone (FSH was performed for 66 postmenopausal breast cancer patients who had been started on AI therapy. For this study, we chose anastrozole as the AI. The assays of those hormones were outsourced to a commercial clinical laboratory. Results In 4 of the 66 patients the serum E2 level was decreased at 3 months but had then increased at 6 months, while in 2 other patients E2 was decreased at both 3 and 6 months but had increased at 9 months. Conclusion The results indicate that, in some breast cancer patients with ordinary menopause, E2 rebounds following AI therapy. In the future, E2 monitoring should be performed for a larger number of patients being administered AI therapy. Trial registration Our trial registration number is 19-11-1211.

  3. A systematic review and methodological evaluation of published cost-effectiveness analyses of aromatase inhibitors versus tamoxifen in early stage breast cancer.

    Directory of Open Access Journals (Sweden)

    Ava A John-Baptiste

    Full Text Available BACKGROUND: A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs. For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs of five years of aromatase inhibitors (AI versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS but not overall survival (OS and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions. METHODS: We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY. We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty. RESULTS: We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub-group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities. CONCLUSION: Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost-effectiveness of AIs

  4. Effects of the aromatase inhibitor Letrozole on serum immunoglobulin and lysozyme levels in immunized rainbow trout (Oncorhynchus mykiss Walbaum females

    Directory of Open Access Journals (Sweden)

    Paria Akbary

    2013-12-01

    Full Text Available Letrozole is a synthetic aromatase inhibitor and interfere in the committed step in the synthesis of endogenous estrogens from androgens. Also estrogens regulate the immune system in teleost. Changes of 17- β- esrtradiol (E2, serum immunoglobulin and lysozyme levels were measured using a method based on the ability of lysozyme to lyse the bacterium Micrococcus lysodeikticus, enzyme-linked immunosorbent assay (ELISA and ELISA respectively. Twelve broodstocks were injected weekly with 2.5 mg kg-1 letrozole (an endocrine disrupter component two months before spawning season and vaccinated intraperitoneally (i.p with a bacterin (inactivated L. garviae one month before spawning. Twelve broodstocks for vaccination and twelve female rainbow trout as control group were also immiunised (i.p with the bacterin and injected (i.p with PBS, respectively. In the group received 2.5 mg AI kg-1 per week, serum E2 levels were significantly lower than that of other groups. Total immunoglobulin level and lysozyme activity were significantly higher in the parents received 2.5 mg kg-1 per week and were immunized with 10-9 cells ml-1 Lactococcus garvieae  compared to the group which immunized with L. garvieae and the control (non- immunized. The present study, suggests that aromatase inhibitors such as letrozole may be a potential tool to regulate the synthesis of E2, is involved in the hormone- immune system interaction in rainbow trout.

  5. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study.

    Science.gov (United States)

    Galeazzi, Roberta; Massaccesi, Luca

    2012-03-01

    CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

  6. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

    DEFF Research Database (Denmark)

    Gravgaard Thomsen, Karina Hedelund; Lyng, Maria Bibi; Elias, Daniel;

    2015-01-01

    Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers...... predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated...... by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p

  7. 芳香化酶抑制剂在男性中的应用%Application of Aromatase Inhibitors in Male Patients

    Institute of Scientific and Technical Information of China (English)

    茅江峰; 伍学焱

    2016-01-01

    芳香化酶抑制剂(Aromatase Inhibitor,AI)能抑制睾酮向雌二醇的转化,从而减少雌激素对下丘脑和垂体的负反馈抑制作用,促进垂体分泌促性腺激素。对男性部分性低促性腺激素性性腺功能减退症、男性身材矮小、肥胖相关性性腺功能减退症以及少精症,都具有一定的治疗作用。%Aromatase inhibitors (Aromatase Inhibitor, AI) can inhibit the conversion of testosterone to estradiol, thus reducing the feedback inhibition of estrogen to the hypothalamus and pituitary gland, promote the secretion of pituitary gonadotropins. And it is useful for the treatment of male sexual lower gonadotropin induced gonad hypofunction, men short stature, obesity relevance gonad hypofunction and oligospermia.

  8. miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors.

    Science.gov (United States)

    Bacci, Marina; Giannoni, Elisa; Fearns, Antony; Ribas, Ricardo; Gao, Qiong; Taddei, Maria Letizia; Pintus, Gianfranco; Dowsett, Mitch; Isacke, Clare M; Martin, Lesley-Ann; Chiarugi, Paola; Morandi, Andrea

    2016-03-15

    Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER(+)) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER(+) breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. PMID:26795347

  9. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhao XH

    2015-09-01

    Full Text Available Xihe Zhao,1 Lei Liu,2 Kai Li,1 Wusheng Li,1 Li Zhao,1 Huawei Zou1 1Department of Oncology, 2Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49–2.78, letrozole and anastrozole was 1.80 (95% CI =0.40–3.92, and letrozole and exemestane was 1.46 (95% CI =0.34–3.4. OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence. Keywords: CV risk, breast cancer, AI, network meta-analysis

  10. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients.

    Science.gov (United States)

    Thomsen, Karina G; Lyng, Maria B; Elias, Daniel; Vever, Henriette; Knoop, Ann S; Lykkesfeldt, Anne E; Lænkholm, Anne-Vibeke; Ditzel, Henrik J

    2015-12-01

    Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment.

  11. Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

    Science.gov (United States)

    Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

    2016-01-01

    The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups

  12. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    OpenAIRE

    Abhinav Iyengar; Dawn Sheppard

    2013-01-01

    A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO) level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no...

  13. Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

    Science.gov (United States)

    Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

    2016-01-01

    The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups

  14. QUALITY OF LIFE OF WOMEN RECIEVING ADJUVANT HORMONAL TREATMENT FOR BREAST CANCER – A RANDOMIZED TRIAL COMPARING TAMOXIFEN WITH AROMATASE INHIBITORS

    Directory of Open Access Journals (Sweden)

    C. Volovat

    2011-05-01

    Full Text Available Purpose: The assessment and comparison of the quality of life in women with early stages breast cancer receiving Tamoxifen versus aromatase inhibitors (AINs. Methods: There were selected 223 patients treated at Center of Medical Oncology Iasi, with early stages breast cancer. The patients were divided in two groups: 115 patients receiving Tamoxifen and 107 patients receiving aromatase inhibitors. From the patients receiving AINs, 33 of patients have received Exemestane, 60 patients Letrozole and 14 patients Anastrazole. The patients have completed an EORTC C30 and EORTC BR23 questionnaire at the beginning of the treatment (after one month and after 2 years of treatment. There was calculated the difference related with global status, functional scales, emotional scales, cognitive scales and symptom scales. Results: Statistic results show a better quality of life for Anastrazole vs. Letrozole and for AINs vs. Tamoxifen group, mainly on physical scales both after 2 months and after 2 years of treatment. In the same time, the physical scales were with better results after 1 month of treatment vs. 2 years of treatment. Conclusions: Following the hormonal treatment period, there is a mild worsening of quality of life for Tamoxifen and AINs too. In the same time, the quality of life is better in the group with AINs treatment comparative with the Tamoxifen treatment.

  15. VEGF Inhibitors for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Prakash S. Sukhramani

    2010-01-01

    Full Text Available Despite significant advances in systemic therapies, radiation oncology, and surgical techniques, many patients with cancer are still incurable. A novel therapeutic approach has been to target the vascular endothelial growth factors (VEGFs which are often mutated and/or over-expressed in many tumors. The ligands and receptors of VEGF family are well established as key regulators of angiogenesis and vasculogenesis processes. VEGF is a homodimeric, basic, 45 kDa glycoprotein specific for vascular endothelial cells. Specifically, VEGF participates in regulation of the female reproductive cycle, wound healing, inflammation, vascular permeability, vascular tone, hematopoiesis and also contributes to pathological angiogenesis disorders such as cancer, rheumatoid arthritis, diabetic retinopathy and the neovascular form of macular degeneration. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Clinical trials have anti-VEGF therapies are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. The aim of present review is on the cellular responses of VEGF inhibitors and their implications for cancer therapy.

  16. Structural basis for androgen specificity and oestrogen synthesis in human aromatase

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Debashis; Griswold, Jennifer; Erman, Mary; Pangborn, Walter; (HWMRI)

    2009-03-06

    Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O{sub 2}, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16{alpha}-hydroxytestosterone to oestrone, 17{beta}-oestradiol and 17{beta},16{alpha}-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

  17. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.

    Science.gov (United States)

    Donders, G; Bellen, G; Neven, P; Grob, P; Prasauskas, V; Buchholz, S; Ortmann, O

    2015-10-01

    This study was a detailed microscopic analysis of the changes of vaginal microflora characteristics after application of 0.03 mg estriol-lactobacilli combination on the vaginal ecosystem in postmenopausal breast cancer (BC) survivors on aromatase inhibitors (AI) with severe atrophic vaginitis. A total of 16 BC women on AI applied daily one vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of three tablets weekly for 8 weeks. During four follow up visits a smear from the upper lateral vaginal wall was analysed by phase contrast microscopy at 400 times magnification in order to classify the lactobacillary grades(LBG), bacterial vaginosis (BV), aerobic vaginitis (AV), vulvovaginal candidosis (VVC), proportional number of leukocytes and evidence of parabasal cells and epitheliolysis. LBG improved from 81% LBG-III at entry to 88% LBG-I&IIa after 2 weeks of initial therapy, which further improved upon follow up (p lactobacilli results in rapid and enduring improvement of all markers of the vaginal microflora and epithelial vaginal cell quality in women with breast cancer on AI with dyspareunia. Candida may develop soon after its use, but rapidly disappears again upon their prolonged use. Due to its excellent safety profiles and clinical efficacy we recommend this product as first choice in women on AI with severe dyspareunia.

  18. Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial.

    Science.gov (United States)

    Fontein, Duveken B Y; Houtsma, Daniel; Nortier, Johan W R; Baak-Pablo, Renee F; Kranenbarg, Elma Meershoek-Klein; van der Straaten, Tahar R J H M; Putter, Hein; Seynaeve, Caroline; Gelderblom, Hans; van de Velde, Cornelis J H; Guchelaar, Henk-Jan

    2014-04-01

    Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment. PMID:24590773

  19. Cancer therapy disparity: unequal access to breast cancer therapeutics and drug funding in Canada

    OpenAIRE

    Verma, S.; Sehdev, S.; Joy, A.A.

    2007-01-01

    Adjuvant therapy has made a significant contribution in reducing breast cancer–specific mortality. Standard chemotherapeutics and tamoxifen have been the mainstay treatment for years, but recent clinical evidence supports the use of novel small-molecule therapy and aromatase inhibitor therapy in selected settings, challenging not only the traditional paradigm of breast cancer treatment, but also provincial funding of oncologic care across Canada. The disparity in access to aromatase inhibitor...

  20. The Efficacy of Bisphosphonates in Preventing Aromatase Inhibitor Induced Bone Loss for Postmenopausal Women with Early Breast Cancer: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Pooleriveetil Padikkal Anagha

    2014-01-01

    Full Text Available Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329–21.959, P value = 0.018 and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249–7.143, P value = 0.0002. Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR’s than patients with delayed ZOL.

  1. 芳香化酶抑制剂致骨质疏松研究进展%Research of aromatase inhibitor induced osteoporosis

    Institute of Scientific and Technical Information of China (English)

    马翠翠

    2008-01-01

    Breast cancer patients treated by aromatase inhibitor(AI) may cause ovarian failure, resulting in decreased hormone levels. Then bone loss increases, which may result in thinning bone and osteoporosis. In clinic, attention should be given and appropriate means must be chosen to prevent and treat this disease. Calcium + vitamin D, diphosphonate, selective estrogen receptor modulator, Chinese medicine are recommen-ded to reduce the incidence of esteoporosis.%乳腺癌患者服用芳香化酶抑制剂(AI)使得卵巢功能缺失导致体内雌激素水平下降,从而加速骨代谢发生骨质疏松.在临床中应给予重视并根据具体情况选择适当防治手段.推荐使用钙剂+维生素D、双膦酸盐、选择性雌激素受体调节剂、中药等药物治疗,减少骨质疏松的发病率.

  2. Cutaneous adverse effects of hormonal adjuvant therapy for breast cancer: a case of localised urticarial vasculitis following anastrozole therapy and a review of the literature.

    Science.gov (United States)

    Bock, Vanessa L; Friedlander, Michael; Waring, Dale; Kossard, Steven; Wood, Glenda K

    2014-11-01

    Hormonal therapy with either tamoxifen or aromatase inhibitors is commonly used to treat women with breast cancer in both the adjuvant and recurrent disease setting. Cutaneous adverse reactions to these drugs have been rarely reported in the literature. We report an unusual case of urticarial vasculitis following the aromatase inhibitor anastrozole that localised to the unilateral trunk and mastectomy scar, and review the literature on the cutaneous adverse effects of hormonal therapy for breast cancer. PMID:24575835

  3. Effects of 17α-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco.

    Science.gov (United States)

    Shen, Zhi-Gang; Fan, Qi-Xue; Yang, Wei; Zhang, Yun-Long; Wang, Han-Ping

    2015-04-01

    Monosex populations are in demand in many fish species with sexual dimorphism, e.g., better growth performance, higher gonad value, superior ornamental value. From the point of view of research, a monosex population is one of the best materials for investigating sex-determining mechanisms, sex differentiation, and sex-linked markers. Sex reversal of females (phenotypic reversal from XX female to XX male) is the first step in all-female production in species with an XX/XY system for sex determination. In the present study, masculinization of yellow catfish, a species with XX/XY sex determination, was investigated by oral administration of various doses of 17α-methyltestosterone (MT) or an aromatase inhibitor (AI) letrozole (LZ); effects on survival, growth performance, sex ratio, and changes in gonadal structure were evaluated. Three doses (20, 50, and 100 mg kg(-1) diet) of oral MT or LZ were administered to fry from 10 days post-hatching (DPH) to 59 DPH. Oral administration of MT at all doses did not significantly change the ratio of males (45.8%, 33.3%, and 50.0% respectively) compared to the control group (37.5%), while yielding intersex fish at all doses (4.2% to 8.3%). Oral administration of LZ produced a significantly higher proportion of males in all doses (75.5%, 83.3%, and 75.0%, respectively). Additionally, the lowest dose of LZ improved the growth of treated fish compared to the control, and all doses of LZ enhanced spermatogenesis in treated males. PMID:25920714

  4. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.

    Science.gov (United States)

    Donders, G; Bellen, G; Neven, P; Grob, P; Prasauskas, V; Buchholz, S; Ortmann, O

    2015-10-01

    This study was a detailed microscopic analysis of the changes of vaginal microflora characteristics after application of 0.03 mg estriol-lactobacilli combination on the vaginal ecosystem in postmenopausal breast cancer (BC) survivors on aromatase inhibitors (AI) with severe atrophic vaginitis. A total of 16 BC women on AI applied daily one vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of three tablets weekly for 8 weeks. During four follow up visits a smear from the upper lateral vaginal wall was analysed by phase contrast microscopy at 400 times magnification in order to classify the lactobacillary grades(LBG), bacterial vaginosis (BV), aerobic vaginitis (AV), vulvovaginal candidosis (VVC), proportional number of leukocytes and evidence of parabasal cells and epitheliolysis. LBG improved from 81% LBG-III at entry to 88% LBG-I&IIa after 2 weeks of initial therapy, which further improved upon follow up (p treatment (p < 0.01). While at entry most patients had moderate or severe AV, after maintenance therapy no patient except one had AV. The number of leukocytes dropped dramatically from a score of 1.78 ± 0.70 to 1.06 ± 0.25 which was consistent till the end of the study (p < 0.01). Parabasal cells dropped from a score of 3.4 ± 0.64 at entry to 1.3 ± 0.60 at the final visit (p trend < 0.01). Starting from a low rate of Candida colonisation of 2/14 (14%), a sudden rise to 7/16 (44%) occurred after 2 weeks, to return back to base levels at subsequent visits. The vaginal use of ultra-low dose estriol and lactobacilli results in rapid and enduring improvement of all markers of the vaginal microflora and epithelial vaginal cell quality in women with breast cancer on AI with dyspareunia. Candida may develop soon after its use, but rapidly disappears again upon their prolonged use. Due to its excellent safety profiles and clinical efficacy we recommend this product as first choice in women on AI with severe dyspareunia. PMID:26223323

  5. Molecular simulations of aromatase reveal new insights into the mechanism of ligand binding.

    Science.gov (United States)

    Park, Jiho; Czapla, Luke; Amaro, Rommie E

    2013-08-26

    CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next-generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate. PMID:23927370

  6. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial.

    Science.gov (United States)

    Rastelli, Antonella L; Taylor, Marie E; Gao, Feng; Armamento-Villareal, Reina; Jamalabadi-Majidi, Shohreh; Napoli, Nicola; Ellis, Matthew J

    2011-08-01

    A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated. PMID:21691817

  7. Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural Polyphenols

    OpenAIRE

    Neves, Marco A. C.; Dinis, Teresa C. P.; Colombo, Giorgio; Melo, M. Luísa Sá e

    2007-01-01

    Aromatase, an enzyme of the cytochrome P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti-aromatase activity of a set of natural polyphenolic compounds was evaluated in vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti-aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques bas...

  8. Origin of aromatase inhibitory activity via proteochemometric modeling.

    Science.gov (United States)

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents.

  9. Use of proteasome inhibitors in anticancer therapy

    Directory of Open Access Journals (Sweden)

    Sara M. Schmitt

    2011-10-01

    Full Text Available The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (--EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers.

  10. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters

    Directory of Open Access Journals (Sweden)

    Walker Larry A

    2011-06-01

    Full Text Available Abstract Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7 aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for

  11. Inhibitors

    Science.gov (United States)

    ... wrong place in the body. Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor reaction from ... body to accept clotting factor concentrate treatments. With ITI therapy, people receive large amounts of clotting factor ...

  12. Alternative therapies for the management of inhibitors.

    Science.gov (United States)

    Shima, M; Lillicrap, D; Kruse-Jarres, R

    2016-07-01

    The development of inhibitors to factor VIII (FVIII) or factor IX (FIX) remains a major treatment complication encountered in the treatment of haemophilia. Not all patients with even the same severity and genotype develop inhibitors suggesting an underlying mechanism of tolerance against FVIII- or FIX-related immunity. One mechanism may be central tolerance observed in patients in whom the FVIII mutation enables some production of the protein. The other is a peripheral tolerance mechanism which may be evident in patients with null mutation. Recently, recombinant porcine FVIII (rpFVIII, Obixur, OBI-1, BAX801) has been developed for the haemostatic treatment of both congenital haemophilia with inhibitor (CHAWI) and acquired haemophilia A (AHA). In 28 subjects with AHA with life-/limb-threatening bleeding, rpFVIII reduced or stopped bleeding in all patients within 24 h. The cross-reactivity of anti-human FVIII antibodies to rpFVIII remains around 30-50%. Recently, new therapeutics based on the quite novel concepts have been developed and clinical studies are ongoing. These are humanized asymmetric antibody mimicking FVIIIa function by maintaining a suitable interaction between FIXa and FX (Emicizumab, ACE910), and small interfering RNAs (siRNA, ALN-AT3) suppress liver production of AT through post-transcriptional gene silencing and a humanized anti-TFPI monoclonal antibody (Concizumab). Their main advantages are longer half-life, subcutaneous applicability and efficacy irrespective of the presence of inhibitors which will make it easier to initiate more effective treatment especially early childhood. PMID:27405674

  13. Prostaglandin Inhibitors: Rational Therapy for Dysmenorrhea

    OpenAIRE

    Sorbie, Janet

    1982-01-01

    Dysmenorrhea affects at least 50% of women at some time in their lives. Painful contractions of the uterine muscle (similar to labor pains) are triggered by increased endometrial synthesis of prostaglandins, which appear in elevated amounts in the plasma and menstrual fluid of women with dysmenorrhea. Non-steroidal anti-inflammatory drugs, which have been used for years in arthritis, are effective prostaglandin inhibitors. Taken by mouth at the onset of menstruation, they can relieve dysmenor...

  14. Changing Adjuvant Breast-Cancer Therapy with a Signal for Prevention.

    OpenAIRE

    Chlebowski, RT; Budoff, MJ

    2016-01-01

    Five randomized, full-scale studies have reported that 10 years of adjuvant endocrine therapy is beneficial for postmenopausal women with hormone-receptor-positive breast cancer. However, no prior study has involved more than 5 years of aromatase-inhibitor use or assessed a duration of adjuvant endocrine therapy of more than 10 years.(1) Goss and colleagues(2) now provide results from the MA.17R trial supporting the use of an aromatase inhibitor for 10 years and the use of adjuvant endocrine ...

  15. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-12

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [{sup 11}C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in [{sup 11}C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  16. The Aurora kinase inhibitors in cancer research and therapy.

    Science.gov (United States)

    Cicenas, Jonas

    2016-09-01

    Compounds that affect enzymatic function of kinases are valuable for the understanding of the complex biochemical processes in cells. Aurora kinases (AURKs) play a key role in the control of the mitosis. These kinases are frequently deregulated in different human cancers: overexpression, amplifications, translocations and deletions were reported in many cancer cell lines as well as patient tissues. These findings steered a rigorous hunt for small-molecule AURK inhibitors not only for research purposes as well as for therapeutic uses. In this review, we describe a number of AURK inhibitors and their use in cancer research and/or therapy. We hope to assist researchers and clinicians in deciding which inhibitor is most appropriate for their specific purpose. The review will also provide a broad overview of the clinical studies performed with some of these inhibitors (if such studies have been performed). PMID:26932147

  17. Endocrine therapy for breast cancer patients in South Africa

    NARCIS (Netherlands)

    Taghipour Bazargani, Y.; De Boer, Anthonius; Leufkens, Hubertus G.M.; Mantel-Teeuwisse, Aukje K.

    2014-01-01

    Background: Endocrine therapy (tamoxifen and aromatase inhibitors (AIs)) has been shown to reduce the risk of recurrence and death in estrogen receptor positive(ER+) breast cancer patients. Objectives: The aim of this study is to assess access to these medicines by comparing the estimated number of

  18. Diabetes therapies in hemodialysis patients: Dipeptidase-4inhibitors

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Although several previous studies have been publishedon the effects of dipeptidase-4 (DPP-4) inhibitors indiabetic hemodialysis (HD) patients, the findings haveyet to be reviewed comprehensively. Eyesight failurecaused by diabetic retinopathy and aging-relateddementia make multiple daily insulin injections difficultfor HD patients. Therefore, we reviewed the effectsof DPP-4 inhibitors with a focus on oral antidiabeticdrugs as a new treatment strategy in HD patients withdiabetes. The following 7 DPP-4 inhibitors are availableworldwide sitagliptin, vildagliptin, alogliptin, linagliptin,teneligliptin, anagliptin, and saxagliptin. All of theseare administered once daily with dose adjustmentsin HD patients. Four types of oral antidiabetic drugscan be administered for combination oral therapy withDPP-4 inhibitors, including sulfonylureas, meglitinide,thiazolidinediones, and alpha-glucosidase inhibitor. Ninestudies examined the antidiabetic effects in HD patients.Treatments decreased hemoglobin A1c and glycatedalbumin levels by 0.3% to 1.3% and 1.7% to 4.9%,respectively. The efficacy of DPP-4 inhibitor treatmentis high among HD patients, and no patients exhibitedsignificant severe adverse effects such as hypoglycemiaand liver dysfunction. DPP-4 inhibitors are key drugs innew treatment strategies for HD patients with diabetesand with limited choices for diabetes treatment.

  19. Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine;

    2015-01-01

    Selective serotonin reuptake inhibitors are known to have a range of disorders that are often linked to the endocrine system e.g. hormonal imbalances, breast enlargement, sexual dysfunction, and menstrual cycle disorders. The mechanisms behind most of these disorders are not known in details...

  20. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Keya De Mukhopadhyay

    Full Text Available In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

  1. Marine-Derived Angiogenesis Inhibitors for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Ying-Qing Wang

    2013-03-01

    Full Text Available Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs.

  2. Marine-Derived Angiogenesis Inhibitors for Cancer Therapy

    OpenAIRE

    Ying-Qing Wang; Ze-Hong Miao

    2013-01-01

    Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis ...

  3. Alopecia With Endocrine Therapies in Patients With Cancer

    OpenAIRE

    Saggar, Vishal; Wu, Shenhong; Dickler, Maura N.; Lacouture, Mario E.

    2013-01-01

    Whereas the frequency of alopecia to cytotoxic chemotherapies has been well described, the incidence of alopecia during endocrine therapies (i.e., anti-estrogens, aromatase inhibitors) has not been investigated. We performed a systematic analysis of the literature to ascertain the incidence and risk for alopecia while receiving endocrine therapies and found that alopecia is a common yet underreported adverse event of endocrine-based cancer therapies.

  4. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro.

    Science.gov (United States)

    Vinggaard, A M; Hnida, C; Breinholt, V; Larsen, J C

    2000-06-01

    Many pesticides are able to block or activate the steroid hormone receptors and/or to affect the levels of sex hormones, thereby potentially affecting the development or expression of the male and female reproductive system or both. This emphasizes the relevance of screening pesticides for a wide range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [(3)H](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon (all fungicides), and dicofol (an acaricide) gave rise to a statistically significant inhibition of aromatase activity. The IC(50)s of prochloraz, imazalil, propioconazole fenarimol, triadimenol, and triadimefon were calculated from dose-response curves to be 0.04, 0.34, 6.5, 10, 21 and 32 microM, respectively. The IC(50) of dicofol was greater than 50 microM. The positive control 4-hydroxyandrostendione (1 microM) caused an inhibition of aromatase activity by 74%. The compounds, which did not affect the aromatase activity, were bromopropylate, chlorfenvinphos, chlorobenzilate, chlorpyrifos, diuron, heptachlor, iprodion, linuron, pentachlorphenol, procymidon, propyzamide, quintozen, tetrachlorvinphos and tetradifon. With the purpose of comparing the results for fenarimol obtained with the microsomal system with data from an intact cell system, an aromatase assay based on JEG-3 cells was established. 4-Hydroxyandrostendione (1 microM) inhibited the aromatase activity in JEG-3 cells by 94%. The IC(50) for fenarimol in this system was 2 microM, slightly lower than that observed in the microsomal system. For the first time, fenarimol has been demonstrated to inhibit aromatase activity in human tissues and, furthermore, propioconazole, triadimefon, and triadimenol were identified as weak aromatase inhibitors. In conclusion, seven out of 22 tested pesticides turned out to be weak to moderate aromatase inhibitors in

  5. Genetics Home Reference: aromatase excess syndrome

    Science.gov (United States)

    ... males, the increased aromatase and subsequent conversion of androgens to estrogen are responsible for the gynecomastia and limited bone growth characteristic of aromatase excess syndrome . Increased estrogen in females can cause symptoms ...

  6. Research progress on criteria for discontinuation of EGFR inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Zhuang HQ

    2012-10-01

    Full Text Available Hong-qing Zhuang, Zhi-yong Yuan, Jun Wang, Ping Wang, Lu-jun Zhao, Bai-lin ZhangDepartment of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin, People's Republic of ChinaAbstract: The clinical success of the epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKI as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.Keywords: epidermal growth factor receptor, drug discontinuation, acquired drug-resistance

  7. Ocular toxicities of MEK inhibitors and other targeted therapies.

    Science.gov (United States)

    Stjepanovic, N; Velazquez-Martin, J P; Bedard, P L

    2016-06-01

    Many classes of anticancer therapy, including chemotherapeutic agents, hormonal and molecular targeted treatments, can produce ocular toxicity. Novel agents that target different cellular pathways have been related to a wide spectrum of ophthalmologic toxicities that can range from mild to severe, and include conjunctivitis, blurred vision, keratitis and optic neuritis, among others. Special attention has been drawn to the inhibitors of the MEK signaling pathway, due to their sine qua non ocular toxicity, defined as MEK retinopathy and described as symmetrical bilateral disease that develops in a time-dependent and dose-dependent manner. In this review, we discuss ophthalmologic toxicities associated with molecular targeted therapies, with particular focus on MEK retinopathy, including its nomenclature, incidence, symptoms and management. PMID:26951625

  8. Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy

    Directory of Open Access Journals (Sweden)

    Morgan Gareth

    2005-06-01

    Full Text Available Abstract Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor κB-α, which prevents activation of nuclear factor κB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with

  9. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy.

    Directory of Open Access Journals (Sweden)

    Avadhut D Joshi

    Full Text Available Glioblastoma multiforme (GBM is the most common intracranial cancer but despite recent advances in therapy the overall survival remains about 20 months. Whole genome exon sequencing studies implicate mutations in the receptor tyrosine kinase pathways (RTK for driving tumor growth in over 80% of GBMs. In spite of various RTKs being mutated or altered in the majority of GBMs, clinical studies have not been able to demonstrate efficacy of molecular targeted therapies using tyrosine kinase inhibitors in GBMs. Activation of multiple downstream signaling pathways has been implicated as a possible means by which inhibition of a single RTK has been ineffective in GBM. In this study, we sought a combination of approved drugs that would inhibit in vitro and in vivo growth of GBM oncospheres. A combination consisting of gefitinib and sunitinib acted synergistically in inhibiting growth of GBM oncospheres in vitro. Sunitinib was the only RTK inhibitor that could induce apoptosis in GBM cells. However, the in vivo efficacy testing of the gefitinib and sunitinib combination in an EGFR amplified/PTEN wild type GBM xenograft model revealed that gefitinib alone could significantly improve survival in animals whereas sunitinib did not show any survival benefit. Subsequent testing of the same drug combination in a different syngeneic glioma model that lacked EGFR amplification but was more susceptible to sunitinib in vitro demonstrated no survival benefit when treated with gefitinib or sunitinib or the gefitinib and sunitinib combination. Although a modest survival benefit was obtained in one of two animal models with EGFR amplification due to gefitinib alone, the addition of sunitinib, to test our best in vitro combination therapy, did not translate to any additional in vivo benefit. Improved targeted therapies, with drug properties favorable to intracranial tumors, are likely required to form effective drug combinations for GBM.

  10. Genetics Home Reference: aromatase deficiency

    Science.gov (United States)

    ... regulating bone growth and blood sugar levels. During fetal development, aromatase converts androgens to estrogens in the placenta, ... link between the mother's blood supply and the fetus. This conversion in the ... sexual development in female fetuses. After birth, the conversion of ...

  11. Aromatase inhibitors in the treatment of endometriosis

    OpenAIRE

    Słopień, Radosław; Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and c...

  12. Aromatase Inhibitors for IVF Poor Responders

    Institute of Scientific and Technical Information of China (English)

    R.B. Quintero; L.C Giudice; L.M. Westphal

    2006-01-01

    Objective To evaluate whether letrozole enhanced follicular recruitment, embryo numbers, and pregnancy rates in poor responders undergoing IVF.Methods We reviewed all IVF cycles between January 2002 and September 2003 using letrozole at Stanford University Medical Center. The entry criteria were the requirement of at least 450 IU/d of injectable gonadotropins in a prior failed cycle,which was used as a control.Results A total of 27 charts were reviewed revealing information on 54 cycles. The number of oocytes retrieved, fertilization embryo quality and embryos transferred yielded no statistical significance, although there appeared to be a trend toward higher numbers of each in the letrozole group. The clinical pregnancy rate was 9/27 (33.3%, P<0. 001)with a viable pregnancy rate of 7/27 (25.9%, P=0.002) in the letrozole cycle.Conclusion Our study is one of the first to evaluate letrozole with in vitro fertilization.Although this study showed no difference in number of oocytes or embryos, 25.9% of these "poor responding" patients achieved a pregnancy after a failed cycle at our center.

  13. Aromatase inhibitors in stimulated IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, Evangelos G; Polyzos, Nikolaos P; Al Humaidan, Peter Samir Heskjær;

    2011-01-01

    are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears...... to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels....

  14. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro

    DEFF Research Database (Denmark)

    Andersen, Helle Raun; Vinggaard, Anne; Rasmussen, Thomas Høj;

    2002-01-01

    . Prochloraz reacted as both an estrogen and an androgen antagonist. Furthermore, fenarimol and prochloraz were potent aromatase inhibitors while endosulfan was a weak inhibitor. Hence, these three pesticides possess at least three different ways to potentially disturb sex hormone actions. In addition...... assay. Vinclozolin reacted as a potent AR antagonist and dichlorvos as a very weak one. Methomyl, pirimicarb, propamocarb, and iprodion weakly stimulated aromatase activity. Although the potencies of the pesticides to react as hormone agonists or antagonists are low compared to the natural ligands...

  15. Tailored-therapy of ACE-inhibitors in Coronary Artery Disease: Pharmacogenetic Profiling of Treatment Benefit

    NARCIS (Netherlands)

    J.J. Brugts (Jasper)

    2010-01-01

    textabstractTo optimally treat patients, and to develop ways to guide ACE-inhibitor treatment, it remains essential to identify those patients most likely to benefit from therapy. New research to elucidate such heterogeneity is necessary. If feasible, guided-therapy of ACE-inhibitors will have a lar

  16. Selective inhibition of aromatase by a dihydroisocoumarin from Xyris pterygoblephara.

    Science.gov (United States)

    Endringer, Denise C; Guimarães, Keller G; Kondratyuk, Tamara P; Pezzuto, John M; Braga, Fernão C

    2008-06-01

    Aromatase is a well-established target for the chemoprevention of breast cancer. The dihydroisocoumarin (3 R,4 R)-(-)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1 H-isochromen-4-yl acetate (1) (IC 50 = 1.6 +/- 0.1 microM), isolated from aerial parts of Xyris pterygoblephara, showed aromatase inhibitory activity. The specificity of 1 was evaluated by inhibition assays with cytochrome P450 enzymes. CYP1A1 was inhibited modestly (IC 50 = 38.0 +/- 2.0 microM), while CYP2C8 and CYP3A4 enzymes were not affected. Dihydroisocoumarin 1 showed weak antiproliferative activity against MCF-7 (IC 50 = 66.9 +/- 2.3 microM) and LNCaP (IC 50 = 57.5 +/- 2.0 microM) cells and was inactive against LU-1 and HepG2 cells in culture. These results demonstrate the potential of dihydroisocoumarin 1 to serve as a selective aromatase inhibitor. PMID:18462007

  17. C peptides as entry inhibitors for gene therapy.

    Science.gov (United States)

    Egerer, Lisa; Kiem, Hans-Peter; von Laer, Dorothee

    2015-01-01

    Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVE-based gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens. PMID:25757622

  18. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial

    DEFF Research Database (Denmark)

    Hansen, Ann-Brit Eg; Obel, N; Nielsen, H;

    2011-01-01

    The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART).......The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART)....

  19. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

    Science.gov (United States)

    Tran, Khiem A; Cheng, Michelle Y; Mitra, Anupam; Ogawa, Hiromi; Shi, Vivian Y; Olney, Laura P; Kloxin, April M; Maverakis, Emanual

    2016-01-01

    The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy. PMID:26730180

  20. Safety of ACE inhibitor therapies in patients with chronic kidney disease

    NARCIS (Netherlands)

    Sidorenkov, Grigory; Navis, Gerjan

    2014-01-01

    Introduction: ACE inhibitors are first-line therapy in patients with chronic kidney disease (CKD). The main adverse effects of ACE inhibitors are hypotension, renal function impairment and hyperkalemia. Areas covered: This paper reviews evidence from clinical studies regarding adverse effects of ACE

  1. Aromatase inhibitors in adjuvant endocrine treatment of breast cancer: ending the debate of sequence or upfront?——interpretation of BIG 1-98 clinical trial%乳腺癌芳香化酶抑制剂辅助内分泌治疗:序贯或初始应用争论的结束?——解读BIG 1-98临床试验

    Institute of Scientific and Technical Information of China (English)

    陈小松; 沈坤炜

    2010-01-01

    The third generation of aromatase inhibitors (AI) play an important role in the adjuvant treatment of hormonal positive postmenopausal breast cancer. Compared with tamoxifen, either upfront or sequential using of Al can both significantly improve the outcome of breast cancer patients. However, there is a continuous debate of sequence or upfront usage of Al in clinical applications. With the publication result of BIG 1-98 clinical trial and interpretation of the data, we can further recognize and optimize the usage of Al in breast cancer treatment.%第三代芳香化酶抑制剂(aromatase inhibitors,AI)在绝经后激素受体阳性乳腺癌辅助治疗中占据着重要的地位.与他莫昔芬相比,初始或序贯应用AI均可显著提高乳腺癌患者的预后,但在临床实践中,具体是选择初始还是序贯应用AI一直存在争议.随着BIG 1-98临床试验结果的公布及对其数据的解读,可进一步认识并优化AI在乳腺癌临床上的应用.

  2. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    International Nuclear Information System (INIS)

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24−/CD44+) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer

  3. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of); Lee, Janet [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Lee, Chang-Woo [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Suwon, Gyeonggi 440-746 (Korea, Republic of); Yang, Kwangmo [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of); Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of); Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-709 (Korea, Republic of); Lee, Chang Geun, E-mail: cglee@dirams.re.kr [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953 (Korea, Republic of)

    2013-01-25

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.

  4. Effects of transferrin on aromatase activity in porcine granulosa cells in vitro.

    Directory of Open Access Journals (Sweden)

    Małgorzata Duda

    2009-01-01

    Full Text Available Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor. Recent studies have reported that transferrin plays a crucial role in the local regulation of ovarian function, apart from its iron-binding characteristic. Therefore, the present study was undertaken to explore the possible role of transferrin in porcine granulosa cells function by examining its influence on aromatase activity, the most important indicator of follicular cell differentiation. In the first series of studies, pig granulosa cells isolated from small, immature follicles were cultured in the presence of transferrin alone (10 microg/ml or 100 microg/ml or with the addition of FSH (100ng/ml. The second series of studies was undertaken to determine transferrin-stimulated granulosa cells ability to aromatize exogenous testosterone (1x10(-7M. One hour after the establishment of cultures an aromatase inhibitor CGS16949A was added to test its influence on estradiol production. After 48 hours, cultures were terminated and cells were processed for immunocytochemical staining of aromatase. Media were frozen for further estradiol level analysis. Positive immunostaining for aromatase was found in all granulosa cell cultures. The intensity of immunostaining was always stronger in cultures supplemented with FSH whereas the addition of transferrin had no effect. Granulosa cells in vitro synthesized the highest amount of estradiol after the addition of FSH and exogenous testosterone as measured radioimmunologically. Concomitant treatment with FSH and transferrin caused an inhibition of FSH-stimulated aromatase activity. The production of estradiol also declined in the presence of FSH, testosterone and transferrin. This study demonstrates that transferrin had a dose-dependent inhibitory effect on FSH-stimulated aromatase activity, which was confirmed by radioimmunoassay. Our results indicate

  5. Targeting histone deacetylase inhibitors for anti-malarial therapy.

    Science.gov (United States)

    Andrews, Katherine T; Tran, Thanh N; Wheatley, Nicole C; Fairlie, David P

    2009-01-01

    It is now clear that histone acetylation plays key roles in regulating gene transcription in both eukaryotes and prokaryotes, the acetylated form inducing gene expression while deacetylation silences genes. Recent studies have identified roles for histone acetyltransferases (HATs) and/or histone deacetylases (HDACs) in a number of parasites including Entamoeba histolytica, Toxoplasma gondii, Schistosoma mansoni, Cryptosporidium sp., Leishmania donovani, Neospora caninum, and Plasmodium falciparum. Here we survey fairly limited efforts to date in profiling antimalarial activities of HDAC inhibitors, showing that such compounds are potent inhibitors of the growth of P. falciparum in vitro and in vivo. Most of the compounds evaluated so far have borne a zinc-binding hydroxamate group that tends to be metabolized in vivo, and thus new zinc-binding groups need to be incorporated into second generation inhibitors in order to mask the catalytic zinc in the active site of HDACs. Also the development of compounds that are selective for parasitic HDACs over mammalian HDACs is still in relative infancy and it will take some time to derive antiparasitic HDAC inhibitor compounds with minimal toxicity for the host and acceptable pharmacokinetic and pharmacodynamic profiles for human treatment. Nevertheless, results to date suggest that HDAC inhibitor development represents a promising new approach to the potential treatment of parasitic infections, including those induced by malaria protozoa, and may offer new therapeutic targets within increasingly drug-resistant malarial parasites. PMID:19355992

  6. Therapy with JAK2 inhibitors for Myeloproliferative Neoplasms

    OpenAIRE

    Santos, Fabio P S; Verstovsek, Srdan

    2012-01-01

    The development of JAK2 inhibitors followed the discovery of activating mutation of JAK2 (JAK2V617F) in patients with classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs). It is now known that mutations activating the JAK-STAT pathway are ubiquitous in Ph-negative MPNs, and that deregulated JAK-STAT pathway plays a central role in the pathogenesis of these disorders. JAK2 inhibitors thus are effective in both patients with and without the JAK2V617F mutation. Clinical ...

  7. Proton-Pump Inhibitors Therapy and Blood Pressure Control

    OpenAIRE

    Juan Francisco Sánchez Muñoz-Torrero; Pedro Joya-Vazquez; M Asunción Bacaicoa; Raul Velasco; Jose L. Chicón; Sara Trejo; M. Antonia Carrasco; N. Roberto Robles

    2014-01-01

    Objective: To evaluate  the potential impact of inhibitors of proton-pump in blood-pressure. .Methods: In a 24-hour-ambulatory-blood-pressure-monitoring (AMBP)-database we analyzed records of 462-hypertensive-patients according Proton-Pump Inhibitors (PPI). 150(33%)-patients were regularly users of PPI, and 312(67%) nonusers of PPI. Ambulatory-blood-pressure was measured non-invasively for 24--hours by the Spacelab-devices programmed-to-measure every 20-minutes during-daytime and every 60-min...

  8. Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy

    OpenAIRE

    Koppikar, Priya; Bhagwat, Neha; Kilpivaara, Outi; Manshouri, Taghi; Adli, Mazhar; HRICIK, Todd; Liu, Fan; Saunders, Lindsay M.; Mullally, Ann; Abdel-Wahab, Omar; Leung, Laura; Weinstein, Abby; Marubayashi, Sachie; Goel, Aviva; Gönen, Mithat

    2012-01-01

    The identification of somatic activating mutations in JAK2 1–4 and in the thrombopoietin receptor (MPL) 5 in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors 6,7 . JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, but does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic JAK2 inhi...

  9. A mathematical model of combined therapies against cancer using viruses and inhibitors

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    This paper deals with a procedure for combined therapies against cancer using oncolytic viruses and inhibitors. Replicating genetically modified adenoviruses infect cancer cells, reproduce inside them and eventually cause their death (lysis). As infected cells die, the viruses inside them are released and then proceed to infect other tumor cells. The successful entry of virus into cancer cells is related to the presence of the coxsackie-adenovirus receptor (CAR). Mitogen-activated protein kinase kinase (known as MEK) inhibitors can promote CAR expression, resulting in enhanced adenovirus entry into cancer cells. However, MEK inhibitors can also cause G1 cell-cycle arrest, inhibiting reproduction of the virus. To design an effective synergistic therapy, the promotion of virus infection must be optimally balanced with inhibition of virus production. We introduce a mathematical model to describe the effects of MEK inhibitors and viruses on tumor cells, and use it to explore the reduction of the tumor size that can be achieved by the combined therapies. Furthermore, we find an optimal dose of inhibitor: Poptimal = 1 - μ/δ for a certain initial density of cells (where μ is the removal rate of the dead cells and δ is the death rate of the infected cells). The optimal timing of MEK inhibitors is also numerically studied.

  10. A mathematical model of combined therapies against cancer using viruses and inhibitors

    Institute of Scientific and Technical Information of China (English)

    TAO YouShan; GUO Qian

    2008-01-01

    This paper deals with a procedure for combined therapies against cancer using oncolytic viruses and inhibitors. Replicating genetically modified adenoviruses infect cancer cells, reproduce inside them and eventually cause their death (lysis). As infected cells die, the viruses inside them are released and then proceed to infect other tumor cells. The successful entry of virus into cancer cells is related to the presence of the coxsackie-adenovirus receptor (CAR). Mitogen-activated protein kinase kinase (known as MEK) inhibitors can promote CAR expression, resulting in enhanced adenovirus entry into cancer cells. However, MEK inhibitors can also cause G1 cell-cycle arrest, inhibiting reproduction of the virus. To design an effective synergistic therapy, the promotion of virus infection must be optimally balanced with inhibition of virus production. We introduce a mathematical model to describe the effects of MEK inhibitors and viruses on tumor cells, and use it to explore the reduction of the tumor size that can be achieved by the combined therapies. Furthermore, we find an optimal dose of inhibitor: Poptimal = I - μ/δ for a certain initial density of cells (where μ is the removal rate of the dead cells and δ is the death rate of the infected cells). The optimal timing of MEK inhibitors is also numerically studied.

  11. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

    Directory of Open Access Journals (Sweden)

    Tran KA

    2015-12-01

    Full Text Available Khiem A Tran,1,* Michelle Y Cheng,1,* Anupam Mitra,1 Hiromi Ogawa,1 Vivian Y Shi,1 Laura P Olney,1 April M Kloxin,2 Emanual Maverakis1 1Department of Dermatology, University of California, Davis, Sacramento, CA, USA; 2Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA *These authors contributed equally to this work Abstract: The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib, which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy. Keywords: cobimetinib, trametinib, vemurafenib, dabrafenib, BRAF inhibitor, MAPK pathway

  12. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers

    Science.gov (United States)

    Miller, Christopher A.; Gindin, Yevgeniy; Lu, Charles; Griffith, Obi L; Griffith, Malachi; Shen, Dong; Hoog, Jeremy; Li, Tiandao; Larson, David E.; Watson, Mark; Davies, Sherri R; Hunt, Kelly; Suman, Vera J.; Snider, Jacqueline; Walsh, Thomas; Colditz, Graham A.; DeSchryver, Katherine; Wilson, Richard K.; Mardis, Elaine R.; Ellis, Matthew J.

    2016-01-01

    Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER− ‘collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information. PMID:27502118

  13. Tolerability of Therapies Recommended for the Treatment of Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer.

    Science.gov (United States)

    Ohno, Shinji

    2016-08-01

    For women with hormone receptor-positive advanced breast cancer, endocrine therapies, including the selective estrogen receptor modulator tamoxifen, the aromatase inhibitors anastrozole, letrozole, and exemestane, and the selective estrogen receptor degrader fulvestrant, are recommended in clinical guidelines. The addition of targeted agents such as everolimus or palbociclib to aromatase inhibitors are also recommended as treatment options. Chemotherapy remains an option, although clinical guidelines have recommended these agents be reserved for patients with immediately life-threatening disease or if resistance to endocrine therapy is known or suspected. The present review has consolidated the tolerability profiles of the agents approved for use in the treatment of hormone receptor-positive advanced or metastatic breast cancer based on phase III registration trial data. Endocrine therapies are generally well tolerated, although the addition of targeted therapies to aromatase inhibitors or fulvestrant appears to increase the proportion of patients experiencing adverse events, and palbociclib and chemotherapy appear to be more closely associated with serious adverse events, including neutropenia. PMID:27151773

  14. Development of novel arginase inhibitors for therapy of endothelial dysfunction

    Directory of Open Access Journals (Sweden)

    Jochen eSteppan

    2013-09-01

    Full Text Available Endothelial dysfunction and resulting vascular pathology have been identified as an early hallmark of multiple diseases, including diabetes mellitus. One of the major contributors to endothelial dysfunction is a decrease in nitric oxide (NO bioavailability, impaired NO signaling and an increase in the amount of reactive oxygen species (ROS. In the endothelium NO is produced by eNOS (endothelial nitric oxide synthase, for which L-arginine is a substrate. Arginase, an enzyme critical in the urea cycle also metabolizes L-arginine, thereby directly competing with eNOS for their common substrate and constraining its bioavailability for eNOS, thereby compromising NO production. Arginase expression and activity is upregulated in many cardiovascular diseases including ischemia reperfusion injury, hypertension, atherosclerosis, and diabetes mellitus. More importantly, since the 1990s, specific arginase inhibitors such as N-hydroxy-guanidinium or N-hydroxy-nor-L-arginine, and boronic acid derivatives, such as, 2(S-amino-6-boronohexanoic acid, and S-(2-boronoethyl-L-cysteine (BEC, that can bridge the binuclear manganese cluster of arginase have been developed. These highly potent and specific inhibitors can now be used to probe arginase function and thereby modulate the redox milieu of the cell by changing the balance between NO and ROS. Inspired by this success, drug discovery programs have recently led to the identification of α-α-disubstituted amino acid based arginase inhibitors (such as (R-2-amino-6-borono-2-(2-(piperidin-1-ylethylhexanoic acid, that are currently under early investigation as therapeutics. Finally, some investigators concentrate on identification of plant derived compounds with arginase inhibitory capability, such as piceatannol-3'-O-β-D-glucopyranoside (PG. All of these synthesized or naturally derived small molecules may represent novel therapeutics for vascular disease particularly that associated with diabetes.

  15. Anti-Angiogenic Therapy: Strategies to Develop Potent VEGFR-2 Tyrosine Kinase Inhibitors and Future Prospect.

    Science.gov (United States)

    Shi, Leilei; Zhou, Jianfeng; Wu, Jifeng; Shen, Yuemao; Li, Xun

    2016-01-01

    Tumor angiogenesis has always been a major gap for effective cancer therapy. Interruption of aberrant angiogenesis by specific inhibitors targeting receptor tyrosine kinases (RTKs) has been of great interests to medicinal chemists. Among the factors that are involved in tumor angiogenesis, vascular endothelial growth factor receptor-2 (VEGFR-2) is validated as the most closely related factor which can drive angiogenesis through binding with its natural ligand VEGF. The well-validated VEGF-driven VEGFR-2 signaling pathway can stimulate many endothelial responses, including increasing vessel permeability and enhancing endothelial cell proliferation, migration and differentiation. Consequently, circumventing angiogenesis by VEGFR-2 inhibitors represents a promising strategy for counteracting various VEGFR-2-mediated disorders as well as drug resistance. Over the past decades, a considerable number of novel small molecular VEGFR-2 inhibitors have been exploited with diverse chemical scaffolds. Especially, recent frequently launched inhibitors have declared their research values and therapeutic potentials in oncology. Still, the antiangiogenesis based treatment remains an ongoing challenge. In this review, a comprehensive retrospective of newly emerged VEGFR-2 inhibitors have been summarized, with the emphasis on the structure-activity relationship (SAR) investigation, and also binding patterns of representative inhibitors with biotargets. On the basis of all of this information, varied strategies for developing potent VEGFR-2 inhibitors and the future prospect of the clinical application of antiangiogenic inhibitors are discussed hereby.

  16. Nox Inhibitors & Therapies: Rational Design of Peptidic and Small Molecule Inhibitors

    Science.gov (United States)

    Cifuentes-Pagano, M. Eugenia; Meijles, Daniel N.; Pagano, Patrick J.

    2016-01-01

    Oxidative stress-related diseases underlie many if not all of the major leading causes of death in United States and the Western World. Thus, enormous interest from both academia and pharmaceutical industry has been placed on the development of agents which attenuate oxidative stress. With that in mind, great efforts have been placed in the development of inhibitors of NADPH oxidase (Nox), the major enzymatic source of reactive oxygen species and oxidative stress in many cells and tissue. The regulation of a catalytically active Nox enzyme involves numerous protein-protein interactions which, in turn, afford numerous targets for inhibition of its activity. In this review, we will provide an updated overview of the available Nox inhibitors, both peptidic and small molecules, and discuss the body of data related to their possible mechanisms of action and specificity towards each of the various isoforms of Nox. Indeed, there have been some very notable successes. However, despite great commitment by many in the field, the need for efficacious and well-characterized, isoform-specific Nox inhibitors, essential for the treatment of major diseases as well as for delineating the contribution of a given Nox in physiological redox signalling, continues to grow. PMID:26510437

  17. Peripheral artery disease: potential role of ACE-inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Giuseppe Coppola

    2008-12-01

    Full Text Available Giuseppe Coppola, Giuseppe Romano, Egle Corrado, Rosa Maria Grisanti, Salvatore NovoDepartment of Internal Medicine, Cardiovascular and Nephro-Urological Diseases, Chair of Cardiovascular Disease, University of Palermo, Palermo, ItalyAbstract: Subjects with peripheral arterial disease (PAD of the lower limbs are at high risk for cardiovascular and cerebrovascular events and the prevalence of coronary artery disease in such patients is elevated. Recent studies have shown that regular use of cardiovascular medications, such as therapeutic and preventive agents for PAD patients, seems to be promising in reducing long-term mortality and morbidity. The angiotensin-converting-enzyme (ACE system plays an important role in the pathogenesis and progression of atherosclerosis, and ACE-inhibitors (ACE-I seem to have vasculoprotective and antiproliferative effects as well as a direct antiatherogenic effect. ACE-I also promote the degradation of bradykinin and the release of nitric oxide, a potent vasodilator; further, thay have shown important implications for vascular oxidative stress. Other studies have suggested that ACE-I may also improve endothelial dysfunction. ACE-I are useful for reducing the risk of cardiovascular events in clinical and subclinical PAD. Particularly, one agent of the class (ie, ramipril has shown in many studies to able to significantly reduce cardiovascular morbidity and mortality in patients with PAD.Keywords: atherosclerosis, peripheral arterial disease, endothelial dysfunction, ACE-inhibitors

  18. Aromatase inhibition attenuates desflurane-induced preconditioning against acute myocardial infarction in male mouse heart in vivo.

    Directory of Open Access Journals (Sweden)

    Virginija Jazbutyte

    Full Text Available The volatile anesthetic desflurane (DES effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17β- estradiol (E2 and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group and DES alone (DES group or in combination (A+DES group for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group. All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94 ± 15.5% vs. 17.1 ± 3.62% without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model.

  19. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole.

    Science.gov (United States)

    Biegon, Anat; Kim, Sung Won; Alexoff, David L; Jayne, Millard; Carter, Pauline; Hubbard, Barbara; King, Payton; Logan, Jean; Muench, Lisa; Pareto, Deborah; Schlyer, David; Shea, Colleen; Telang, Frank; Wang, Gene-Jack; Xu, Youwen; Fowler, Joanna S

    2010-11-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-(11)C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V(T)) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V(T) in all regions, though the size of the reduction was region-dependent, ranging from ∼70% blocking in thalamus andpreoptic area to ∼10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  20. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-10-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  1. Evolution of Long-Term Adjuvant Anti-hormone Therapy: Consequences and Opportunities. The St. Gallen Prize Lecture

    OpenAIRE

    Jordan, V Craig; Obiorah, Ifeyinwa; Fan, Ping; Kim, Helen R.; Ariazi, Eric; Cunliffe, Heather; Brauch, Hiltrud

    2011-01-01

    The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5-years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-sav...

  2. Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study

    DEFF Research Database (Denmark)

    Bladbjerg, E-M; Madsen, J S; Kristensen, S R;

    2003-01-01

    arterial tissue factor expression and higher thrombin formation, and changes in tissue factor pathway coagulation inhibitor (TFPI) and thrombin activatable fibrinolysis inhibitor (TAFI) may be deleterious. Healthy postmenopausal women (n = 719) were randomized to hormone therapy [n = 357; opposed (n = 290...

  3. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the D: A: D study

    NARCIS (Netherlands)

    Bruyand, M.; Ryom, L.; Shepherd, L.; Fatkenheuer, G.; Grulich, A.; Reiss, P.; Wit, S. de; Monforte, A.M.; Furrer, H.; Pradier, C.; Lundgren, J.; Sabin, C.; Warris, A.

    2015-01-01

    BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or

  4. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy : the D: A: D study

    NARCIS (Netherlands)

    Bruyand, Mathias; Ryom, Lene; Shepherd, Leah; Fatkenheuer, Gerd; Grulich, Andrew; Reiss, Peter; de Wit, Stéphane; D Arminio Monforte, Antonella; Furrer, Hansjakob; Pradier, Christian; Lundgren, Jens; Sabin, Caroline; Schölvinck, Elisabeth H.

    2015-01-01

    BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or

  5. Reducing the Burden of Difficult-to-Treat Major Depressive Disorder: Revisiting Monoamine Oxidase Inhibitor Therapy

    OpenAIRE

    Culpepper, Larry

    2013-01-01

    Objective: Difficult-to-treat depression (eg, depression with atypical or anxious symptoms, treatment-resistant depression, or depression with frequent recurrence) is a challenging real-world health issue. This critical review of the literature focuses on monoamine oxidase inhibitor (MAOI) therapy and difficult-to-treat forms of depression.

  6. Alternative Agents in Type 1 Diabetes in Addition to Insulin Therapy: Metformin, Alpha-Glucosidase Inhibitors, Pioglitazone, GLP-1 Agonists, DPP-IV Inhibitors, and SGLT-2 Inhibitors.

    Science.gov (United States)

    DeGeeter, Michelle; Williamson, Bobbie

    2016-04-01

    Insulin is the mainstay of current treatment for patients with type 1 diabetes mellitus (T1DM). Due to increasing insulin resistance, insulin doses are often continually increased, which may result in weight gain for patients. Medications currently approved for the treatment of type 2 diabetes offer varying mechanisms of action that can help to reduce insulin resistance and prevent or deter weight gain. A MEDLINE search was conducted to review literature evaluating the use of metformin, alpha-glucosidase inhibitors, pioglitazone, glucagon-like peptide 1 agonists, dipeptidyl peptidase, and sodium-dependent glucose transporter 2 inhibitors, in patients with T1DM. Varying results were found with some benefits including reductions in hemoglobin A1c, decreased insulin doses, and favorable effects on weight. Of significance, a common fear of utilizing multiple therapies for diabetes treatment is the risk of hypoglycemia, and this review displayed limited evidence of hypoglycemia with multiple agents. PMID:25312263

  7. Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte L; Kümler, Iben; Palshof, Jesper Andreas;

    2013-01-01

    Therapies targeting the human epidermal growth factor receptor (HER) 2 are effective in metastatic breast cancer (MBC). We review the efficacy of HER2-directed therapies, focussing on monoclonal antibodies and tyrosine kinase inhibitors targeting HER2 that have been tested in phase II-III studies...... to those obtained for capecitabine plus lapatinib (48%), continuing trastuzumab in combination with capecitabine (48%), pertuzumab plus trastuzumab (24%), and neratinib (24%). Strategies combining multiple HER2-directed therapies might yield additive or synergistic effects and lead to improved outcome...

  8. Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy

    OpenAIRE

    Kang, Min H.; Reynolds, C. Patrick

    2009-01-01

    Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic ...

  9. Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system

    OpenAIRE

    MacLean Charles D; Ramos-Nino Maria E; Littenberg Benjamin

    2008-01-01

    Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly sele...

  10. The effect of opiates on the activity of human placental aromatase/CYP19.

    Science.gov (United States)

    Zharikova, Olga L; Deshmukh, Sujal V; Kumar, Meena; Vargas, Ricardo; Nanovskaya, Tatiana N; Hankins, Gary D V; Ahmed, Mahmoud S

    2007-01-15

    Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates L-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E(2) and E(3) formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E(3) formation was more pronounced than that on E(2) due to the lower affinity of 16-OHT than testosterone to aromatase. The K(i) values for the opiates that inhibited E(3) formation were sufentanil, 7 +/- 1 microM; LAAM, 13 +/- 8 microM; fentanyl, 25 +/- 5 microM; oxycodone, 92 +/- 22 microM; codeine, 218 +/- 69 microM; (+)-pentazocine, 225 +/- 73 microM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E(3) formation by 124-160% of control but had no effect on E(2) formation. Moreover, oxycodone and codeine did not inhibit E(2) formation and the IC(50) values for fentanyl, sufentanil, and (+)-pentazocine were >1000 microM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time. PMID:17118343

  11. Inhibitory Aromatase Effects of Flavonoids from Ginkgo Biloba Extracts on Estrogen Biosynthesis.

    Science.gov (United States)

    Park, Yong Joo; Choo, Wun Hak; Kim, Ha Ryong; Chung, Kyu Hyuck; Oh, Seung Min

    2015-01-01

    Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion. PMID:26434836

  12. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma

    Institute of Scientific and Technical Information of China (English)

    Teresa Kim; Rodabe N Amaria; Christine Spencer; Alexandre Reuben; Zachary A Cooper; Jennifer A Wargo

    2014-01-01

    Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past ifve years with the introduction of targeted therapy (BARF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. hTis article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.

  13. The osteoporosis knowledge and self-efficacy investigation in patients of breast cancer treated with aromatase inhibitors%乳腺癌芳香化酶抑制剂治疗患者骨质疏松知识掌握情况与自我效能水平的调查

    Institute of Scientific and Technical Information of China (English)

    倪建芬; 方群英; 吴怡; 张永芳; 蒋春儿; 江子芳

    2015-01-01

    Objective To investigate the mastering of osteoporosis knowledge and the level of self-efficacy in patients treated with aromatase inhibitors and to provide references for further preventive interventions. Methods A total of seventy five patients with breast cancer treated with aromatase inhibitors were recruited from Zhejiang Cancer Hospital using convenience sampling method. They were investigated with osteoporosis knowledge test ( OKT ) and osteoporosis self-efficacy scale ( OSES ) . Results The total score of osteoporosis knowledge was 51. 90, in which the score of risk factors of osteoporosis, exercise and calcium intake were 55. 75,50. 67 and 47. 67, respectively. The correct rate of osteoporosis knowledge was statistically different in people with different educational level and approach of health education (P<0. 05). The total score of self-efficacy and factor scores of exercise and calcium intake were (59. 80 ± 19. 88),(60. 25 ± 21. 99),(59. 35 ± 17. 76)respectively. Conclusions It is suggested to strengthen osteoporosis related health education for patients with breast cancer, and to increase their health information and beliefs, and help them to formulate health behaviors to prevent osteoporosis.%目的:探讨乳腺癌芳香化酶抑制剂治疗患者的骨质疏松知识掌握情况和自我效能的水平,为进一步预防干预提供依据。方法应用便利抽样的方法,于2014年1—6月在浙江省肿瘤医院选取符合标准的75例患者,采用骨质疏松知识问卷、骨质疏松自我效能问卷进行调查。结果75例芳香化酶抑制剂治疗的乳腺癌患者骨质疏松知识总标准分为51.90分,其中,危险因素、运动量表和钙量表的标准分分别为55.75,50.67,47.67分。不同文化程度、健康教育接受情况患者骨质疏松知识正确率差异有统计学意义(P<0.05)。75例乳腺癌患者骨质疏松自我效能总量表、运动分量表和钙摄入分量表的平均得分分别为(59.80±19

  14. Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

    Directory of Open Access Journals (Sweden)

    Prachayasittikul V

    2014-08-01

    Full Text Available Veda Prachayasittikul,1 Ratchanok Pingaew,2 Chanin Nantasenamat,3 Supaluk Prachayasittikul,3 Somsak Ruchirawat,4,5 Virapong Prachayasittikul1 1Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 2Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand; 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 4Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 5Chulabhorn Graduate Institute, Bangkok, Thailand Purpose: Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni complexes of 8-hydroxyquinoline (8HQ and uracil derivatives (4–9 were investigated for their aromatase inhibitory and cytotoxic activities. Methods: The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5 using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Results: Only Cu complexes (6 and 9 exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 µM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6, as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 µM. Conclusion: Cu complexes (6 and 9 were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer

  15. Proton pump inhibitor step-down therapy for GERD: A multi-center study in Japan

    Institute of Scientific and Technical Information of China (English)

    Takao Tsuzuki; Hiroyuki Okada; Yoshiro Kawahara; Ryuta Takenaka; Junichiro Nasu; Hidehiko Ishioka; Akiko Fujiwara; Fumiya Yoshinaga; Kazuhide Yamamoto

    2011-01-01

    AIM: To investigate the predictors of success in stepdown of proton pump inhibitor and to assess the quality of life (QOL). METHODS: Patients who had heartburn twice a week or more were treated with 20 mg omeprazole (OPZ) once daily for 8 wk as an initial therapy (study 1). Patients whose heartburn decreased to once a week or less at the end of the initial therapy were enrolled in study 2 and treated with 10 mg OPZ as maintenance therapy for an additional 6 mo (study 2). QOL was investigated using the gastrointestinal symptom rating scale (GSRS) before initial therapy, after both 4 and 8 wk of initial therapy, and at 1, 2, 3, and 6 mo after starting maintenance therapy. RESULTS: In study 1, 108 patients were analyzed. Their characteristics were as follows; median age: 63 (range: 20-88) years, sex: 46 women and 62 men. The success rate of the initial therapy was 76%. In the patients with successful initial therapy, abdominal pain, indigestion and reflux GSRS scores were improved. In study 2, 83 patients were analyzed. Seventy of 83 patients completed the study 2 protocol. In the per-protocol analysis, 80% of 70 patients were successful for stepdown. On multivariate analysis of baseline demographic data and clinical information, no previous treatment for gastroesophageal reflux disease (GERD) [odds ratio (OR) 0.255, 95% CI: 0.06-0.98] and a lower indigestion score in GSRS at the beginning of step-down therapy (OR 0.214, 95% CI: 0.06-0.73) were found to be the predictors of successful step-down therapy. The improved GSRS scores by initial therapy were maintained through the step-down therapy. CONCLUSION: OPZ was effective for most GERD patients. However, those who have had previous treatment for GERD and experience dyspepsia before stepdown require particular monitoring for relapse.

  16. Challenges Associated with Tyrosine Kinase Inhibitor Therapy for Metastatic Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Maria E. Cabanillas

    2011-01-01

    Full Text Available Tyrosine kinase inhibitors (TKIs which target angiogenesis are promising treatments for patients with metastatic medullary and differentiated thyroid cancers. Sorafenib, sunitinib, and pazopanib are commercially available drugs which have been studied in these diseases. Vandetanib is the first drug approved in the United States for treatment of medullary thyroid cancer. These TKIs are used as chronic therapies, and therefore it is imperative to understand the adverse event profile in order to avoid excessive toxicity and maintain patients on therapy as long as it proves beneficial. Here we review common toxicities, management of these, and other challenging situations that arise when using TKIs in patients with thyroid cancer.

  17. Developmental regulation of aromatase activity in the rat hypothalamus

    Energy Technology Data Exchange (ETDEWEB)

    Lephart, E.D.

    1989-01-01

    The brain of all mammalian species studied thus far contain an enzymatic activity (aromatase) that catalyzes the conversion of androgens to estrogens. The activity is highest during prenatal development and contributes to the establishment of sex differences which determine adult gonadotropin secretion patterns and reproductive behavior. The studies presented in this dissertation represent a systematic effort to elucidate the mechanism(s) that control the initiation of and contribute to maintaining rat hypothalamic aromatase activity during pre- and postnatal development. Aromatase enzyme activity was measured by the {sup 3}H{sub 2}O release assay or by traditional estrogen product isolation. Brain aromatase mRNA was detected by hybridization to a cDNA encoding rat aromatase cytochrome P-450. In both males and females the time of puberty was associated with a decline in hypothalamic aromatase activity. This decline may represent a factor underlying the peri-pubertal decrease in the sensitivity to gonadal steroid feedback that accompanies completion of puberty. The results also indicate that androgens regulate brain aromatase levels during both the prepubertal and peri-pubertal stages of sexual development and that this regulation is transiently lost in young adults. Utilizing a hypothalamic organotypic culture system, aromatase activity in vitro was maintained for as long as two days. The results of studies of a variety of hormonal and metabolic regulators suggest that prenatal aromatase activity is regulated by factor(s) that function independently from the classical cyclic AMP and protein kinase C trans-membrane signaling pathways.

  18. Roles of PARP inhibitor in synthetic lethality and as a sensitizer in cancer therapy

    International Nuclear Information System (INIS)

    In a search for novel chemotherapeutic targets for cancer, recent interest has focused on DNA repair pathways. Poly (ADP-ribose) polymerase (PARP)-1 is an important protein for base excision repair and inhibitors of this pathway show anti-cancer effects when used as a mono-therapy for BRCA-deficient cancers in clinical trials. The results of such studies proved the concept of ''synthetic lethality'' by targeting DNA repair pathways. Considering the action of the PARP inhibitor (PARPi) in DNA repair pathways, PARPi is also predicted to act as a sensitizer for DNA damaging agents, such as certain chemotherapeutic drugs and radiation. A number of clinical trials using PARPi in combination with existing therapies are underway. We investigated the use of PARPi as a radiosensitizer for high LET (linear energy transfer) radiation. PARPi showed the radiosensitization effect of carbon-ion radiation, and the radiosensitization effect of PARPi was attributed to a delay in the DNA damage response and double strand break processing. Via its effects on DNA repair, the PARP inhibitor might be applicable as a radiosensitizer for a wide range of therapeutic LET radiation. This study suggests that development of research into DNA repair pathways could yield still further targets for cancer therapy. (author)

  19. Perioceutics: Matrix metalloproteinase inhibitors as an adjunctive therapy for inflammatory periodontal disease

    Directory of Open Access Journals (Sweden)

    Esther Nalini Honibald

    2012-01-01

    Full Text Available Matrix metalloproteinases (MMPs form a group of more than 20 zinc-dependent enzymes that are crucial in the degradation of the main components in the extracellular matrix, and thereby play important roles in cell migration, wound healing, and tissue remodeling. MMPs have outgrown the field of extracellular matrix biology and have progressed toward being important regulatory molecules in inflammation, and hence are key components in the pathogenesis of periodontitis. This rise in status has led to the development of MMP inhibitors which can act as switches or delicate tuners in acute and chronic inflammation and the regenerative phase after inflammation. The new challenge in MMP research is to better understand the complex role these enzymes play in periodontal disease and to design inhibitors that are successful in the clinic. Perioceutics or the use of the pharmacological agents specifically developed to manage periodontitis is an interesting and emerging aid in the management of periodontal diseases along with mechanical debridement. The purpose of this review is to provide an introduction to MMPs and their inhibitors, the pathologic effects of a disturbance in the functions of enzyme cascades in balance with natural inhibitors, and highlight on the adjunctive use of MMP inhibitors in periodontal therapy and some of the current challenges with an overview of what has been achieved till date.

  20. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    International Nuclear Information System (INIS)

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC50: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They inhibited

  1. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jiajia [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Yuan, Yun [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Lu, Danfeng; Du, Baowen [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Xiong, Liang; Shi, Jiangong [State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Yang, Lijuan [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Liu, Wanli [MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Yuan, Xiaohong [School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Zhang, Guolin, E-mail: zhanggl@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China); Wang, Fei, E-mail: wangfei@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China)

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC{sub 50}: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They

  2. Modulation of Δ9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

    International Nuclear Information System (INIS)

    Δ9-Tetrahydrocannabinol (Δ9-THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141-146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E2), the interaction of Δ9-THC and E2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E2-sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ9-THC-mediated MCF-7 cell proliferation. It was shown that Δ9-THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ9-THC was not stimulated by PGE2, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE2, suggesting that there is a disconnection between COX-2 (PGE2) and aromatase in Δ9-THC-mediated MCF-7 cell proliferation. On the other hand, Δ9-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ9-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E2, it is suggested that (1) the growth stimulatory effects of Δ9-THC are mediated by the product(s) of COX-2 except for PGE2, (2) the action of Δ9-THC is modulated by E2, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ9-THC.

  3. Does the Presence of a Hiatal Hernia Affect the Efficacy of the Reflux Inhibitor Baclofen During Add-On Therapy?

    NARCIS (Netherlands)

    H. Beaumont; G.E.E. Boeckxstaens

    2009-01-01

    OBJECTIVES: Reflux inhibitors, like the gamma-aminobutyric acid type B (GABA(B)) receptor agonist, baclofen, block transient lower esophageal sphincter relaxations (TLESRs) and are proposed as an add-on therapy in patients with proton pump inhibitor (PPI)-resistant gastroesophageal reflux. However,

  4. Melatonin modulates aromatase activity and expression in endothelial cells.

    Science.gov (United States)

    Alvarez-García, Virginia; González, Alicia; Martínez-Campa, Carlos; Alonso-González, Carolina; Cos, Samuel

    2013-05-01

    Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens. The presence of aromatase on endothelial cells indicates that endothelial cells may contribute to tumor growth by producing estrogens. Since human umbilical vein endothelial cells (HUVECs) express both aromatase and melatonin receptors, the aim of the present study was to evaluate the ability of melatonin to regulate the activity and expression of aromatase on endothelial cells, thus, modulating local estrogen biosynthesis. In the present study, we demonstrated that melatonin inhibits the growth of HUVECs and reduces the local biosynthesis of estrogens through the downregulation of aromatase. These results are supported by three lines of evidence. Firstly, 1 mM of melatonin counteracted the testosterone-induced cell proliferation of HUVECs, which is dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. Secondly, we found that 1 mM of melatonin reduced the aromatase activity of HUVECs. Finally, by real‑time RT-PCR, we demonstrated that melatonin significantly downregulated the expression of aromatase as well as its endothelial-specific aromatase promoter region I.7. We conclude that melatonin inhibits aromatase activity and expression in HUVECs by regulating gene expression of specific aromatase promoter regions, thereby reducing the local production of estrogens. PMID:23450505

  5. 芳香化酶抑制剂对暗纹东方鲀CYP19A、DMRT1基因表达及性腺分化的影响%Effect of aromatase inhibitor on expression of CYP19A, DMRT1, and gonadal sex differentiation in Takifugu obscures

    Institute of Scientific and Technical Information of China (English)

    黄波; 杨小玉; 戴奇; 汪奇; 云丹; 周忠良

    2013-01-01

      采用组织学和分子生物学方法,研究了投喂芳香化酶抑制剂来曲唑(LE)后暗纹东方(Takifugu obscures)初鲀孵仔鱼CYP19A、DMRT1基因表达以及性腺的组织学变化,以期进一步了解P450芳香化酶(P450arom)在鱼类早期性别分化过程中的作用.RT-PCR 结果显示,对照组样品 CYP19A 和 DMRT1表达显示性二态,雌性表达 CYP19A基因,雄性表达 DMRT1基因.LE 处理组在性别分化期间,雄性样品单一表达 DMRT1,雌性样品则同时表达CYP19A 和 DMRT1.qRT-PCR 结果显示: LE 处理组雌性仔鱼 CYP19A 基因表达被显著抑;虽然在仔鱼出膜后22 d(dph)的表达水平高于9 dph,但仅为同日对照组的2.11%.LE处理组雌性样品22 dph时DMRT1基因表达量上调,至150 dph时达对照组雄性水平.55 dph的性腺组织学结果表明, LE处理可导致暗纹东方稚鱼原始卵巢退化,并鲀向功能性精巢发育.150 dph的LE处理组性腺均为精巢,并与对照组精巢发育同步.结论认为,暗纹东方性腺鲀分化期间P450arom是卵巢形成和维持发育所必须的,抑制P450arom活性可导致雌性暗纹东方发生雄性化逆转.鲀%As in all other lower vertebrates, sex differentiation in fish is susceptible to environmental and steroi-dogenic stimulation or inhibition. Alteration of the sex differentiation process is possible in many fishes through the manipulation of the environment and steroid function. Some chemicals, which have androgenic or estrogenic function, are known to alter the gonadal sex in fish from female to male or vice versa if administered during the period of gonadal sex differentiation. Other than direct androgenic or estrogenic effects, there are chemicals which are capable of disrupting the enzymatic pathway of natural androgenic-estrogenic balance in fish. Among the non-steroidal aromatase inhibitors (AI), letrozole is typically used as an effective human drug in the treatment of estrogen-dependent disease, including breast

  6. The role of proton pump inhibitor therapy in the management of eosinophilic esophagitis.

    Science.gov (United States)

    Molina-Infante, Javier; Prados-Manzano, Raul; Gonzalez-Cordero, Pedro Luis

    2016-09-01

    Eosinophilic esophagitis (EoE) is a chronic esophageal disease characterized by a Th2 inflammatory response triggered by food/environmental allergens. Solid data confirm that up to half of patients with suspected EoE achieve complete remission on proton pump inhibitors (PPI) therapy. This disease phenotype is currently labelled as PPI-responsive esophageal eosinophilia (PPI-REE). Albeit initially believed to represent gastro-esophageal reflux disease (GERD), evolving evidence has underscored that PPI-REE and EoE show a significant overlap regarding clinic, endoscopic, histologic, Th2 immune-mediated inflammation and gene expression features. Moreover, PPI therapy can effectively reverse Th2 inflammation and the EoE transcriptome expression in PPI-REE patients. Therefore, EoE and PPI-REE likely represent a common allergic disorder, where PPI therapy should be considered a short- and long-term therapeutic asset, along with diet and topical steroids. PMID:27097787

  7. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors.

    Science.gov (United States)

    Rafael, Adilia; Torres, Tiago

    2016-01-01

    Psoriasis is a common, chronic and disabling skin disorder affecting approximately 2% of the population, associated with significant negative impact on the patient's quality of life. Approximately 80% of those affected with psoriasis have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease. In the past three decades, the major advances in psoriasis therapy have been in systemic agents for the treatment of moderate-to-severe psoriasis, particularly new immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged over the past decades. Indeed, topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis. Thus, there is a need to develop new and more effective topical agents in the short and long term, with a better efficacy and safety profile than corticosteroids and vitamin D3 analogs. Over the past five years, investigation into topical therapy has expanded, with exciting new drugs being developed. Preliminary results of these emerging agents that selectively target disease-defining pathogenic pathways seem to be promising, although long-term and large-scale studies assessing safety and efficacy are still lacking. The aim of this article was to review the clinical and research data of some emerging topical agents, focusing on Janus kinase-signal transducer and activator of transcription and phosphodiesterase type 4 inhibitors, which are currently being investigated.

  8. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors.

    Science.gov (United States)

    Rafael, Adilia; Torres, Tiago

    2016-01-01

    Psoriasis is a common, chronic and disabling skin disorder affecting approximately 2% of the population, associated with significant negative impact on the patient's quality of life. Approximately 80% of those affected with psoriasis have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease. In the past three decades, the major advances in psoriasis therapy have been in systemic agents for the treatment of moderate-to-severe psoriasis, particularly new immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged over the past decades. Indeed, topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis. Thus, there is a need to develop new and more effective topical agents in the short and long term, with a better efficacy and safety profile than corticosteroids and vitamin D3 analogs. Over the past five years, investigation into topical therapy has expanded, with exciting new drugs being developed. Preliminary results of these emerging agents that selectively target disease-defining pathogenic pathways seem to be promising, although long-term and large-scale studies assessing safety and efficacy are still lacking. The aim of this article was to review the clinical and research data of some emerging topical agents, focusing on Janus kinase-signal transducer and activator of transcription and phosphodiesterase type 4 inhibitors, which are currently being investigated. PMID:26552963

  9.  Poly(ADP-ribose polymerase (PARP inhibitors in BRCA1/2 cancer therapy

    Directory of Open Access Journals (Sweden)

    Katarzyna Kluzek

    2012-06-01

    Full Text Available  A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose polymerases (PARP. PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP-ribose polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers.

  10. Efflux pump inhibitors: targeting mycobacterial efflux systems to enhance TB therapy.

    Science.gov (United States)

    Pule, Caroline M; Sampson, Samantha L; Warren, Robin M; Black, Philippa A; van Helden, Paul D; Victor, Tommie C; Louw, Gail E

    2016-01-01

    The emergence of drug resistance continues to plague TB control, with a global increase in the prevalence of MDR-TB. This acts as a gateway to XDR-TB and thus emphasizes the urgency for drug development and optimal treatment options. Bedaquiline is the first new anti-TB drug approved by the FDA in 40 years and has been shown to be an effective treatment option for MDR Mycobacterium tuberculosis infection. Bedaquiline has also recently been included in clinical trials for new regimens with the aim of improving and shortening treatment periods. Alarmingly, efflux-mediated bedaquiline resistance, as well as efflux-mediated cross-resistance to clofazimine, has been identified in treatment failures. This mechanism of resistance results in efflux of a variety of anti-TB drugs from the bacterial cell, thereby decreasing the intracellular drug concentration. In doing so, the bacillus is able to render the antibiotic treatment ineffective. Recent studies have explored strategies to reverse the resistance phenotype conferred by efflux pump activation. It was observed that the addition of efflux pump inhibitors partially restored drug susceptibility in vitro and in vivo. This has significant clinical implications, especially in MDR-TB management where treatment options are extremely limited. This review aims to highlight the current efflux pump inhibitors effective against M. tuberculosis, the effect of efflux pump inhibitors on mycobacterial growth and the clinical promise of treatment with efflux pump inhibitors and standard anti-TB therapy. PMID:26472768

  11. Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.

    Science.gov (United States)

    Schwartz, Harvey; Scroggins, Brad; Zuehlke, Abbey; Kijima, Toshiki; Beebe, Kristin; Mishra, Alok; Neckers, Len; Prince, Thomas

    2015-09-01

    The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas. PMID:26070366

  12. Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

    Science.gov (United States)

    Wilding, John P H; Rajeev, Surya Panicker; DeFronzo, Ralph A

    2016-08-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials. PMID:27440828

  13. Increasing Deaths Due to Malignancy in HIV+ Patients is Associated with Integrase Inhibitor Therapy

    Institute of Scientific and Technical Information of China (English)

    Daniel O. Griffin[1,2,3; Arif Dharsee[1; Juan Carlos Rico[1; Joseph McGowan[1

    2014-01-01

    Despite reductions in AIDS-related deaths, registries show HIV+ patients are still dying at a younger age than HIV-peers. Although overall mortality has declined in this population, a growing percent of deaths are due to malignancy. Since the data demonstrating the growing percentage of deaths due to malignancy in the HIV+ population is derived from registries, the study explores whether the subset dying from malignancy has particular characteristics that can be seen in a well-characterized cohort. In the well-characterized HIV+ cohort, the percentage of deaths due to cancer was seen to increase over four years (2010-2013) from 21% to 24% to 38% to 40%. The mean CD4-count of those who died from malignancy was 252+/-42 and 333+/-36 in patients with death from other causes. The viral load was not suppressed in 26% of patients dying from malignancy. Of patients on integrase inhibitor therapy, 48% of deaths were due to malignancy while in patients not on this therapy, 10% of deaths were due to malignancy (relative risk = 4.8). In HIV+ patients, a low CD4-count, failure to achieve viral suppression, and use of integrase inhibitors were associated with malignancy as the cause of death. The association of a specific therapy, integrase inhibition, with malignancy is seen in the study.

  14. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010-2014).

    Science.gov (United States)

    Tanaka, Minoru; Roberts, Justin M; Qi, Jun; Bradner, James E

    2015-01-01

    Gene regulatory pathways comprise an emerging and active area of chemical probe discovery and investigational drug development. Emerging insights from cancer genome sequencing and chromatin biology have identified leveraged opportunities for development of chromatin-directed small molecules as cancer therapies. At present, only six agents in two epigenetic target classes have been approved by the US FDA, limited to treatment of hematological malignancies. Recently, new classes of epigenetic inhibitors have appeared in literatures. First-in-class compounds have successfully transitioned to clinical investigation, importantly also in solid tumors and pediatric malignancies. This review considers patent applications for small-molecule inhibitors of selected epigenetic targets from 2010 to 2014. Included are exemplary classes of chromatin-associated epigenomic writers (DOT1L and EZH2), erasers (LSD1) and readers (BRD4).

  15. New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy.

    Science.gov (United States)

    Gentile, Francesco; Tuszynski, Jack A; Barakat, Khaled H

    2016-04-01

    Many cancer chemotherapy agents act by targeting the DNA of cancer cells, causing substantial damage within their genome and causing them to undergo apoptosis. An effective DNA repair pathway in cancer cells can act in a reverse way by removing these drug-induced DNA lesions, allowing cancer cells to survive, grow and proliferate. In this context, DNA repair inhibitors opened a new avenue in cancer treatment, by blocking the DNA repair mechanisms from removing the chemotherapy-mediated DNA damage. In particular, the nucleotide excision repair (NER) involves more than thirty protein-protein interactions and removes DNA adducts caused by platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1)-xeroderma pigmentosum, complementation group A (XPA) protein (XPA-ERCC1) complex seems to be one of the most promising targets in this pathway. ERCC1 is over expressed in cancer cells and the only known cellular function so far for XPA is to recruit ERCC1 to the damaged point. Here, we build upon our recent advances in identifying inhibitors for this interaction and continue our efforts to rationally design more effective and potent regulators for the NER pathway. We employed in silico drug design techniques to: (1) identify compounds similar to the recently discovered inhibitors, but more effective at inhibiting the XPA-ERCC1 interactions, and (2) identify different scaffolds to develop novel lead compounds. Two known inhibitor structures have been used as starting points for two ligand/structure-hybrid virtual screening approaches. The findings described here form a milestone in discovering novel inhibitors for the NER pathway aiming at improving the efficacy of current platinum-based therapy, by modulating the XPA-ERCC1 interaction. PMID:26939044

  16. [Mode of action, clinical profile and relevance of carbonic anhydrase inhibitors in glaucoma therapy].

    Science.gov (United States)

    Eichhorn, M

    2013-02-01

    Since their introduction the local carbonic anhydrase inhibitors (CAH) dorzolamide and brinzolamide have become well established in the drug therapy of glaucoma. They lower intraocular pressure (IOP) by blocking specifically carbonic anhydrase in the ciliary epithelium and thereby the secretion of aqueous humor. The IOP lowering effect is comparable with that of beta-blockers, but less than that of prostaglandin agonists. Because of their specific mode of action they produce an additive pressure lowering effect with any other glaucoma drug. Therefore they are ideal for being combined with other drugs. In addition, CAH may improve perfusion of the posterior eye. Preliminary results in glaucoma patients under dorzolamide therapy suggesting a reduction in the risk of progression due to enhanced blood flow need further confirmation. PMID:23430679

  17. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy

    International Nuclear Information System (INIS)

    Standard therapies for high grade glioma have failed to substantially improve survival and are associated with significant morbidity. At relapse, high grade gliomas, such as glioblastoma multiforme, are refractory to therapy and universally fatal. BRAF V600E-mutations have been described in a modest 6% to 7% of primary central nervous system (CNS) tumors, but with increased prevalence in the pediatric population and in certain brain tumor subtypes. The use of BRAF inhibitors have transformed melanoma therapy however their use in brain tumors remains unproven. We describe the pediatric case of a now 12 year old Caucasian male who originally presented at age 9 with a right fronto-parietal glioblastoma multiforme that recurred 2 ½ years from diagnosis. Molecular analysis of the primary tumor revealed a BRAF V600E mutation and the patient was placed on the BRAF inhibitor vemurafenib. A complete response was observed after 4 months of therapy and remains sustained at 6 months. This is the first report of a complete response of relapsed glioblastoma multiforme to targeted BRAF inhibitor therapy. While not a predominant mutation in glioblastoma multiforme, the increased prevalence of BRAF V600 mutations in pediatric CNS tumors and certain subtypes marks a population to whom this therapy could be applied. Response to this therapy suggests that BRAF inhibitors can affect primary CNS lesions when a documented and targetable mutation is present

  18. A case of recurrent organizing pneumonia after radiation therapy for postoperative breast cancer

    International Nuclear Information System (INIS)

    We report the case of a 61-year-old female patient with breast cancer who developed recurrent organizing pneumonia outside the radiation field after radiation therapy for postoperative breast cancer. The patient had received tangential radiation therapy and aromatase inhibitors for postoperative breast cancer. Chest computed tomography confirmed an irregular nodule and ground-glass opacities in the left lower lobe outside the radiation field 10 months after radiation therapy. The nodule demonstrated high uptake on 18F-fluorodeoxyglucose positron emission tomography; therefore, lung cancer could not be ruled out. We performed partial resection of the lung, and a diagnosis of organized pneumonia was made on histopathological examination of the resected specimen. Three days after surgery, a chest radiograph revealed an abnormal shadow in the right lower field. The possibility of organizing pneumonia was considered when pulmonary infiltrate did not respond to conventional antibiotic therapy and the patient recovered completely after treatment with steroids. Furthermore, chest CT performed 4 months after surgery revealed consolidation in the right lower lobe. Again, the patient recovered completely with steroid treatment, indicating the possibility of recurrent organizing pneumonia. The number of such reported cases has increased in recent years; however, the etiology remains unclear. In the case presented, aromatase inhibitor therapy combined with radiation therapy may have been the cause of the organizing pneumonia. (author)

  19. The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism.

    Science.gov (United States)

    Kadlub, Natacha; Vazquez, Marie-Paule; Galmiche, Louise; L'Herminé, Aurore Coulomb; Dainese, Linda; Ulinski, Tim; Fauroux, Brigitte; Pavlov, Ioana; Badoual, Cécile; Marlin, Sandrine; Deckert, Marcel; Leboulanger, Nicolas; Berdal, Ariane; Descroix, Vianney; Picard, Arnaud; Coudert, Amélie E

    2015-05-01

    Cherubism is a rare genetic disorder characterized by extensive growth of a bilateral granuloma of the jaws, resulting in facial disfigurement. Cherubism is caused by gain-of-function mutations in the SH3BP2 gene, leading to overactivation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-dependent osteoclastogenesis. Recent findings in human and mouse cherubism have suggested that calcineurin inhibitors might be drug candidates in cherubism medical treatment. A 4-year-old boy with aggressive cherubism was treated with the calcineurin inhibitor tacrolimus for 1 year, and clinical, radiological, and molecular data were obtained. Immunohistologic analysis was performed to compare preoperative and postoperative NFATc1 staining and tartrate resistant acid phosphatase (TRAP) activity. Real-time PCR was performed to analyze the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilization of jaw size and intraosseous osteogenesis. Immunohistologic analyses on granuloma showed that tacrolimus caused a significant reduction in the number of TRAP-positive osteoclasts and NFATc1 nuclear staining in multinucleated giant cells. Molecular analysis showed that tacrolimus treatment also resulted in increased OPG expression. We present the first case of effective medical therapy in cherubism. Tacrolimus enhanced bone formation by stimulating osteogenesis and inhibiting osteoclastogenesis.

  20. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis.

    Science.gov (United States)

    Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus F; Hohenberger, Werner; Heinzerling, Lucie

    2016-06-01

    Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics. PMID:27471608

  1. Proton-pump inhibitors in patients requiring antiplatelet therapy: new FDA labeling.

    Science.gov (United States)

    Johnson, David A; Chilton, Robert; Liker, Harley R

    2014-05-01

    Proton-pump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper gastrointestinal bleeding. Proton-pump inhibitors should also be considered for patients receiving antiplatelet therapy who have other risk factors for gastrointestinal bleeding, including use of aspirin. Thus, evidence of pharmacokinetic and pharmacodynamic interactions between PPIs and consequent impaired effectiveness of the antiplatelet agent clopidogrel has caused concern. Here, we discuss comparative studies suggesting that the extent to which a PPI reduces exposure to the active metabolite of clopidogrel and attenuates its antithrombotic effect differs among PPIs. Although a clinically meaningful effect of the interaction between PPIs and clopidogrel on cardiovascular outcomes has not been established, these studies provided the basis for recent changes in US Food and Drug Administration (FDA) labeling for several PPIs and clopidogrel. New labeling suggests that PPI use among patients taking clopidogrel be limited to pantoprazole, rabeprazole, lansoprazole, or dexlansoprazole. Because comparative studies indicate that omeprazole and esomeprazole have a greater effect on the CYP2C19-mediated conversion of clopidogrel to its active metabolite and, consequently, clopidogrel's effect on platelet reactivity, FDA labeling recommends avoiding omeprazole and esomeprazole in patients taking clopidogrel. Even a 12-hour separation of dosing does not appear to prevent drug interactions between omeprazole and clopidogrel. PMID:24918808

  2. Neuroinflammation induces glial aromatase expression in the uninjured songbird brain

    Directory of Open Access Journals (Sweden)

    Saldanha Colin J

    2011-07-01

    Full Text Available Abstract Background Estrogens from peripheral sources as well as central aromatization are neuroprotective in the vertebrate brain. Under normal conditions, aromatase is only expressed in neurons, however following anoxic/ischemic or mechanical brain injury; aromatase is also found in astroglia. This increased glial aromatization and the consequent estrogen synthesis is neuroprotective and may promote neuronal survival and repair. While the effects of estradiol on neuroprotection are well studied, what induces glial aromatase expression remains unknown. Methods Adult male zebra finches (Taeniopygia guttata were given a penetrating injury to the entopallium. At several timepoints later, expression of aromatase, IL-1β-like, and IL-6-like were examined using immunohisotchemistry. A second set of zebra birds were exposed to phytohemagglutinin (PHA, an inflammatory agent, directly on the dorsal surface of the telencephalon without creating a penetrating injury. Expression of aromatase, IL-1β-like, and IL-6-like were examined using both quantitative real-time polymerase chain reaction to examine mRNA expression and immunohistochemistry to determine cellular expression. Statistical significance was determined using t-test or one-way analysis of variance followed by the Tukey Kramers post hoc test. Results Following injury in the zebra finch brain, cytokine expression occurs prior to aromatase expression. This temporal pattern suggests that cytokines may induce aromatase expression in the damaged zebra finch brain. Furthermore, evoking a neuroinflammatory response characterized by an increase in cytokine expression in the uninjured brain is sufficient to induce glial aromatase expression. Conclusions These studies are among the first to examine a neuroinflammatory response in the songbird brain following mechanical brain injury and to describe a novel neuroimmune signal to initiate aromatase expression in glia.

  3. Aromatase Inhibitors and Other Compounds for Lowering Breast Cancer Risk

    Science.gov (United States)

    ... Cancer? Breast Cancer Colon/Rectum Cancer Lung Cancer Prostate Cancer Skin Cancer Show All Cancer Types News and Features Cancer Glossary ACS Bookstore Cancer Information Cancer Basics Cancer Prevention & Detection Signs & Symptoms of Cancer Treatments & Side Effects ...

  4. Paternal Retrieval Behavior Regulated by Brain Estrogen Synthetase (Aromatase) in Mouse Sires that Engage in Communicative Interactions with Pairmates

    Science.gov (United States)

    Akther, Shirin; Huang, Zhiqi; Liang, Mingkun; Zhong, Jing; Fakhrul, Azam A. K. M.; Yuhi, Teruko; Lopatina, Olga; Salmina, Alla B.; Yokoyama, Shigeru; Higashida, Chiharu; Tsuji, Takahiro; Matsuo, Mie; Higashida, Haruhiro

    2015-01-01

    Parental behaviors involve complex social recognition and memory processes and interactive behavior with children that can greatly facilitate healthy human family life. Fathers play a substantial role in child care in a small but significant number of mammals, including humans. However, the brain mechanism that controls male parental behavior is much less understood than that controlling female parental behavior. Fathers of non-monogamous laboratory ICR mice are an interesting model for examining the factors that influence paternal responsiveness because sires can exhibit maternal-like parental care (retrieval of pups) when separated from their pups along with their pairmates because of olfactory and auditory signals from the dams. Here we tested whether paternal behavior is related to femininity by the aromatization of testosterone. For this purpose, we measured the immunoreactivity of aromatase [cytochrome P450 family 19 (CYP19)], which synthesizes estrogen from androgen, in nine brain regions of the sire. We observed higher levels of aromatase expression in these areas of the sire brain when they engaged in communicative interactions with dams in separate cages. Interestingly, the number of nuclei with aromatase immunoreactivity in sires left together with maternal mates in the home cage after pup-removing was significantly larger than that in sires housed with a whole family. The capacity of sires to retrieve pups was increased following a period of 5 days spent with the pups as a whole family after parturition, whereas the acquisition of this ability was suppressed in sires treated daily with an aromatase inhibitor. The results demonstrate that the dam significantly stimulates aromatase in the male brain and that the presence of the pups has an inhibitory effect on this increase. These results also suggest that brain aromatization regulates the initiation, development, and maintenance of paternal behavior in the ICR male mice. PMID:26696812

  5. Photodynamic therapy for inactivating endodontic bacterial biofilms and effect of tissue inhibitors on antibacterial efficacy

    Science.gov (United States)

    Shrestha, Annie; Kishen, Anil

    Complex nature of bacterial cell membrane and structure of biofilm has challenged the efficacy of antimicrobial photodynamic therapy (APDT) to achieve effective disinfection of infected root canals. In addition, tissue-inhibitors present inside the root canals are known to affect APDT activity. This study was aimed to assess the effect of APDT on bacterial biofilms and evaluate the effect of tissue-inhibitors on the APDT. Rose-bengal (RB) and methylene-blue (MB) were tested on Enterococcus faecalis (gram-positive) and Pseudomonas aeruginosa (gram-negative) biofilms. In vitro 7- day old biofilms were sensitized with RB and MB, and photodynamically activated with 20-60 J/cm2. Photosensitizers were pre-treated with different tissue-inhibitors (dentin, dentin-matrix, pulp tissue, bacterial lipopolysaccharides (LPS), and bovine serum albumin (BSA)) and tested for antibacterial effect of APDT. Microbiological culture based analysis was used to analyze the cell viability, while Laser Scanning Confocal Microscopy (LSCM) was used to examine the structure of biofilm. Photoactivation resulted in significant reduction of bacterial biofilms with RB and MB. The structure of biofilm under LSCM was found to be disrupted with reduced biofilm thickness. Complete biofilm elimination could not be achieved with both tested photosensitizers. APDT effect using MB and RB was inhibited in a decreasing order by dentin-matrix, BSA, pulp, dentin and LPS (Pbacterial biofilms resisted complete elimination after APDT and the tissue inhibitors existing within the root canal reduced the antibacterial activity at varying degrees. Further research is required to enhance the antibacterial efficacy of APDT in an endodontic environment.

  6. Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy-generated vaccine.

    Science.gov (United States)

    Korbelik, Mladen; Banáth, Judit; Zhang, Wei; Saw, Kyi Min; Szulc, Zdzislaw M; Bielawska, Alicja; Separovic, Duska

    2016-09-15

    Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 µM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill. PMID:27136745

  7. Adeno-associated virus mediated endostatin gene therapy in combination with topoisomerase inhibitor effectively controls liver tumor in mouse model

    Institute of Scientific and Technical Information of China (English)

    Sung Yi Hong; Myun Hee Lee; Kyung Sup Kim; Hyun Cheol Jung; Jae Kyung Roh; Woo Jin Hyung; Sung Hoon Noh; Seung Ho Choi

    2004-01-01

    AIM: rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer. However,a sustained and high protein delivery is required to achieve the desired therapeutic effects. We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model.METHODS: rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines. To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin, Western blotting and ELISA were performed. The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays.The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor, etoposide, were evaluated in a mouse liver tumor model.RESULTS: Topoisomerase inhibitors, including camptothecin and etoposide, were found to increase the endostatin expression level in vitro. The over-expressed endostatin,as a result of pretreatment with a topoisomerase inhibitor,was also biologically active. In animal experiments, the combined therapy of topoisomerase inhibitor, etoposide with the rAAV-endostatin vector had the best tumorsuppressive effect and tumor foci were barely observed in livers of the treated mice. Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice. Finally, the mice treated with rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models.CONCLUSION: rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.

  8. Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery.

    Science.gov (United States)

    Görtz, Dieter; Braun, Gerald S; Maruta, Yuichi; Djudjaj, Sonja; van Roeyen, Claudia R; Martin, Ina V; Küster, Andrea; Schmitz-Van de Leur, Hildegard; Scheller, Jürgen; Ostendorf, Tammo; Floege, Jürgen; Müller-Newen, Gerhard

    2015-01-01

    Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. PMID:26423228

  9. 他莫昔芬治疗芳香化酶抑制剂耐药的激素受体阳性绝经后转移性乳腺癌患者的临床研究%Clinical observation of tamoxifen in hormone receptor - positive postmenopausal patients with metastatic breast cancer failing to Aromatase inhibitors

    Institute of Scientific and Technical Information of China (English)

    童刚领; 李柱; 农巧红; 何艳玲; 申东兰; 王树滨

    2015-01-01

    Objective:To investigate the curative effect and safety of tamoxifen in hormone receptor - positive (HR + )postmenopausal patients with metastatic breast cancer(MBC)failing to Aromatase inhibitors(AIs). Meth-ods:Retrospectively analyzed clinical data of 30 patients with HR + postmenopausal MBC treated with tamoxifen after AIs resistance. The endpoints were response rate(RR),clinical benefit rate(CBR),time of tumor progression(TTP) and safety. Results:In 30 patients,the patients who acquired CR,PR and SD were 1,9 and 15. The RR and CBR were 33. 3% and 50% . The median TTP was 6. 1 months. The RR and CBR in 23 cases with bone and/ or soft tissue me-tastasis and 7 cases of liver and/ or pulmonary metastasis were 34. 8% ,52. 2% and 28. 6% ,42. 8% . The median TTP were 7. 3 and 4. 8 months in two groups(P = 0. 019). The most common adverse reactions were hot flashes,vaginal dryness,vaginal discharge,vaginal bleeding,nausea,vomiting,diarrhea and so on. Most side effects were grade Ⅰ orⅡ on the WHO scale. Conclusion:Treatment with tamoxifen in AIs resistant HR + postmenopausal patients with MBC is safe and effective,can improve prognosis of patients.%目的:探讨他莫昔芬治疗芳香化酶抑制剂(AIs)耐药的激素受体阳性(HR +)绝经后转移性乳腺癌(MBC)患者的疗效和安全性。方法:回顾性分析他莫昔芬治疗 AIs 耐药的30例 HR +绝经后 MBC 患者的临床资料,观察终点为缓解率(RR)、临床获益率(CBR)、疾病进展时间(TTP)和安全性。结果:30例患者中,CR 1例,PR 9例,SD 15例,RR 为33.3%,CBR 为50%,中位 TTP 6.1个月。23例骨和/或软组织转移患者中,RR为34.8%,CBR 为52.2%,中位 TTP 7.3 个月;7例肝脏和/或肺部转移患者中,RR 为28.6%,CBR 为42.8%,中位 TTP 4.8 个月(P =0.019)。不良反应多为面部潮红、阴道干燥、白带增多、阴道出血、恶心、呕吐、腹泻等,均为 I、II 级

  10. Cytochrome P450 aromatase expression in human seminoma

    OpenAIRE

    Montanaro Daniela; Aquila Saveria; Romeo Francesco; Rago Vittoria; Andò Sebastiano; Carpino Amalia

    2005-01-01

    Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression ...

  11. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte Lisbet; Andersson, Michael; Kamby, Claus

    2008-01-01

    There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination...... with taxanes and vinorelbine has been established. In the preoperative setting inclusion of trastuzumab has significantly increased the pathological complete response rate. Results from large phase III trials evaluating adjuvant therapy in HER2-positive early breast cancer indicate that the addition...... of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has...

  12. Novel systemic therapies for breast cancer.

    Science.gov (United States)

    Lo, Soo; Johnston, Stephen R D

    2003-12-01

    The rapid expansion in our knowledge of the molecular pathogenesis of cancer has created several opportunities for novel strategies in anti-cancer drug design and development. Recent developments have included a series of new endocrine therapies such as pure anti-oestrogens and selective oestrogen receptor modulators, and trials are in progress to determine their role in the sequence of therapies given the first-line role now occupied by the aromatase inhibitors. Novel cytotoxic drugs have been developed with an improved toxicity profile, including oral prodrugs that are activated within tumour cells, and liposomal delivery mechanisms for conventional drugs that reduce some of the systemic toxicities. There has been much success with monoclonal antibodies targeted against growth factor receptors, both as monotherapy and in enhancing the efficacy of cytotoxic drugs. A number of small molecule signal transduction inhibitors are in early stages of clinical development for breast cancer, including tyrosine-kinase inhibitors and farnesyl transferase inhibitors. Emerging pre-clinical evidence suggests that these drugs may best be used in combination with endocrine therapy. Other novel strategies that are being tested include vaccines and anti-angiogenesis drugs. As these new therapies evolve towards the clinic, the challenge to oncologists is whether their potential seen in the laboratory can be matched by further substantial improvements in clinical outcome.

  13. Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model.

    Directory of Open Access Journals (Sweden)

    Christian T Farrar

    Full Text Available MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI and a slight decrease in the water apparent diffusion coefficient (ADC were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV, relative microvascular blood volume (rMBV, transverse relaxation time (T2, blood vessel permeability (K(trans, and extravascular-extracellular space (ν(e. The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology.

  14. Plasma tissue inhibitor of matrix metalloproteinase-1 (TIMP-1): an independent predictor of poor response to cardiac resynchronization therapy

    OpenAIRE

    Tolosana, Jose María; Mont, Lluís; Sitges, Marta; Berruezo, Antonio; Delgado, Victoria; Vidal, Bàrbara; Tamborero, David; Morales, Manel; Batlle, Montserrat; Roig, Eulalia; Castel, M. Angeles; Pérez-Villa, Félix; Godoy, Miguel; Brugada, Josep

    2010-01-01

    Aims Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors of poor response to cardiac resynchronization therapy (CRT). Methods and results A cohort of 42 CRT patients from our centre was prospectively evaluated at baseline and after 12-month follow-up. MMP-2 and TIMP-1 assays were performed prior to CRT implant. Cardiac resynchronization therapy res...

  15. Medial Amygdalar Aromatase Neurons Regulate Aggression in Both Sexes

    Directory of Open Access Journals (Sweden)

    Elizabeth K. Unger

    2015-02-01

    Full Text Available Aromatase-expressing neuroendocrine neurons in the vertebrate male brain synthesize estradiol from circulating testosterone. This locally produced estradiol controls neural circuits underlying courtship vocalization, mating, aggression, and territory marking in male mice. How aromatase-expressing neuronal populations control these diverse estrogen-dependent male behaviors is poorly understood, and the function, if any, of aromatase-expressing neurons in females is unclear. Using targeted genetic approaches, we show that aromatase-expressing neurons within the male posterodorsal medial amygdala (MeApd regulate components of aggression, but not other estrogen-dependent male-typical behaviors. Remarkably, aromatase-expressing MeApd neurons in females are specifically required for components of maternal aggression, which we show is distinct from intermale aggression in pattern and execution. Thus, aromatase-expressing MeApd neurons control distinct forms of aggression in the two sexes. Moreover, our findings indicate that complex social behaviors are separable in a modular manner at the level of genetically identified neuronal populations.

  16. Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition.

    Science.gov (United States)

    Dean, Afshan; Nilsen, Margaret; Loughlin, Lynn; Salt, Ian P; MacLean, Margaret R

    2016-08-01

    Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1 Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase. PMID:27296990

  17. Glycolytic inhibitors 2-deoxyglucose and 3-bromopyruvate synergize with photodynamic therapy respectively to inhibit cell migration.

    Science.gov (United States)

    Feng, Xiaolan; Wang, Pan; Liu, Quanhong; Zhang, Ting; Mai, Bingjie; Wang, Xiaobing

    2015-06-01

    Most cancer cells have the specially increased glycolytic phenotype, which makes this pathway become an attractive therapeutic target. Although glycolytic inhibitor 2-deoxyglucose (2-DG) has been demonstrated to potentiate the cytotoxicity of photodynamic therapy (PDT), the impacts on cell migration after the combined treatment has never been reported yet. The present study aimed to analyze the influence of glycolytic inhibitors 2-DG and 3-bromopyruvate (3-BP) combined with Ce6-PDT on cell motility of Triple Negative Breast Cancer MDA-MB-231 cells. As determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium-bromide-Tetraz-olium (MTT) assay, more decreased cell viability was observed in 2-DG + PDT and 3-BP + PDT groups when compared with either monotherapy. Under optimal conditions, synergistic potentiation on cell membrane destruction and the decline of cell adhesion and cells migratory ability were observed in both 2-DG + PDT and 3-BP + PDT by electron microscope observation (SEM), wound healing and trans-well assays. Besides, serious microfilament network collapses as well as impairment of matrix metalloproteinases-9 (MMP-9) were notably improved after the combined treatments by immunofluorescent staining. These results suggest that 2-DG and 3-BP can both significantly potentiated Ce6-PDT efficacy of cell migration inhibition. PMID:25631472

  18. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis

    NARCIS (Netherlands)

    Ramcharan, A.S.; Stralen, van K.J.; Snoep, J.D.; Mantel-Teeuwisse, A.K.; Doggen, C.J.M.

    2009-01-01

    Background: Statins [3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti-inflammatory properties, and anti-platelet therap

  19. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin

    Directory of Open Access Journals (Sweden)

    Capuano A

    2013-09-01

    Full Text Available Annalisa Capuano,1 Liberata Sportiello,1 Maria Ida Maiorino,2 Francesco Rossi,1 Dario Giugliano,2 Katherine Esposito3 1Department of Experimental Medicine, 2Department of Medical, Surgical, Neurological, Metabolic Sciences, and Geriatrics, 3Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy Abstract: Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4 slows degradation of endogenous glucagon-like peptide-1 (GLP-1 and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug–drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c decrease of 0.5%–0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control

  20. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats.

    Science.gov (United States)

    Kojima, Naoki; Williams, Jan M; Slaughter, Tiffani N; Kato, Sota; Takahashi, Teisuke; Miyata, Noriyuki; Roman, Richard J

    2015-07-01

    This study examined whether control of hyperglycemia with a new SGLT2 inhibitor, luseogliflozin, given alone or in combination with lisinopril could prevent the development of renal injury in diabetic Dahl salt-sensitive (Dahl S) rats treated with streptozotocin (Dahl-STZ). Blood glucose levels increased from normoglycemic to hyperglycemic levels after treatment of STZ in Dahl S rats. Chronic treatment of Dahl-STZ rats with luseogliflozin (10 mg/kg/day) increased the fractional excretion of glucose and normalized blood glucose and HbA1c levels. Lisinopril (20 mg/kg/day) reduced blood pressure from 145 ± 9 to 120 ± 5 mmHg in Dahl-STZ rats, while luseogliflozin had no effect on blood pressure. Combination therapy reduced blood pressure more than that seen in the rats treated with luseogliflozin or lisinopril alone. Dahl-STZ rats exhibited hyperfiltration, mesangial matrix expansion, severe progressive proteinuria, focal glomerulosclerosis and interstitial fibrosis. Control of hyperglycemia with luseogliflozin reduced the degree of hyperfiltration and renal injury but had no effect on blood pressure or the development of proteinuria. Treatment with lisinopril reduced hyperfiltration, proteinuria and renal injury in Dahl-STZ rats. Combination therapy afforded greater renoprotection than administration of either drug alone. These results suggest that long-term control of hyperglycemia with luseogliflozin, especially in combination with lisinopril to lower blood pressure, attenuates the development of renal injury in this rat model of advanced diabetic nephropathy. PMID:26169541

  1. Organizing effects of sex steroids on brain aromatase activity in quail.

    Directory of Open Access Journals (Sweden)

    Charlotte A Cornil

    Full Text Available Preoptic/hypothalamic aromatase activity (AA is sexually differentiated in birds and mammals but the mechanisms controlling this sex difference remain unclear. We determined here (1 brain sites where AA is sexually differentiated and (2 whether this sex difference results from organizing effects of estrogens during ontogeny or activating effects of testosterone in adulthood. In the first experiment we measured AA in brain regions micropunched in adult male and female Japanese quail utilizing the novel strategy of basing the microdissections on the distribution of aromatase-immunoreactive cells. The largest sex difference was found in the medial bed nucleus of the stria terminalis (mBST followed by the medial preoptic nucleus (POM and the tuberal hypothalamic region. A second experiment tested the effect of embryonic treatments known to sex-reverse male copulatory behavior (i.e., estradiol benzoate [EB] or the aromatase inhibitor, Vorozole on brain AA in gonadectomized adult males and females chronically treated as adults with testosterone. Embryonic EB demasculinized male copulatory behavior, while vorozole blocked demasculinization of behavior in females as previously demonstrated in birds. Interestingly, these treatments did not affect a measure of appetitive sexual behavior. In parallel, embryonic vorozole increased, while EB decreased AA in pooled POM and mBST, but the same effect was observed in both sexes. Together, these data indicate that the early action of estrogens demasculinizes AA. However, this organizational action of estrogens on AA does not explain the behavioral sex difference in copulatory behavior since AA is similar in testosterone-treated males and females that were or were not exposed to embryonic treatments with estrogens.

  2. Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report

    Directory of Open Access Journals (Sweden)

    Baumann Gert

    2005-09-01

    Full Text Available Abstract background Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare. Case presentation We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy. Conclusion This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.

  3. Motion and flexibility in human cytochrome p450 aromatase.

    Directory of Open Access Journals (Sweden)

    Wenhua Jiang

    Full Text Available The crystal structures of human placental aromatase in complex with the substrate androstenedione and exemestane have revealed an androgen-specific active site and the structural basis for higher order organization. However, X-ray structures do not provide accounts of movements due to short-range fluctuations, ligand binding and protein-protein association. In this work, we conduct normal mode analysis (NMA revealing the intrinsic fluctuations of aromatase, deduce the internal modes in membrane-free and membrane-integrated monomers as well as the intermolecular modes in oligomers, and propose a quaternary organization for the endoplasmic reticulum (ER membrane integration. Dynamics of the crystallographic oligomers from NMA is found to be in agreement with the isotropic thermal factors from the X-ray analysis. Calculations of the root mean square fluctuations of the C-alpha atoms from their equilibrium positions confirm that the rigid-core structure of aromatase is intrinsic regardless of the changes in steroid binding interactions, and that aromatase self-association does not deteriorate the rigidity of the catalytic cleft. Furthermore, NMA on membrane-integrated aromatase shows that the internal modes in all likelihood contribute to breathing of the active site access channel. The collective intermolecular hinge bending and twisting modes provide the flexibility in the quaternary association necessary for membrane integration of the aromatase oligomers. Taken together, fluctuations of the active site, the access channel, and the heme-proximal cavity, and a dynamic quaternary organization could all be essential components of the functional aromatase in its role as an ER membrane-embedded steroidogenic enzyme.

  4. Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.

    Science.gov (United States)

    Frew, Ailsa J; Lindemann, Ralph K; Martin, Ben P; Clarke, Christopher J P; Sharkey, Janelle; Anthony, Desiree A; Banks, Kellie-Marie; Haynes, Nicole M; Gangatirkar, Pradnya; Stanley, Kym; Bolden, Jessica E; Takeda, Kazuyoshi; Yagita, Hideo; Secrist, J Paul; Smyth, Mark J; Johnstone, Ricky W

    2008-08-12

    Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.

  5. Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review.

    Science.gov (United States)

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c) itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3-5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs) are associated with weight gain and hypoglycemia, pioglitazone increases body weight and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin. PMID:26904466

  6. Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2016-01-01

    Full Text Available The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3–5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs are associated with weight gain and hypoglycemia, pioglitazone increases body weigh and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I and sodium-glucose co-transporter-2 inhibitors (SGLT-2I are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin.

  7. Systemic therapy for endometrial stromal sarcomas: current treatment options.

    Science.gov (United States)

    Serkies, Krystyna; Pawłowska, Ewa; Jassem, Jacek

    2016-01-01

    Uterine endometrial stromal sarcomas including true low-grade endometrial stromal sarcoma (LG-ESS) and high-grade (HG-ESS) or undifferentiated endometrial sarcoma (UES) constitute a group of rare, aggressive malignancies. Most LG-ESSs express steroid receptors. Surgery is the principal primary therapy for endometrial stromal sarcomas and should be considered in all cases. These malignancies are relatively radio- and chemoresistant. Chemotherapy is used in recurrent and advanced HG-ESS and UES. Currently, the combination of gemcitabine and docetaxel is considered the most effective regimen, but at the expense of substantial toxicity. In steroid receptor positive advanced LG-ESS hormonal therapy, mainly with progestins, allows in some patients for a long-term survival. Aromatase inhibitors seem to be equally effective as first- and subsequent-line of treatment, and are well tolerated. The role of molecular-targeted therapies in endometrial stromal sarcomas remains to be established. PMID:27629136

  8. KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

    Directory of Open Access Journals (Sweden)

    Natacha Coen

    2014-11-01

    Full Text Available Kaposi’s sarcoma-associated herpesvirus (KSHV is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing.

  9. Enhancement of the efficiency of photodynamic therapy by combination with the microtubule inhibitor vincristine

    Science.gov (United States)

    Ma, Li Wei; Berg, Kristian; Danielsen, Havard E.; Iani, Vladimir; Moan, Johan

    1996-01-01

    Combination effects of photodynamic therapy (PDT) with meso-tetra (di-adjacent- sulfonatophenyl) porphine (TPPS2a) and the microtubule (MT) inhibitor, vincristine (VCR), were studied in the CaD2 mouse tumor model in mice. A synergistic effect was found when VCR, at an almost nontoxic dose (1 mg/kg), was injected i.p. into the mice 6 hr before PDT. The data on mitotic index show a 4 - 5 fold accumulation of the cells in mitosis 6 hr after injection of VCR into the mice. Cell cycle and ploidy distributions in tumor tissues were determined by means of image analysis with measurement of integrated optical density after Feulgen reaction on monolayers. Ploidy distribution of the tumors was not significantly changed 6 and 12 hr after administration of VCR only, while an increasing aneuploidy was observed 24 and 48 hr after VCR treatment. No prominent changes of the cell cycle and ploidy distributions were found in the tumor tissues after PDT or PDT combined with VCR.

  10. Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy

    Science.gov (United States)

    Petrushev, Bobe; Boca, Sanda; Simon, Timea; Berce, Cristian; Frinc, Ioana; Dima, Delia; Selicean, Sonia; Gafencu, Grigore-Aristide; Tanase, Alina; Zdrenghea, Mihnea; Florea, Adrian; Suarasan, Sorina; Dima, Liana; Stanciu, Raluca; Jurj, Ancuta; Buzoianu, Anca; Cucuianu, Andrei; Astilean, Simion; Irimie, Alexandru; Tomuleasa, Ciprian; Berindan-Neagoe, Ioana

    2016-01-01

    Background and aims Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles. Materials and methods The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay. Results We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein. Conclusion The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic. PMID:26929621

  11. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: A systematic review of current evidence

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2016-01-01

    Full Text Available As type 2 diabetes mellitus (T2DM is a chronic and progressive disease with multiple pathophysiologic defects, no single anti-diabetic agent can tackle all these multi-factorial pathways. Consequently, multiple agents working through the different mechanisms will be required for the optimal glycemic control. Moreover, the combination therapies of different anti-diabetic agents may complement their actions and possibly act synergistic. Furthermore, these combinations could possess the additional properties to counter their undesired physiological compensatory response. Sodium-glucose co-transporter-2 inhibitors (SGLT-2I are newly emerging class of drugs, with a great potential to reduce glucose effectively with an additional quality of lowering cardiovascular events as demonstrated very recently by one of the agents of this class. However, increase in endogenous glucose production (EGP from the liver, either due to the increase in glucagon or compensatory response to glucosuria can offset the glucose-lowering potential of SGLT-2I. Interestingly, another class of drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4I effectively decrease glucagon and reduce EGP. In light of these findings, combination therapies with SGLT-2I and DPP-4I are particularly appealing and are expected to produce a synergistic effect. Preclinical studies of combination therapies with DPP-4I and SGLT-2I have already demonstrated a significant lowering of hemoglobin A1c potential and human studies also find no drug-drug interaction between these agents. This article aims to systematically review the efficacy and safety of combination therapy of SGLT-2I and DPP-4I in T2DM.

  12. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: A systematic review of current evidence.

    Science.gov (United States)

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    As type 2 diabetes mellitus (T2DM) is a chronic and progressive disease with multiple pathophysiologic defects, no single anti-diabetic agent can tackle all these multi-factorial pathways. Consequently, multiple agents working through the different mechanisms will be required for the optimal glycemic control. Moreover, the combination therapies of different anti-diabetic agents may complement their actions and possibly act synergistic. Furthermore, these combinations could possess the additional properties to counter their undesired physiological compensatory response. Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are newly emerging class of drugs, with a great potential to reduce glucose effectively with an additional quality of lowering cardiovascular events as demonstrated very recently by one of the agents of this class. However, increase in endogenous glucose production (EGP) from the liver, either due to the increase in glucagon or compensatory response to glucosuria can offset the glucose-lowering potential of SGLT-2I. Interestingly, another class of drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4I) effectively decrease glucagon and reduce EGP. In light of these findings, combination therapies with SGLT-2I and DPP-4I are particularly appealing and are expected to produce a synergistic effect. Preclinical studies of combination therapies with DPP-4I and SGLT-2I have already demonstrated a significant lowering of hemoglobin A1c potential and human studies also find no drug-drug interaction between these agents. This article aims to systematically review the efficacy and safety of combination therapy of SGLT-2I and DPP-4I in T2DM. PMID:27042423

  13. Aromatase immunolocalization in human ductuli efferentes and proximal ductus epididymis.

    Science.gov (United States)

    Carpino, A; Romeo, F; Rago, V

    2004-03-01

    Abstract Cytochrome P450 aromatase is a terminal enzyme that catalyses the conversion of androgens into oestrogens. This study investigated the immunohistochemical localization of aromatase in human efferent ductules and proximal ductus epididymis using a mouse anti-human monoclonal P450arom IgG as primary antibody and a goat anti-mouse biotinylated IgG as secondary antibody. A strong immunoreaction was observed in the epithelial cell cytoplasm of both ductuli efferentes and proximal ductus epididymis, whereas the smooth muscle cells were immunonegative in the two regions. The results show, for the first time in humans, that epithelial cells of ductuli efferentes and proximal caput epididymis express aromatase, suggesting that locally produced oestrogens may have a role in epididymal function. PMID:15032911

  14. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis

    Science.gov (United States)

    Liang, Hui; Li, Wen-Rong; Zhang, Hua; Tian, Xu; Wei, Wei; Wang, Chun-Mei

    2015-01-01

    Abstract Since the use of tumor necrosis factor (TNF) inhibitor therapy is becoming wider, the effects of concurrent intervention with exercises and stabilized TNF inhibitors therapy in patients with ankylosing spondylitis (AS) are different. The study aimed to objectively evaluate whether concurrent intervention with exercises and stabilized TNF inhibitors can reduce the disease activity in patients with AS. A search from PubMed, Web of Science, EMBASE, and the Cochrane Library was electronically performed to collect studies which compared concurrent intervention with exercise and TNF inhibitor to conventional approach in terms of disease activity in patients with AS published from their inception to June 2015. Studies that measured the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), and chest expansion as outcomes were included. Two independent investigators screened the identified articles, extracted the data, and assessed the methodological quality of the included studies. Quantitative analysis was performed with Review Manager (RevMan) software (version 5.3.0). A total of 5 studies comprising 221 participants were included in the study. Meta-analyses showed that concurrent intervention with exercises and stabilized TNF inhibitors therapy significantly reduced the BASMI scores (MD, −0.99; 95% CI, −1.61 to −0.38) and BASDAI scores (MD, −0.58; 95% CI, −1.10 to −0.06), but the BASFI scores (MD, −0.31; 95% CI, −0.76 to 0.15) was not reduced, and chest expansion (MD, 0.80; 95% CI, −0.18 to 1.78) was not increased. Concurrent intervention with exercises and stabilized TNF inhibitors therapy can reduce the disease activity in patients with AS. More randomized controlled trials (RCTs) with high-quality, large-scale, and appropriate follow-up are warranted to further establish the benefit of concurrent intervention with

  15. Rational combination of targeted therapies as a strategy to overcome the mechanisms of resistance to inhibitors of EGFR signaling.

    Science.gov (United States)

    Bianco, Roberto; Damiano, Vincenzo; Gelardi, Teresa; Daniele, Gennaro; Ciardiello, Fortunato; Tortora, Giampaolo

    2007-01-01

    The epidermal growth factor receptor (EGFR) has been widely used as a target for novel anticancer agents, such as blocking antibodies and small molecular weight tyrosine kinase compounds. In spite of recent advances in cancer cell biology, leading to the introduction of clinically active new drugs, such as cetuximab, panitumumab and erlotinib, unfortunately disease control remains unsuccessful due to the presence of constitutive resistance to EGFR inhibitors in most patients and the development of acquired resistance in the responders. A large number of molecular abnormalities in tumor cells seem to partly contribute to their resistance to anti-EGFR therapy: increased angiogenesis, constitutive activation of downstream mediators, overexpression of other tyrosine kinase receptors. Moreover, some mutations in the EGFR receptor kinase domain seem to play a crucial role in determining the sensitivity of cancer cells to specific inhibitors by altering the conformation of the receptor and its activity. The development of rational combinations of anticancer agents and EGFR inhibitors, able to exert synergistic cytotoxic interactions, has been widely accepted and used in both preclinical and clinical studies. Although the failure of large clinical trial based on empirical combination of anti-EGFR and classic chemotherapeutic agents, several preclinical data seems to support the hypothesis that combining EGFR inhibitors and other novel agents could efficiently inhibit tumor growth and overcome intrinsic resistance to a single-agent based therapy. This review focuses on the role of complementary signalling pathways in the development of resistance to EGFR targeting agents and the rationale to combine novel inhibitors as anticancer therapy.

  16. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex ...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  17. Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

    OpenAIRE

    Karamchand, Sumanth; Leisegang, Rory; Schomaker, Michael; Maartens, Gary; Walters, Lourens; Hislop, Michael; Dave, Joel A; Naomi S Levitt; Cohen, Karen

    2016-01-01

    Abstract Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern Africa...

  18. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Ankylosing Spondylitis.

    Directory of Open Access Journals (Sweden)

    Inês P Perpétuo

    Full Text Available Ankylosing Spondylitis (AS is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC in AS patients.13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed.RANKL+ circulating lymphocytes (B and T cells and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline.In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.

  19. 乳腺癌内分泌药物治疗的研究进展%Research advances in new endocrine therapy drugs of breast cancer

    Institute of Scientific and Technical Information of China (English)

    蒋维平

    2013-01-01

    Breast cancer is one of malignant tumors that seriously impact women's physical and mental health and even cause death. The traditional endocrine therapy drugs of breast cancer are estrogen receptor modulators and aromatase inhibitors that act on metabolic pathway of endogenous estrogenic steroids. The objective of the research on this class of drugs is to find new aromatase inhibitors with tissue selectivity, high efficacy and low toxic-ity. Novel steroid sulfatase inhibitors are effective hormone dependent breast cancer (HDBC) treatment drugs. Sul-famate moiety is confirmed to be the pharmacophore of these drugs. This article reviews research advances in aromatase inhibitors and steroid sulfatase inhibitors.%乳腺癌是严重影响妇女身心健康甚至危及生命的恶性肿瘤之一.传统的乳腺癌内分泌治疗药物是作用于雌激素环节的雌激素受体调节剂、芳香化酶抑制剂,但芳香化酶抑制剂的选择性较差,有中度的治疗相关毒性,如高血脂、骨丢失、肝脂肪化等,因此需要开发具有组织选择性、高效低毒的芳香化酶抑制剂.此外,新型的甾体硫酸酯酶抑制剂也已成为有效的激素依赖性乳腺癌(HDBC)治疗药物,氨基磺酸酯基团被证实是这类药物中的药效团.本文综述了芳香化酶抑制剂和硫酸酯酶抑制剂的研究进展.

  20. Aromatase, estrogen receptors and brain development in fish and amphibians.

    Science.gov (United States)

    Coumailleau, Pascal; Pellegrini, Elisabeth; Adrio, Fátima; Diotel, Nicolas; Cano-Nicolau, Joel; Nasri, Ahmed; Vaillant, Colette; Kah, Olivier

    2015-02-01

    Estrogens affect brain development of vertebrates, not only by impacting activity and morphology of existing circuits, but also by modulating embryonic and adult neurogenesis. The issue is complex as estrogens can not only originate from peripheral tissues, but also be locally produced within the brain itself due to local aromatization of androgens. In this respect, teleost fishes are quite unique because aromatase is expressed exclusively in radial glial cells, which represent pluripotent cells in the brain of all vertebrates. Expression of aromatase in the brain of fish is also strongly stimulated by estrogens and some androgens. This creates a very intriguing positive auto-regulatory loop leading to dramatic aromatase expression in sexually mature fish with elevated levels of circulating steroids. Looking at the effects of estrogens or anti-estrogens in the brain of adult zebrafish showed that estrogens inhibit rather than stimulate cell proliferation and newborn cell migration. The functional meaning of these observations is still unclear, but these data suggest that the brain of fish is experiencing constant remodeling under the influence of circulating steroids and brain-derived neurosteroids, possibly permitting a diversification of sexual strategies, notably hermaphroditism. Recent data in frogs indicate that aromatase expression is limited to neurons and do not concern radial glial cells. Thus, until now, there is no other example of vertebrates in which radial progenitors express aromatase. This raises the question of when and why these new features were gained and what are their adaptive benefits. This article is part of a Special Issue entitled: Nuclear receptors in animal development.

  1. Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

    Directory of Open Access Journals (Sweden)

    Alberto F Rubio-Guerra

    2009-11-01

    Full Text Available Alberto F Rubio-Guerra1, David Castro-Serna2, Cesar I Elizalde Barrera2, Luz M Ramos-Brizuela21Metabolic and Research Clinic, 2Internal Medicine Department, Hospital General de Ticomán SS DF, MéxicoAbstract: Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.Keywords: hypertension, calcium channel blockers, renin-angiotensin-aldosterone system inhibitors, fixed-dose combination, adherence

  2. Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf-DAPK Complex by Raf Inhibitor Combination Therapy.

    Science.gov (United States)

    Tsai, Yi-Ta; Chuang, Mei-Jen; Tang, Shou-Hung; Wu, Sheng-Tang; Chen, Yu-Chi; Sun, Guang-Huan; Hsiao, Pei-Wen; Huang, Shih-Ming; Lee, Hwei-Jen; Yu, Cheng-Ping; Ho, Jar-Yi; Lin, Hui-Kuan; Chen, Ming-Rong; Lin, Chung-Chih; Chang, Sun-Yran; Lin, Victor C; Yu, Dah-Shyong; Cha, Tai-Lung

    2015-09-01

    Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK(S308)), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF(C-Raf-/-) or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK(S308), this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf(S338) and pDAPK(S308) translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK(S308) to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK(S308) modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK(S308) may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation.

  3. Adjuvant therapy for highly malignant canine mammary tumours: Cox-2 inhibitor versus chemotherapy: a case-control prospective study.

    Science.gov (United States)

    Arenas, C; Peña, L; Granados-Soler, J L; Pérez-Alenza, M D

    2016-07-30

    Cyclooxygenase-2 (Cox-2) enzyme participates in different steps of the carcinogenetic process and in canine mammary tumours (CMTs), a high expression of Cox-2 is associated with malignancy and tumour angiogenesis. The objectives of the study were to evaluate the disease-free survival (DFS) and overall survival (OS) of a Cox-2 inhibitor as adjuvant therapy in dogs with highly malignant (HM)-CMTs and compare it with that of dogs treated with chemotherapy and with control dogs. Twenty-eight dogs were prospectively included. After surgery, dogs were alternatively allocated into two treatment groups (chemotherapy with mitoxantrone n=8; Cox-2 inhibitor, firocoxib n=7). Control group (n=13) included dogs whose owners rejected adjuvant therapy. All dogs were followed up for two years or until death. The DFS was significantly higher in dogs that received adjuvant treatment (mitoxantrone or firocoxib) (P=0.030) than in control dogs. Dogs on firocoxib treatment had significantly higher DFS (P=0.015) and OS (P=0.048) than control dogs. The DFS and OS of dogs on mitoxantrone treatment were not statistically different from controls. In conclusion, this study supports the use of firocoxib for the treatment of HM-CMTs. Further studies are needed to compare the efficacy of chemotherapy drugs versus Cox-2 inhibitors as adjuvant treatment in these cases. PMID:27377395

  4. Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy

    Directory of Open Access Journals (Sweden)

    Petrushev B

    2016-02-01

    Full Text Available Bobe Petrushev,1,* Sanda Boca,2,* Timea Simon,2 Cristian Berce,3 Ioana Frinc,4 Delia Dima,4 Sonia Selicean,3 Grigore-Aristide Gafencu,3 Alina Tanase,5 Mihnea Zdrenghea,4,6 Adrian Florea,7 Sorina Suarasan,2 Liana Dima,8 Raluca Stanciu,3 Ancuta Jurj,1 Anca Buzoianu,9 Andrei Cucuianu,4,6,† Simion Astilean,2,10 Alexandru Irimie,11,12 Ciprian Tomuleasa,1,4 Ioana Berindan-Neagoe1,131Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 2Nanobiophotonics and Laser Microscopy Center, Babes Bolyai University, 3Department of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, 5Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, 6Department of Hematology, 7Department of Cell and Molecular Biology, 8School of Dentistry, 9Department of Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 10Faculty of Physics, Babes Bolyai University, 11Department of Surgery, Ion Chiricuta Oncology Institute, 12Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 13Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA*These authors contributed equally to this work†This author passed away in February 2015Background and aims: Every year, in Europe, acute myeloid leukemia (AML is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs that inhibit FLT3 kinase. In this study, we report the

  5. PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications.

    Science.gov (United States)

    Drew, Yvette; Plummer, Ruth

    2009-12-01

    The abundant nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1) represents an important novel target in cancer therapy. PARP-1 is essential to the repair of single strand DNA breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionising radiation and DNA damaging chemotherapy agents such as the methylating agents and topoisomerase-I inhibitors. There are currently at least eight PARP inhibitors in clinical trial development. In vitro data, in vivo preclinical data and most recently early clinical trial data suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA)1 and BRCA2 genes. This theory of selectively exploiting cells defective in one DNA repair pathway by inhibiting another is a major breakthrough in the treatment of cancer. The current clinical data are discussed within this review with reference to the preclinical models which predicted activity and also future directions and the possible dangers/pitfalls of this clinical strategy are explored.

  6. Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

    Science.gov (United States)

    Jones, Katherine; Meier, Julia; Olzscha, Heidi; Monteiro, Octovia; Martin, Sarah; Philpott, Martin; Tumber, Anthony; Filippakopoulos, Panagis; Yapp, Clarence; Wells, Christopher; Che, Ka Hing; Bannister, Andrew; Robson, Samuel; Kumar, Umesh; Parr, Nigel; Lee, Kevin; Lugo, Dave; Jeffrey, Philip; Taylor, Simon; Vecellio, Matteo L.; Bountra, Chas; Brennan, Paul E.; O’Mahony, Alison; Velichko, Sharlene; Müller, Susanne; Hay, Duncan; Daniels, Danette L.; Urh, Marjeta; La Thangue, Nicholas B.; Kouzarides, Tony; Prinjha, Rab; Schwaller, Jürg; Knapp, Stefan

    2016-01-01

    The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ AML cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. PMID:26552700

  7. Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

    Directory of Open Access Journals (Sweden)

    Randhawa Jasleen

    2012-08-01

    Full Text Available Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF, post-polycythemia vera myelofibrosis (post-PV MF, and post-essential thrombocythemia myelofibrosis (post-ET MF that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV or essential thrombocythemia (ET. Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2 activating mutation (JAK2V617F that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2 inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

  8. Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis

    Science.gov (United States)

    Low, Audrey S. L.; Lunt, Mark; Mercer, Louise K.; Watson, Kath D.; Dixon, William G.; Symmons, Deborah P. M.

    2016-01-01

    Objective Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30‐day and 1‐year mortality after ischemic stroke. Methods Patients with RA starting therapy with TNFi and a biologics‐naive comparator group treated with synthetic disease‐modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever‐exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD–treated patients and TNFi‐treated patients using logistic regression, adjusted for age and sex. Results To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD–treated patients and 106 in 11,642 TNFi‐treated patients) occurred during 11,973 and 61,226 person‐years of observation, respectively (incidence rate 175 versus 173 per 100,000 person‐years). After adjustment for confounders, there was no association between ever‐exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54–1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03–1.21] and 0.60 [95

  9. Focus on acetylation: the role of histone deacetylase inhibitors in cancer therapy and beyond.

    Science.gov (United States)

    Konstantinopoulos, Panagiotis A; Karamouzis, Michalis V; Papavassiliou, Athanasios G

    2007-05-01

    Reversal of tumorigenic epigenetic alterations is an exciting strategy for anticancer drug development. Pharmacologic inhibition of histone deacetylases (HDACs) induces differentiation, proliferation arrest and apoptosis of cancer cells. In addition to their effects on histones, HDAC inhibitors increase the acetylation level of several non-histone proteins, such as transcription factors, cytoskeletal proteins and molecular chaperones, which are crucial in tumorigenesis. Most importantly, the therapeutic potential of HDAC inhibitors goes well beyond carcinogenesis and may include neurodegenerative and inflammatory disorders. This editorial discusses the implication of HDACs in carcinogenesis, the molecular basis of the selectivity of HDAC inhibitors and their possible therapeutic role in non-malignant pathologic conditions.

  10. Endocrine therapy use among elderly hormone receptor-pos...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators or aromatase...

  11. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3 inhibitor therapy with evolving actionable targets

    Directory of Open Access Journals (Sweden)

    Pashtoon M. Kasi

    2016-01-01

    Full Text Available For acute myeloid leukemia (AML, identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3 has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215 to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (Clinical Trial: NCT02014558; registered at: 〈https://clinicaltrials.gov/ct2/show/NCT02014558〉

  12. EFFECTS OF p53 GENE THERAPY COMBINED WITH CYCLOOXYGENASE-2 INHIBITOR ON CYCLOOXYGENASE-2 GENE EXPRESSION AND GROWTH INHIBITION OF HUMAN LUNG CANCER CELLS

    Institute of Scientific and Technical Information of China (English)

    WANG Zhao-Xia; LU Bin-Bin; WANG Teng; YIN Yong-Mei; DE Wei; SHU Yong-Qian

    2007-01-01

    Background Gene therapy by adenovirus-mediated wild-type p53 gene transfer has been shown to inhibit lung cancer growth in vitro, in animal models, and in human clinical trials. The antitumor effect of selective cyclooxygenase (COX)-2 inhibitors has been demonstrated in preclinical studies. However, no information is available on the effects of p53 gene therapy combined with selective COX-2 inhibitor on COX-2 gene expression and growth inhibition of human lung cancer cells. Methods We evaluated the effects of recombinant adenovirus-p53 (Ad-p53) gene therapy combined with selective COX-2 inhibitor on the proliferation, apoptosis, cell cycle arrest of human lung adenocarcinoma A549 cell line, and the effects of tumor suppressor exogenous wild type p53 on COX-2 gene expression. Results Ad-p53 gene therapy combined with selective COX-2 inhibitor celecoxib shows significant synergistic inhibition effects on the growth of human lung adenocarcinoma A549 cell line. Exogenous p53 gene can suppress COX-2 gene expression. Conclusions Significant synergistic inhibition effects of A549 cell line by the combined Ad-p53 and selective COX-2 inhibitor celecoxib may be achieved by enhancement of growth inhibition, apoptosis induction and suppression of COX-2 gene expression. This study provides first evidence that the administration of p53 gene therapy in combination with COX-2 inhibitors might be a new clinical strategy for the treatment or prevention of NSCLC.

  13. Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system

    Directory of Open Access Journals (Sweden)

    MacLean Charles D

    2008-12-01

    Full Text Available Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE. ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly selected from community practices. Patients were interviewed at home and self-reported their personal and clinical characteristics including comorbidity. Current medications were obtained by direct observation of medication containers. We built logistic regression models with the history of comorbidities as the outcome variable and the current use of ACE inhibitors as the primary predictor variable. We adjusted for possible confounding by social (age, sex, alcohol drinking, cigarette smoking and clinical factors (systolic blood pressure, body mass index (BMI, glycosolated hemoglobin (A1C, number of comorbid conditions, and number of prescription medications. Results ACE users reported a history of any cancer (except the non-life-threatening skin cancers less frequently than non-users (10% vs. 15%; odd ratio = 0.59; 95% confidence interval [0.39, 0.89]; P = 0.01; and a history of stomach ulcers or peptic ulcer disease less frequently than non-users (12% vs. 16%, odd ratio = 0.70, [0.49, 1.01], P = 0.06. After correcting for potential confounders, ACE inhibitors remained significantly inversely associated with a personal history of cancer (odds ratio = 0.59, [0.39, 0.89]; P = 0.01 and peptic ulcer disease (odd ratio = 0.68, [0.46, 1.00], P = 0.05. Conclusion ACE inhibitor use is associated with a lower likelihood of a history of cancer and peptic ulcers in patients with diabetes. These findings are limited by the cross sectional study design, self-report of comorbid

  14. TCPs: privileged scaffolds for identifying potent LSD1 inhibitors for cancer therapy.

    Science.gov (United States)

    Zheng, Yi-Chao; Yu, Bin; Chen, Zhe-Sheng; Liu, Ying; Liu, Hong-Min

    2016-05-01

    Since the first lysine-specific demethylase (KDM), lysine-specific demethylase 1 (LSD1), was characterized in 2004, several families of KDMs have been identified. LSD1 can specifically demethylate H3K4me1/2, H3K9me1/2 as well as some nonhistone substrates. It has been demonstrated to be an oncogene as well as a drug target. Hence, tens of small-molecule LSD1 inhibitors have been designed, synthesized and applied for cancer treatment. However, the two LSD1 inhibitors that have been advanced into early phase clinical trials are trans-2-phenylcyclopropylamine (TCP) derivatives, which indicate that TCP is a druggable scaffold for LSD1 inhibitor. Here, we review the design, synthesis and properties of reported TCP-based LSD1 inhibitors as well as their biological roles. PMID:27102879

  15. Liver injury in HIV-1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy

    Institute of Scientific and Technical Information of China (English)

    LI Zai-cun; LI Hong-jun; DAI Li-li; GAO Yan-qing; CAI Wei-ping; LI Hai-ying; HUANG Xiao-jie; ZHANG Tong; WU Hao

    2010-01-01

    Background Liver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients receiving antiretroviral therapy are limited in China. The purpose of this study was to investigate the features of liver injury in human immunodeficiency virus type 1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy in China.Methods Seventy-five patients on antiretroviral therapy containing non-nucleosides reverse transcriptase inhibitors were retrospectively studied. The patients were divided into 2 groups: group 1 (with liver injury, n=45) and group 2(without liver injury, n=30). The features of liver injury were analyzed. The sex, age, baseline CD4 counts, hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection, hepatotoxic drug use and nevirapine or efavirenz use were compared between two groups.Results Forty-five patients (60.0%), 31 (68.9%) males and 14 (31.1%) females, aged 12 to 52 years (averaged (3g±9)years), experienced at least one episode of liver injury. Forty (53.3%) patients were co-infected with HBV and/or HCV, 42 (56%) patients had concomitant use of antituberculosis drugs or cotrimoxazole, 46 (61.3%) and 29 (38.7%) patients received regimen containing nevirapine and efavirenz, respectively. Grade 1 liver injuries were observed in 26 (57.8%)patients, grade 2 in 16 (35.6%), grade 3 in 2 (4.0%) and grade 4 in 1 (2.2%). Three (6.7%) patients discontinued highly active antiretroviral therapy (HAART) due to liver injury. In group 1, there were 29 (64.4%) patients co-infected with HBV and/or HCV, 32 (71.1%) patients received regimen containing nevirapine, and 30 (66.7%) patients had concomitant use of anti-tuberculosis drugs or cotrimoxazole, respectively, significantly higher than those in group 2 (11 (36.7%), 14 (46.7%)and 12 (40%), respectively; P=0.018, 0.033, 0

  16. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis

    OpenAIRE

    Semren, Nora; Habel-Ungewitter, Nunja C.; Fernandez, Isis E.; Königshoff, Melanie; Eickelberg, Oliver; Stöger, Tobias; Meiners, Silke

    2015-01-01

    Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ), provides antifibrotic effects without systemic toxicity in a mouse model of lu...

  17. Methods for Investigation of Targeted Kinase Inhibitor Therapy using Chemical Proteomics and Phosphorylation Profiling

    OpenAIRE

    Fang, Bin; Haura, Eric B.; Smalley, Keiran S.; Eschrich, Steven A.; Koomen, John M.

    2010-01-01

    Phosphorylation acts as a molecular switch for many regulatory events in signaling pathways that drive cell division, proliferation, and apoptosis. Because of the critical nature of these protein post-translational modifications in cancer, drug development programs often focus on inhibitors for kinases and phosphatases, which control protein phosphorylation. Numerous kinase inhibitors have entered clinical use, but prediction of their efficacy and a molecular basis for patient response remain...

  18. Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor

    DEFF Research Database (Denmark)

    Bladbjerg, E-M; Skouby, S O.; Andersen, L F;

    2002-01-01

    BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor...... pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen...

  19. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

    Directory of Open Access Journals (Sweden)

    Jerusalem G

    2014-04-01

    Full Text Available Guy Jerusalem, Andree Rorive, Joelle Collignon Medical Oncology, CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, Liege, Belgium Abstract: Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2 therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus. This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease. Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is

  20. Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts.

    Science.gov (United States)

    Chottanapund, Suthat; Van Duursen, M B M; Navasumrit, Panida; Hunsonti, Potchanee; Timtavorn, Supatchaya; Ruchirawat, Mathuros; Van den Berg, Martin

    2014-10-01

    Targeting the estrogen pathway has been proven effective in the treatment for estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment. PMID:24929094

  1. Differential expression of genes for aromatase and estrogen receptor during the gonadal development in chicken embryos.

    Science.gov (United States)

    Nakabayashi, O; Kikuchi, H; Kikuchi, T; Mizuno, S

    1998-04-01

    In birds, differentiation of embryonic gonads is not as strictly determined by the genetic sex as it is in mammals, and can be influenced by early manipulation with a sex steroid hormone. Thus administration of an aromatase inhibitor induces testis development in the genetic female, and administration of estrogen induces a left ovotestis in the genetic male embryo. Another feature of avian gonadogenesis is that only the left ovary develops in most species. Molecular mechanisms underlying these features at the level of gene expression have not been elucidated. In this paper, we present evidence that a gene for aromatase cytochrome P-450, an enzyme required for the last step in the synthesis of estradiol-17beta, is expressed in medullae of the left and right gonads of a female chicken embryo, but not in those of a male chicken embryo, and that an estrogen receptor gene is expressed only in epithelium (and cortex later, in the female) of the left, not the right, gonad of both sexes, but the expression in the male left gonad is temporary and restricted to an early stage of development. Differential expression of these two genes serves well to explain the above features of gonadal development in birds. Furthermore, in ovo administration of estradiol-17beta from the 5th to the 14th day of incubation does not cause expression of the estrogen receptor gene in the right gonad of chicken embryos of either sex, suggesting that the absence of expression of the estrogen receptor gene in the right gonad is not the result of down-regulation, but may be regarded as an important cause of the unilateral ovarian development. PMID:9584834

  2. Review of current classification, molecular alterations, and tyrosine kinase inhibitor therapies in myeloproliferative disorders with hypereosinophilia

    Directory of Open Access Journals (Sweden)

    Havelange V

    2013-08-01

    Full Text Available Violaine Havelange,1,2 Jean-Baptiste Demoulin1 1de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 2Department of Hematology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Abstract: Recent advances in our understanding of the molecular mechanisms underlying hypereosinophilia have led to the development of a 'molecular' classification of myeloproliferative disorders with eosinophilia. The revised 2008 World Health Organization classification of myeloid neoplasms included a new category called “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.” Despite the molecular heterogeneity of PDGFR (platelet-derived growth factor receptor rearrangements, tyrosine kinase inhibitors at low dose induce rapid and complete hematological remission in the majority of these patients. Other kinase inhibitors are promising. Further discoveries of new molecular alterations will direct the development of new specific inhibitors. In this review, an update of the classifications of myeloproliferative disorders associated with hypereosinophilia is discussed together with open and controversial questions. Molecular mechanisms and promising results of tyrosine kinase inhibitor treatments are reviewed. Keywords: hypereosinophilia, classification, myeloproliferative disorders, molecular alterations, tyrosine kinase inhibitor

  3. PI3K inhibitors for cancer therapy: what has been achieved so far?

    Science.gov (United States)

    Wu, Peng; Liu, Tao; Hu, Yongzhou

    2009-01-01

    PI3K is a large duel lipid and protein kinase that catalyzes phosphorylation of the 3-hydroxyl position of phosphatidylinositides (PIs) and plays a crucial role in the cellular signaling network. Inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a newly identified strategy for the discovery and development of certain therapeutic agents. Among the various subtypes of PI3K, class IA PI3Kalpha has gained increasing attention as a promising drug target for the treatment of cancer due to its frequent mutations and amplifications in various human cancers. Here, we discuss the insights gained so far relevant to the development of PI3K inhibitors for the treatment of human cancers. Emphasis is on the structure-activity relationship of PI3K inhibitors which bear the most significant PI3Kalpha inhibitory activities. We also highlight PI3K inhibitors that are currently under clinical trials for cancers. PMID:19275602

  4. DPP-4 inhibitor therapy: new directions in the treatment of type 2 diabetes

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Carr, Richard D; Holst, Jens Juul

    2008-01-01

    Many patients with type 2 diabetes fail to achieve adequate glycaemic control with available treatments, even when used in combination, and eventually develop microvascular and macrovascular diabetic complications. Even intensive interventions to control glycaemia reduce macrovascular complications...... of type 2 diabetes; long-acting stable analogues of GLP-1, the so-called incretin mimetics, and inhibitors of dipeptidyl peptidase 4 (DPP-4, the enzyme responsible for the rapid degradation of the incretin hormones), the so-called incretin enhancers. This article focuses on DPP-4 inhibitors....

  5. Cytochrome P450 aromatase expression in human seminoma

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    Montanaro Daniela

    2005-12-01

    Full Text Available Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression in human seminoma, which is the most common germ cell tumour of the testis. Methods The tumour-bearing testes were obtained from 20 patients with classic seminoma undergoing to therapeutic orchidectomy. Paraffin embedded tissues were processed for immunohistochemistry using a mouse monoclonal antibody generated against human placental cytochrome P450 arom, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. Furthermore, Western blot analysis of seminoma extracts was carried out. Results Intense P450 arom immunoreactivity was observed in the seminoma cells and Western blot analysis confirmed the immunodetection. A strong immunostaining was also detected in cells of intratubular germ cell neoplasia (IGCN, adjacent to seminoma. Conclusion The present study demonstrated, for the first time in human, aromatase expression in neoplastic cells of seminoma suggesting a relation between local estrogen biosynthesis and germ cell tumorigenesis. The P450 arom immunolocalization in the cells of IGCN, representing the common precursor of most germ cell tumors, seems to support these findings.

  6. Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy.

    Science.gov (United States)

    Kim, Hyun-Yi; Choi, Sehee; Yoon, Ji-Hye; Lim, Hwan Jung; Lee, Hyuk; Choi, Jiwon; Ro, Eun Ji; Heo, Jung-Nyoung; Lee, Weontae; No, Kyoung Tai; Choi, Kang-Yell

    2016-01-01

    Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti-resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)-based anabolic drugs present limitations and adverse effects including osteosarcoma during long-term use. Also, the antibody-based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/β-catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl-CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small-molecule inhibitors of the Dvl-CXXC5 interaction via a newly established in vitro assay system. The screened compounds were found to activate the Wnt/β-catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY-02061, a representative of the screened compounds. Oral administration of KY-02327, one of 55 newly synthesized KY-02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small-molecule inhibitors of the Dvl-CXXC5 interaction that block negative feedback regulation of Wnt/β-catenin signaling are potential candidates for the development of bone anabolic anti-osteoporosis drugs.

  7. Long-term effectiveness of initiating non-nucleoside reverse transcriptase inhibitor- versus ritonavir-boosted protease inhibitor-based antiretroviral therapy: implications for first-line therapy choice in resource-limited settings

    Directory of Open Access Journals (Sweden)

    Viviane D Lima

    2016-08-01

    Full Text Available Introduction: In many resource-limited settings, combination antiretroviral therapy (cART failure is diagnosed clinically or immunologically. As such, there is a high likelihood that patients may stay on a virologically failing regimen for a substantial period of time. Here, we compared the long-term impact of initiating non-nucleoside reverse transcriptase inhibitor (NNRTI- versus boosted protease inhibitor (bPI-based cART in British Columbia (BC, Canada. Methods: We followed prospectively 3925 ART-naïve patients who started NNRTIs (N=1963, 50% or bPIs (N=1962; 50% from 1 January 2000 until 30 June 2013 in BC. At six months, we assessed whether patients virologically failed therapy (a plasma viral load (pVL >50 copies/mL, and we stratified them based on the pVL at the time of failure ≤500 versus >500 copies/mL. We then followed these patients for another six months and calculated their probability of achieving subsequent viral suppression (pVL 500 copies/mL, they had a 20% lower probability of suppressing at 12 months than pVL-matched bPI initiators (0.37 (0.29–0.45 vs. 0.46 (0.38–0.54. In terms of evolving HIV drug resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed with a viral load >500 copies/mL. Conclusions: Our results show that patients who virologically failed at six months on NNRTI and continued on the same regimen had a lower probability of subsequently achieving viral suppression and a higher chance of evolving HIV drug resistance. These results suggest that improving access to regular virologic monitoring is critically important, especially if NNRTI-based cART is to remain a preferred choice for first-line therapy in resource-limited settings.

  8. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    Energy Technology Data Exchange (ETDEWEB)

    Gorrochategui, Eva; Pérez-Albaladejo, Elisabet [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Casas, Josefina [Department of Biomedicinal Chemistry, IQAC–CSIC, 08034 Barcelona, Catalonia (Spain); Lacorte, Sílvia, E-mail: slbqam@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Porte, Cinta, E-mail: cinta.porte@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain)

    2014-06-01

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  9. Misdiagnosis and mistreatment of ace-inhibitor induced cough decreases therapy compliance

    NARCIS (Netherlands)

    Vegter, S.; de Boer, P.; van Dijk, K. W.; Visser, S. T.; de Jong-van den Berg, L. T.

    2012-01-01

    OBJECTIVES: A common adverse effect of angiotensin-converting enzyme inhibitors (ACEi) is a persistent dry cough. Physicians and pharmacists who fail to recognise dry cough to be ACEi related may prescribe cough suppressants (antitussives), instead of recommended ACEi substitution. The aim of this s

  10. PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Irene Paterniti

    Full Text Available BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs, which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score, and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI.

  11. Pharmacophore development and screening for discovery of potential inhibitors of ADAMTS-4 for osteoarthritis therapy.

    Science.gov (United States)

    Verma, Priyanka; Dalal, Krishna; Chopra, Madhu

    2016-08-01

    In the development of osteoarthritis, aggrecan degrades prior to cartilage destruction. Aggrecanase-1 (ADAMTS-4) is considered to be the major enzyme responsible for cleaving the Glu373-Ala374 bond in the interglobular domain of aggrecan in humans. Therefore, inhibitors of ADAMTS-4 have therapeutic potential in the treatment of osteoarthritis. In the present work, we developed a chemical feature based pharmacophore model of ADAMTS-4 inhibitors using the HipHop module within the Catalyst program package in order to elucidate the structure-activity relationship and to carry out in-silico screening. The Maybridge database was screened using Hypo1 as a 3D query, and the best-fit hits that followed Lipinski's rule of five were subsequently screened to select the compounds. The hit compounds were then docked into the active site of ADAMTS-4, and interactions were visualized to determine the potential lead molecules. After subjecting all of the hits to various screening and filtering processes, 13 compounds were finally evaluated for their in vitro inhibitory activities. This study resulted in the identification of two lead compounds with potent inhibitory effects on ADAMTS-4 activity, with IC50 values of 0.042 μM and 0.028 μM, respectively. These results provide insight into the pharmacophoric requirements for the development of more potent ADAMTS-4 inhibitors. Graphical Abstract The aggrecan-degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. In this work, we used HipHop-based pharmacophore modeling and virtual screening of the Maybridge database to identify novel ADAMTS-4 inhibitors. These novel lead compounds act as potent and specific inhibitors for the ADAMTS-4 enzyme and could have therapeutic potential in the treatment of OA. PMID:27401455

  12. Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

    Directory of Open Access Journals (Sweden)

    Weidemann AK

    2013-09-01

    Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

  13. Pharmacophore development and screening for discovery of potential inhibitors of ADAMTS-4 for osteoarthritis therapy.

    Science.gov (United States)

    Verma, Priyanka; Dalal, Krishna; Chopra, Madhu

    2016-08-01

    In the development of osteoarthritis, aggrecan degrades prior to cartilage destruction. Aggrecanase-1 (ADAMTS-4) is considered to be the major enzyme responsible for cleaving the Glu373-Ala374 bond in the interglobular domain of aggrecan in humans. Therefore, inhibitors of ADAMTS-4 have therapeutic potential in the treatment of osteoarthritis. In the present work, we developed a chemical feature based pharmacophore model of ADAMTS-4 inhibitors using the HipHop module within the Catalyst program package in order to elucidate the structure-activity relationship and to carry out in-silico screening. The Maybridge database was screened using Hypo1 as a 3D query, and the best-fit hits that followed Lipinski's rule of five were subsequently screened to select the compounds. The hit compounds were then docked into the active site of ADAMTS-4, and interactions were visualized to determine the potential lead molecules. After subjecting all of the hits to various screening and filtering processes, 13 compounds were finally evaluated for their in vitro inhibitory activities. This study resulted in the identification of two lead compounds with potent inhibitory effects on ADAMTS-4 activity, with IC50 values of 0.042 μM and 0.028 μM, respectively. These results provide insight into the pharmacophoric requirements for the development of more potent ADAMTS-4 inhibitors. Graphical Abstract The aggrecan-degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. In this work, we used HipHop-based pharmacophore modeling and virtual screening of the Maybridge database to identify novel ADAMTS-4 inhibitors. These novel lead compounds act as potent and specific inhibitors for the ADAMTS-4 enzyme and could have therapeutic potential in the treatment of OA.

  14. Nanoformulation of Geranylgeranyltransferase-I Inhibitors for Cancer Therapy: Liposomal Encapsulation and pH-Dependent Delivery to Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Jie Lu

    Full Text Available Small molecule inhibitors against protein geranylgeranyltransferase-I such as P61A6 have been shown to inhibit proliferation of a variety of human cancer cells and exhibit antitumor activity in mouse models. Development of these inhibitors could be dramatically accelerated by conferring tumor targeting and controlled release capability. As a first step towards this goal, we have encapsulated P61A6 into a new type of liposomes that open and release cargos only under low pH condition. These low pH-release type liposomes were prepared by adjusting the ratio of two types of phospholipid derivatives. Loading of geranylgeranyltransferase-I inhibitor (GGTI generated liposomes with average diameter of 50-100 nm. GGTI release in solution was sharply dependent on pH values, only showing release at pH lower than 6. Release of cargos in a pH-dependent manner inside the cell was demonstrated by the use of a proton pump inhibitor Bafilomycin A1 that Increased lysosomal pH and inhibited the release of a dye carried in the pH-liposome. Delivery of GGTI to human pancreatic cancer cells was demonstrated by the inhibition of protein geranylgeranylation inside the cell and this effect was blocked by Bafilomycin A1. In addition, GGTI delivered by pH-liposomes induced proliferation inhibition, G1 cell cycle arrest that is associated with the expression of cell cycle regulator p21CIP1/WAF1. Proliferation inhibition was also observed with various lung cancer cell lines. Availability of nanoformulated GGTI opens up the possibility to combine with other types of inhibitors. To demonstrate this point, we combined the liposomal-GGTI with farnesyltransferase inhibitor (FTI to inhibit K-Ras signaling in pancreatic cancer cells. Our results show that the activated K-Ras signaling in these cells can be effectively inhibited and that synergistic effect of the two drugs is observed. Our results suggest a new direction in the use of GGTI for cancer therapy.

  15. Aromatase inhibition abolishes courtship behaviours in the ring dove (Streptopelia risoria) and reduces androgen and progesterone receptors in the hypothalamus and anterior pituitary gland.

    Science.gov (United States)

    Belle, M D C; Sharp, P J; Lea, R W

    2005-08-01

    The aim of this study was to determine in the ring dove, the effects of aromatase inhibition on the expression of aggressive courtship and nest-soliciting behaviours in relation to the distribution of cells containing immunoreactive androgen (AR) and progesterone (PR) receptor in the hypothalamus and pituitary gland. Isolated sexually experienced ring doves were transferred in opposite sex pairs to individual breeding cages, and then injected with the aromatase inhibitor, fadrozole (four males and four females), or saline vehicle (four males and four females) for 3 days at 12 hourly intervals. Saline-injected control males displayed aggressive courtship behaviours (bow-cooing and hop-charging) and nest-soliciting throughout the study, and control females displayed nest-soliciting. By day 3, fadrozole treatment resulted in the disappearance of all these behaviours and in a decrease or disappearance of AR and PR in the anterior pituitary gland, and in the nucleus preopticus paraventricularis magnocellularis (PPM), nucleus preopticus medialis (POM), nucleus hypothalami lateralis posterioris (PLH), and ventral, lateral and dorsal nucleus tuberalis in the hypothalamus (VTu, LTu, DTu). In the nucleus preopticus anterior (POA), fadrozole treatment decreased AR in both sexes and decreased PR in females but not in males. Cells containing co-localized nuclear AR and PR were found in all hypothalamic areas examined, and in the anterior pituitary gland. Fadrozole is suggested to reduce the local availability of estrogen required indirectly for the induction of AR, and except in cells containing PR in the male POA, for the direct induction of PR. It is suggested that aggressive courtship behaviour is terminated by "cross talk" between aromatase-independent PR and aromatase-dependent AR co-localized in neurons in the POA. Aromatase-independent PR may increase in the male POA in response to visual cues provided by a partner. Aromatase-dependent PR in the POM, and basal

  16. Low level HIV viremia is more frequent under protease-inhibitor containing firstline therapy than under NNRTI-regimens

    Directory of Open Access Journals (Sweden)

    Frank Wiesmann

    2014-11-01

    Full Text Available Introduction: An association of persistent low level viremia (LLV below 500 copies/mL and a higher risk of therapy failure is still point of controversial discussion. Furthermore, it seems that LLV occurs more frequently in patients with protease-inhibitor regimens than in NNRTI- / or integrase-inhibitor containing therapies. The focus of this work was to assess the prevalence of LLV (50–200 copies/mL and weak viremia (201–500 copies/mL in firstline-treated patients according to their therapy regimen. Methods: A total of 832 and 944 patients from 23 German centres were under firstline therapy in 2012 and 2013, respectively. All patients received their therapy for more than 24 weeks. VL data was related to clinical data retrospectively including ART-composition, subdivided into NNRTIs (Efavirenz, Nevirapine, PIs (Atazanavir, Darunavir, Lopinavir and INIs (Raltegravir. Low viremic patients were classified into two arms of 50–200 copies/mL (group A and 201–500 copies/mL (group B. Results: Success of therapy was defined as <50 copies/mL and was observed in 90.0% and 91.1% (2012/2013, respectively. An additional 2.0% and 2.3% had LLV. The amount of viremic patients with VLs <500 copies/mL differed significantly between NNRTI-based firstline regimens 1.7% and 2.5% and PI-based regimens 4.8% and 5.7% (2012/2013, respectively. LLV was clearly less often observed in EFV-based- (1.6% and 1.1% [group A] / 0.4% and 0.4% [group B] or NVP-based firstline therapies (1.0% and 3.6% [group A] + 0% and 0% [group B] than in ATV-based- (7.5% and 3.8% [group A] + 1.5% and 2.5% [group B], DRV-based- (2.9% and 3.0% [group A] + 2.2% and 0% [group B] or LPV-based firstline therapies (1.6% and 3.3% [group A] + 0.8% and 2.5% [group B] and also in parts for RAL-based regimens (0% and 3.7% [group A] + 0% and 1.9% [group B]. Conclusions: LLV is more often observed under PI-based firstline than under NNRTI-regimens. Only one NNRTI-patient of group B remained on therapy

  17. Combination therapy of intravenous glycoprotein IIB/IIIA inhibitors and tissue plasminogen activator for acute ischemic stroke

    Directory of Open Access Journals (Sweden)

    Divyanshu Dubey

    2014-01-01

    Full Text Available Objectives: Retrospective pooled analysis of data from published prospective studies and randomized phase 1 and 2 trials was done to assess efficacy and safety profile of intravenous combination therapy [glycoprotein IIb/IIIa inhibitors and IV tissue plasminogen activator (tPA] in management of acute ischemic stroke. Materials and Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, and EMBASE databases; two reviewers independently selected studies reporting safety endpoints and outcome measures in acute ischemic stroke patients treated with combination therapy. tPA arm of the National Institute of Neurological Disorders and Stroke (NINDS tPA trial was included in tPA-only group. Weighted means and proportions were calculated for numeric and categorical variables respectively. Bivariate analysis using Fisher′s exact test was done to compare baseline descriptors, safety endpoints, and outcome measures. Results: Combination therapy arm included 188 patients and IV tPA arm had 218 patients. Mean National Institutes of Health Stroke Scale (NIHSS in two groups were 12.8 and 14.6, respectively. Mean time-to-treatment was 2.3 hours in combination therapy arm and 2.55 hours in tPA arm. Treatment with combination therapy was associated with significant reduction in rate of symptomatic intracranial hemorrhage (sICH [odds ratio (OR 0.26, 95% cumulative incidence (CI 0.07 0.83, P value 0.01. Difference in better functional outcome at 90 days (OR 0.87, 95% CI 0.59-1.30, P value 0.54 and death at 90 days (OR 1.16, 95% CI 0.69-1.93, P value 0.60 were not significantly different in two groups. Conclusion: Combination of low dose IV TPA with glycoprotein IIb/IIIa inhibitors is associated with reduction in sICH rates in patients with acute ischemic stroke as compared to standard dose of IV tPA.

  18. Inhibitor of Apoptosis (IAP proteins in pediatric leukemia: Molecular pathways and novel approaches to therapy

    Directory of Open Access Journals (Sweden)

    Simone eFulda

    2014-01-01

    Full Text Available Inhibitor of Apoptosis (IAP proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programmed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit in vitro and in vivo antitumor activities against childhood pediatric leukemia in several preclinical studies. Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia which warrants further exploitation.

  19. Comparison of efavirenz and protease inhibitor based combination antiretroviral therapy regimens in treatment-naïve people living with HIV with baseline resistance.

    Science.gov (United States)

    Lim, Charlotte; McFaul, Katie; Kabagambe, Samuel; Sonecha, Sonali; Jones, Rachael; Asboe, David; Pozniak, Anton; Nwokolo, Nneka; Boffito, Marta

    2016-07-17

    A retrospective cohort analysis comparing the efficacy of boosted protease inhibitor-based and efavirenz-based combination antiretroviral therapy in treatment-naïve people living with HIV with baseline resistance found that efavirenz-based treatment led to a shorter mean time to undetectable viral load. A higher proportion of patients with nonnucleoside reverse transcriptase inhibitor related baseline resistance mutations in the efavirenz-treatment group achieved an undetectable viral load at both 6 and 12 months post-treatment initiation, compared with the boosted protease-inhibitor-treatment group.Supplementary content: http://links.lww.com/QAD/A930. PMID:27139315

  20. Present status and upcoming prospects of hedgehog pathway inhibitors in small cell lung cancer therapy

    OpenAIRE

    Naqvi, Syed Hassan Abbas; Naqvi, Syed Hassan Shiraz; Bandukda, Muhammad Yasin; Naqvi, Syed Mumtaz Ali

    2013-01-01

    Lung cancer is an important etiology of malignant mortality worldwide with global statistics indicating over 1 million deaths annually. Although there have been advances in cytotoxic chemotherapy, the prognosis after treatment still remains poor. Remarkably, recent studies on the molecular level are creating the possibility to hamper lung cancer by inhibiting the hedgehog pathway. Currently, hedgehog pathway inhibitors include IWP-2, cyclopamine and aprotinin. However, Vismodegib is a new upc...

  1. Finding Inhibitors of Mutant Superoxide Dismutase-1 for Amyotrophic Lateral Sclerosis Therapy from Traditional Chinese Medicine

    OpenAIRE

    2014-01-01

    Superoxide dismutase type 1 (SOD1) mutations cause protein aggregation and decrease protein stability, which are linked to amyotrophic lateral sclerosis (ALS) disease. This research utilizes the world's largest traditional Chinese medicine (TCM) database to search novel inhibitors of mutant SOD1, and molecular dynamics (MD) simulations were used to analyze the stability of protein that interacted with docked ligands. Docking results show that hesperidin and 2,3,5,4′-tetrahydroxystilbene-2-O- ...

  2. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Nora Semren

    Full Text Available Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ, provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ. OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.

  3. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression.

    Science.gov (United States)

    Thomas, Samantha J; Shin, Mirae; McInnis, Melvin G; Bostwick, Jolene R

    2015-04-01

    combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants. PMID:25884531

  4. Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation.

    Science.gov (United States)

    Rochani, Ankit K; Balasubramanian, Sivakumar; Ravindran Girija, Aswathy; Raveendran, Sreejith; Borah, Ankita; Nagaoka, Yutaka; Nakajima, Yoshikata; Maekawa, Toru; Kumar, D Sakthi

    2016-09-10

    Heat Shock Protein 90 (Hsp90) has been extensively explored as a potential drug target for cancer therapies. 17- N-allylamino- 17-demethoxygeldanamycin (17AAG) was the first Hsp90 inhibitor to enter clinical trials for cancer therapy. However, native drug is being shown to have considerable anticancer efficacy against pancreatic cancer when used in combination therapy regime. Further, magnetic hyperthermia has shown to have promising effects against pancreatic cancer in combination with known cyto-toxic drugs under both target and non-targeted scenarios. Hence, in order to enhance the efficacy of 17AAG against pancreatic cancer, we developed poly (lactic-co-glycolic acid) (PLGA) coated, 17AAG and Fe3O4 loaded magnetic nanoparticle formulations by varying the relative concentration of polymer. We found that polymer concentration affects the magnetic strength and physicochemical properties of formulation. We were also able to see that our aqueous dispensable formulations were able to provide anti-pancreatic cancer activity for MIA PaCa-2 cell line in dose and time dependent manner in comparison to mice fibroblast cell lines (L929). Moreover, the in-vitro magnetic hyperthermia against MIA PaCa-2 provided proof principle that our 2-in-1 particles may work against cancer cell lines effectively. PMID:27469073

  5. Mutation analysis of circulating plasma DNA to determine response to EGFR tyrosine kinase inhibitor therapy of lung adenocarcinoma patients

    Science.gov (United States)

    Riediger, Anja Lisa; Dietz, Steffen; Schirmer, Uwe; Meister, Michael; Heinzmann-Groth, Ingrid; Schneider, Marc; Muley, Thomas; Thomas, Michael; Sültmann, Holger

    2016-01-01

    Long-lasting success in lung cancer therapy using tyrosine kinase inhibitors (TKIs) is rare since the tumors develop resistance due to the occurrence of molecularly altered subclones. The aim of this study was to monitor tumors over time based on the quantity of mutant plasma DNA and to identify early indications for therapy response and tumor progression. Serial plasma samples from lung adenocarcinoma patients treated with TKIs were used to quantify EGFR and KRAS mutations in circulating DNA by digital PCR. Mutant DNA levels were compared with the courses of responses to treatment with TKIs, conventional chemotherapy, radiotherapy, or combinations thereof. Variations in plasma DNA mutation levels over time were found in 15 patients. We categorize three major courses: First, signs of therapy response are associated with a fast clearing of plasma DNA mutations within a few days. Second, periods of stable disease are accompanied by either absence of mutations or fluctuation at low levels. Finally, dramatic increase of mutational load is followed by rapid tumor progression and poor patient survival. In summary, the serial assessment of EGFR mutations in the plasma of NSCLC patients allows conclusions about controlled disease and tumor progression earlier than currently available methods. PMID:27640882

  6. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Kay Andrea

    2009-10-01

    Full Text Available Abstract The mammalian target of rapamycin (mTOR is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA and the European Medicines Agency (EMEA for the treatment of advanced renal cell carcinoma (RCC. Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

  7. Combination Therapy of PPAR Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jordi Tauler

    2008-01-01

    Full Text Available Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPAR. Targeting LOX/COX enzymes and inducing activation of PPAR have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPAR activation through synthetic ligands (TZDs has revealed a great mechanistic complexity since effects are produced through PPAR-dependent and -independent mechanisms. Furthermore, PPAR could also be involved in regulation of COX-2. Overexpression of PPAR has reported to play a role in control of invasion and differentiation. Exploring the function of PPAR, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

  8. Disruptions in aromatase expression in the brain, reproductive behavior, and secondary sexual characteristics in male guppies (Poecilia reticulata) induced by tributyltin.

    Science.gov (United States)

    Tian, Hua; Wu, Peng; Wang, Wei; Ru, Shaoguo

    2015-05-01

    Although bioaccumulation of tributyltin (TBT) in fish has been confirmed, information on possible effects of TBT on reproductive system of fish is still relatively scarce, particularly at environmentally relevant levels. To evaluate the adverse effects and intrinsic toxicological properties of TBT in male fish, we studied aromatase gene expression in the brain, sex steroid contents, primary and secondary sexual characteristics, and reproductive behavior in male guppies (Poecilia reticulata) exposed to tributyltin chloride at the nominal concentrations of 5, 50, and 500 ng/L for 28 days in a semi-static exposure system. Radioimmunoassay demonstrated that treatment with 50 ng/L TBT caused an increase in systemic levels of testosterone of male guppies. Gonopodial index, which showed a positive correlation with testosterone levels, was elevated in the 5 ng/L and 50 ng/L TBT treated groups. Real-time PCR revealed that TBT exposure had inhibiting effects on expression of two isoforms of guppy aromatase in the brain, and these changes at the molecular levels were associated with a disturbance of reproductive behavior of the individuals, as measured by decreases in frequencies of posturing, sigmoid display, and chase activities when males were paired with females. This study provides the first evidence that TBT can cause abnormalities of secondary sexual characteristics in teleosts and that suppression of reproductive behavior in teleosts by TBT is due to its endocrine-disrupting action as an aromatase inhibitor targeting the nervous system.

  9. Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV/AIDS

    Directory of Open Access Journals (Sweden)

    Hogg Robert S

    2005-02-01

    Full Text Available Abstract Background Protease inhibitors are known to alter the lipid profiles in subjects treated for HIV/AIDS. However, the magnitude of this effect on plasma lipoproteins and lipids has not been adequately quantified. Objective To estimate the changes in plasma lipoproteins and triglycerides occurring within 12 months of initiating PI-based antiretroviral therapy among HIV/AIDS afflicted subjects. Methods We included all antiretroviral naïve HIV-infected persons treated at St-Paul's Hospital, British Columbia, Canada, who initiated therapy with protease inhibitor antiretroviral (ARV drugs between August 1996 and January 2002 and who had at least one plasma lipid measurement. Longitudinal associations between medication use and plasma lipids were estimated using mixed effects models that accounted for repeated measures on the same subjects and were adjusted for age, sex, time dependent CD4+ T-cell count, and time dependent cumulative use of non-nucleoside reverse transcriptase inhibitors and adherence. The cumulative number of prescriptions filled for PIs was considered time dependent. We estimated the changes in the 12 months following any initiation of a PI based regimen. Results A total of 679 eligible subjects were dispensed nucleoside analogues and PI at the initiation of therapy. Over a median 47 months of follow-up (interquartile range (IQR: 29–62, subjects had a median of 3 (IQR: 1–6 blood lipid measurements. Twelve months after treatment initiation of PI use, there was an estimated 20% (95% confidence interval: 17% – 24% increase in total cholesterol and 22% (12% – 33% increase in triglycerides. Conclusions Twelve months after treatment initiation with PIs, statistically significant increases in total cholesterol and triglycerides levels were observed in HIV-infected patients under conditions of standard treatment. Our results contribute to the growing body of evidence implicating PIs in the development of blood lipid

  10. Synthesis of highly-labeled with tritium steroid hormones and their use for estimation of aromatase activity

    International Nuclear Information System (INIS)

    Highly-labeled steroids - progesterone, estradiol, and androsterone are synthesized. They are used for determination of aromatase activity in different pathologies. It is shown that high activity of aromatase in endometrium in patients with endometrium neoplasms without myome deteriorates disease prognosis. At the same time high aromatase activity in endometrium in patients with endometrium neoplasms with myome has frequently opportune result

  11. Aromatase enzyme expression in acromegaly and its possible relationship with disease prognosis.

    Science.gov (United States)

    Selek, Alev; Cetinarslan, Berrin; Gurbuz, Yesim; Tarkun, Ilhan; Canturk, Zeynep; Cabuk, Burak

    2015-05-01

    The purpose of this study was to evaluate aromatase enzyme expression in growth hormone (GH) secreting adenomas and comparison with prolactinomas, nonfunctional adenomas, and normal pituitary tissues. Also the impact of its expression on clinical and prognostic features was evaluated. 38 acromegaly, 26 prolactinoma, and 31 nonfunctional pituitary adenoma and 11 normal pituitary gland samples from autopsies were included. Aromatase and estrogen receptor-alpha (ERα) were evaluated by Immunohistochemical method; demographic, pre- and postoperative features of the patients were noted. Aromatase was expressed in varying degrees in all cases in study including controls. Aromatase expression in patients with acromegaly was significantly higher than patients with prolactinoma, nonfunctional adenoma, and controls (p = 0.04, p = 0.01 and p acromegaly, aromatase expression was negatively correlated with ER-alpha (p = 0.02, r = -0.34). Also, Ki-67 immunohistochemical results were negatively correlated with aromatase expression (p = 0.03, r = -0.27) while positively correlated with ER expression (p acromegaly. In patients with acromegaly and prolactinoma, aromatase expression was negatively correlated with Ki-67 score, and also it was higher in patients with complete postoperative remission than without remission. Therefore, aromatase expression may be a good prognostic marker predominantly in acromegaly.

  12. Effects of Nutrition Relevant Mixtures of Phytoestrogens on Steroidogenesis, Aromatase, Estrogen, and Androgen Activity

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Engell-Kofoed, Anders Elleby; Sonne-Hansen, Katrine;

    2010-01-01

    aromatase activity. Furthermore, exposure of the H295R cells to isoflavonoids caused a decrease in testosterone production, and various mixtures of PEs significantly stimulated MCF-7 human breast adenocarcinoma cell growth and induced aromatase activity in JEG-3 choriocarcinoma cells. The estrogenic effect...

  13. Second-line protease inhibitor-based highly active antiretroviral therapy after failing non-nucleoside reverse transcriptase inhibitors-based regimens in Asian HIV-infected children

    Science.gov (United States)

    Bunupuradah, Torsak; Puthanakit, Thanyawee; Fahey, Paul; Kariminia, Azar; Yusoff, Nik Khairulddin Nik; Khanh, Truong Huu; Sohn, Annette H.; Chokephaibulkit, Kulkanya; Lumbiganon, Pagakrong; Hansudewechakul, Rawiwan; Razali, Kamarul; Kurniati, Nia; Huy, Bui Vu; Sudjaritruk, Tavitiya; Kumarasamy, Nagalingeswaran; Fong, Siew Moy; Saphonn, Vonthanak; Ananworanich, Jintanat

    2013-01-01

    Background The WHO recommends boosted protease inhibitor (bPI)-based highly active antiretroviral therapy (HAART) after failing non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment. We examined outcomes of this regimen in Asian HIV-infected children. Methods Children from five Asian countries in the TREAT Asia Pediatric HIV Observational Database (TApHOD) with ≥24 weeks of NNRTI-based HAART followed by ≥24 weeks of bPI-based HAART were eligible. Primary outcomes were the proportions with virologic suppression (HIV-RNA <400 copies/ml) and immune recovery (CD4% ≥25% if age <5 years and CD4 count ≥500 cells/mm3 if age ≥5 years) at 48 and 96 weeks. Results Of 3422 children, 153 were eligible; 52% were female. At switch, median age was 10 years, 26% were in WHO stage 4. Median weight-for-age z-score (WAZ) was −1.9 (n=121), CD4% was 12.5% (n=106), CD4 count was 237 (n=112) cells/mm3, and HIV-RNA was 4.6 log10copies/ml (n=61). The most common PI was lopinavir/ritonavir (83%). At 48 weeks, 61% (79/129) had immune recovery, 60% (26/43) had undetectable HIV-RNA and 73% (58/79) had fasting triglycerides ≥130mg/dl. By 96 weeks, 70% (57/82) achieved immune recovery, 65% (17/26) virologic suppression, and hypertriglyceridemia occurred in 66% (33/50). Predictors for virologic suppression at week 48 were longer duration of NNRTI-based HAART (p=0.006), younger age (p=0.007), higher WAZ (p=0.020), and HIV-RNA at switch <10,000 copies/ml (p=0.049). Conclusion In this regional cohort of Asian children on bPI-based second-line HAART, 60% of children tested had immune recovery by one year, and two-thirds had hyperlipidemia, highlighting difficulties in optimizing second-line HAART with limited drug options. PMID:23296119

  14. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy

    DEFF Research Database (Denmark)

    Reimer, Christina; Søndergaard, Bo; Hilsted, Linda;

    2009-01-01

    -controlled trial with 120 healthy volunteers was conducted. Participants were randomized to 12 weeks of placebo or 8 weeks of esomeprazole 40 mg/d followed by 4 weeks with placebo. The Gastrointestinal Symptom Rating Scale (GSRS) was filled out weekly. A score of >2 on 1 of the questions regarding heartburn, acid...... dyspepsia, heartburn, or acid regurgitation in the PPI group was 13 of 59 (22%) at week 10, 13 of 59 (22%) at week 11, and 12 of 58 (21%) at week 12. Corresponding figures in the placebo group were 7% at week 10 (P = .034), 5% at week 11 (P = .013), and 2% at week 12 (P = .001). CONCLUSIONS: PPI therapy...

  15. Combination Therapy With and Without Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Graudal, Niels; Hubeck-Graudal, Thorbjørn; Faurschou, Mikkel;

    2015-01-01

    OBJECTIVE: The costs of biologic treatment per patient with rheumatoid arthritis (RA) are approximately 100 times the costs of treatment with a combination of conventional disease-modifying antirheumatic drugs (DMARDs). Despite this, biologic agents have not been proven superior. We compared...... the effects of combination DMARD therapies with and without biologic agents as therapy for patients with RA. METHODS: Eight randomized controlled trials published in 10 articles were selected from a systematic literature search of 1,674 identified studies and integrated in a meta-analysis. These trials...

  16. Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits

    DEFF Research Database (Denmark)

    Bygum, Anette; Andersen, Klaus Ejner; Mikkelsen, Carsten Sauer

    2009-01-01

    Hereditary angioedema (HAE) is often debilitating with a serious effect on quality of life (QOL). Treatment of acute HAE attacks is usually with C1 esterase inhibitor (C1-INH) concentrates; however, treatment can be delayed by patients' travel time for attending emergency units. We assessed...... the Dermatology Life Quality Index (DLQI) and 36-Item Short Form Survey (SF-36) questionnaires. Seven patients were recruited into the study. QOL was assessed at baseline and after 3 to 48 months of home therapy. The mean DLQI score fell from 12.6 +/- 4.65 to 2.7 +/- 1.38 (P ... for the individual and combined components also improved significantly. No serious complications were documented during a follow-up period of 27 to 72 months. Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions...

  17. Sex change in the protandrous black porgy, Acanthopagrus schlegeli: a review in gonadal development, estradiol, estrogen receptor, aromatase activity and gonadotropin.

    Science.gov (United States)

    Lee, Y H; Du, J L; Yueh, W S; Lin, B Y; Huang, J D; Lee, C Y; Lee, M F; Lau, E L; Lee, F Y; Morrey, C; Nagahama, Y; Chang, C F

    2001-12-01

    Black porgy, Acanthopagrus schlegeli Bleeker, a marine protandrous hermaphrodite, is functional male for the first two years of life but begins to sexually change to female after the third year. Testicular tissue and ovarian tissue was separated by connective tissue in the bisexual gonad. This sex pattern provides a very good model to study the endocrine mechanism of sex change in fish. The annual profiles of plasma estradiol, vitellogenin and 11-ketotestosterone concentrations in males were significantly different from those in the three-year-old females. Significantly high levels of plasma estradiol during the prespawning/spawning season and low levels of plasma 11-ketotestosterone during the spawning season were observed in the inversing females. No difference of plasma testosterone levels was observed in males and females. Oral administration of estradiol stimulated high levels of gonadal aromatase activity, plasma gonadotropin II levels and sex change in the two-year-old fish. Exogenous estradiol administered for 5-6 months induced a reversible sex change in one- and two-year-old fish. The sensitive period for estradiol treatment of sex change is from early prespawning to spawning season. Implantation with testosterone for more than a year could not block the natural sex change in three-year-old fish. Exogenous aromatase inhibitors (1,4,6-androstatriene-3,17-dione or fadrozole) suppressed aromatase activity in the brain. Oral administration with aromatase inhibitors for a year further inhibited the natural sex change in three-year-old black porgy and all fish became functional male with spermiation. Estrogen receptor alpha gene in the ovarian tissue of bisexual gonad is significantly less expressed than that in the vitellogenic ovary of female on the basis of reverse-transcription polymerase-chain reaction. There was no difference in the annual profiles of the plasma gonadotropin II levels in the males and natural inversing females. Plasma gonadotropin II

  18. In Vivo Screening of S100B Inhibitors for Melanoma Therapy

    OpenAIRE

    Zimmer, Danna B.; Lapidus, Rena G.; Weber, David J.

    2013-01-01

    S100 proteins are markers for numerous cancers, and in many cases high S100 protein levels are a prognostic indicator for poor survival. One such case is S100B, which is overproduced in a very large percentage of malignant melanoma cases. Elevated S100B protein was more recently validated to have causative effects towards cancer progression via down-regulating the tumor suppressor protein, p53. Towards eliminating this problem in melanoma, targeting S100B with small molecule inhibitors was in...

  19. Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer.

    Science.gov (United States)

    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2014-11-01

    Androgens were at one time a therapeutic mainstay in the treatment of advanced breast cancer. Despite comparable efficacy, SERMs and aromatase inhibitors eventually became the therapies of choice due to in part to preferred side-effect profiles. Molecular characterization of breast tumors has revealed an abundance of androgen receptor expression but the choice of an appropriate androgen receptor ligand (agonist or antagonist) has been confounded by multiple conflicting reports concerning the role of the receptor in the disease. Modern clinical efforts have almost exclusively utilized antagonists. However, the recent clinical development of selective androgen receptor modulators with greatly improved side-effect profiles has renewed interest in androgen agonist therapy for advanced breast cancer.

  20. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib

    OpenAIRE

    Wodarz, Dominik; Garg, Naveen; Komarova, Natalia L.; Benjamini, Ohad; Keating, Michael J.; Wierda, William G.; Kantarjian, Hagop; James, Danelle; O’Brien, Susan; Burger, Jan A.

    2014-01-01

    During ibrutinib therapy, 1.7% of blood and 2.7% of tissue CLL cells die per day which is 3 and 5 times higher than without treatment.The fraction of CLL cells that redistribute into the blood during ibrutinib treatment represents 23.3% ± 17% of the tissue disease burden.

  1. Combination therapy with interferon and JAK1-2 inhibitor is feasible

    DEFF Research Database (Denmark)

    Bjørn, M E; de Stricker, K; Kjær, L;

    2014-01-01

    We report a 55 year old woman with post-ET PV for 12 years, who experienced resolution of severe constitutional symptoms within 3 days, a marked reduction in splenomegaly and a rapid decline in the JAK2V617F allele burden during combination therapy with interferon-alpha2a and ruxolitinib. Within 4...

  2. [CLINICAL AND PHARMACOECONOMIC RESULTS OF THE USAGE OF VARIOUS HIV REVERSE TRANSCRIPTASE INHIBITORS IN THE SCHEMES OF ANTIRETROVIRAL THERAPY OF PATIENT RECEIVING THERAPY FOR THE CHRONIC HEPATITIS C VIRUS].

    Science.gov (United States)

    Moshkovich, G F; Minaeva, S V; Varlova, L W; Goryaeva, M P; Gulyaeva, S S; Tichonova, E V

    2016-01-01

    Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors. PMID:27145599

  3. [CLINICAL AND PHARMACOECONOMIC RESULTS OF THE USAGE OF VARIOUS HIV REVERSE TRANSCRIPTASE INHIBITORS IN THE SCHEMES OF ANTIRETROVIRAL THERAPY OF PATIENT RECEIVING THERAPY FOR THE CHRONIC HEPATITIS C VIRUS].

    Science.gov (United States)

    Moshkovich, G F; Minaeva, S V; Varlova, L W; Goryaeva, M P; Gulyaeva, S S; Tichonova, E V

    2016-01-01

    Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.

  4. Small Molecule Inhibitors of Bcl-2 Family Proteins for Pancreatic Cancer Therapy

    International Nuclear Information System (INIS)

    Pancreatic cancer (PC) has a complex etiology and displays a wide range of cellular escape pathways that allow it to resist different treatment modalities. Crucial signaling molecules that function downstream of the survival pathways, particularly at points where several of these pathways crosstalk, provide valuable targets for the development of novel anti-cancer drugs. Bcl-2 family member proteins are anti-apoptotic molecules that are known to be overexpressed in most cancers including PC. The anti-apoptotic machinery has been linked to the observed resistance developed to chemotherapy and radiation and therefore is important from the targeted drug development point of view. Over the past ten years, our group has extensively studied a series of small molecule inhibitors of Bcl-2 against PC and provide solid preclinical platform for testing such novel drugs in the clinic. This review examines the efficacy, potency, and function of several small molecule inhibitor drugs targeted to the Bcl-2 family of proteins and their preclinical progress against PC. This article further focuses on compounds that have been studied the most and also discusses the anti-cancer potential of newer class of Bcl-2 drugs

  5. Synthesis, biodistribution and effects of farnesyltransferase inhibitor therapy on tumour uptake in mice of 99mTc labelled epidermal growth factor.

    NARCIS (Netherlands)

    Cornelissen, B.; Kersemans, V.; Burvenich, I.; Oltenfreiter, R.; Heyden, J.L. van der; Boerman, O.C.; Wiele, C. van de; Slegers, G.

    2005-01-01

    OBJECTIVE: The goal of this study was to develop a 99mTc labelled human epidermal growth factor (hEGF) for the in-vivo prediction of cancer cell response to farnesyltransferase inhibitor (FTI) therapy. This is based on the observation that internalization of EGF receptors is inhibited by FTIs. METHO

  6. Assessment of psychosocial factors and distress in women having adjuvant endocrine therapy for breast cancer: the relationship among emotional distress and patient and treatment-related factors

    OpenAIRE

    Ates, Ozturk; Soylu, Cem; Babacan, Taner; Sarici, Furkan; Kertmen, Neyran; Allen, Deborah; Sever, Ali Riza; Altundag, Kadri

    2016-01-01

    Purpose The aims of this study were to comprehensively describe the psychosocial and medical characteristics of women who initiated tamoxifen or aromatase inhibitors for breast cancer and to compare levels of emotional distress according to their medical (tumor demographics, treatment type, treatment duration) and psychosocial (self-esteem, perceived social support, sociodemographic) characteristics. Methods A total of 104 women currently receiving tamoxifen or aromatase inhibitors was recrui...

  7. RESIDUAL PLATELET REACTIVITY DURING THERAPY WITH INHIBITORS OF CYCLOOXIGENASE OR ADENOSINE DIPHOSPHATE RECEPTORS

    Directory of Open Access Journals (Sweden)

    A. A. Lomonosova

    2012-01-01

    Full Text Available Aim. To compare effects of acetylsalicylic acid (ASA and two clopidogrel drugs on residual platelet aggregative reactivity (RPAR. Material and methods. Patients (n=40 with ischemic heart disease aged under 70 years were involved into the crossover study. Clinical examination included questionnaire survey , blood pressure (BP measurement, ECG registration, 24-hour ECG and BP monitoring, determination of blood levels of total cholesterol, high density lipoproteins, triglycerides, transaminases, and creatinine, complete blood cell count, including platelets number and hemoglobin level. Besides evaluation of the platelet aggregation by optical aggregometry was performed initially , after one week ASA treatment and after every next 3 week clopidogrel treatment period.  Results. RPAR during ASA monotherapy was 56.4±0.3%. There were no significant differences in effects of original and generic clopidogrel on RPAR. Сlopidogrel therapy reduced RPAR more significantly (42.2±0.2% than ASA monotherapy did (p=0.0003. Authors proposed definition for high level of RPAR during therapy - it is platelet aggregation more than 46%. Data analysis taking into account this criterion showed that a number of patients with high RPAR was 70 and 30% among patients treated with enterosoluble ASA and clopidogrel, respectively. Conclusion. Study results show that a significant number of patients receiving antiplatelet monotherapy does not achieve the target level of RPAR(<46%. These results may be a rationale for combined therapy in patients of this type.

  8. Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin: rationale and evidences.

    Science.gov (United States)

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are recently approved class of anti-hyperglycaemic agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT-2I inhibits renal glucose reabsorption, thereby ensuing urinary glucose excretion in a dose-dependent manner. This caloric loss and osmotic diuresis, secondary to increased urinary glucose excretion, has a unique potential to counter insulin induced weight gain and fluid retention, with little potential of hypoglycemic exacerbation. Also, as these agents act independently of insulin secretion or action, they are effective even in long-standing diabetes with depleted β-cell reserve. Improvement in insulin sensitivity, as observed with SGLT-2I can also facilitate insulin action. Furthermore, significant reduction in total daily insulin dosage and reduction of body weight as observed during combination therapy renders SGLT-2I, a near-ideal partner to insulin. This review aims to evaluate the safety and efficacy of currently used SGLT-2I as an add-on to insulin therapy in the treatment of T2DM. PMID:26732230

  9. Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin: rationale and evidences.

    Science.gov (United States)

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are recently approved class of anti-hyperglycaemic agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT-2I inhibits renal glucose reabsorption, thereby ensuing urinary glucose excretion in a dose-dependent manner. This caloric loss and osmotic diuresis, secondary to increased urinary glucose excretion, has a unique potential to counter insulin induced weight gain and fluid retention, with little potential of hypoglycemic exacerbation. Also, as these agents act independently of insulin secretion or action, they are effective even in long-standing diabetes with depleted β-cell reserve. Improvement in insulin sensitivity, as observed with SGLT-2I can also facilitate insulin action. Furthermore, significant reduction in total daily insulin dosage and reduction of body weight as observed during combination therapy renders SGLT-2I, a near-ideal partner to insulin. This review aims to evaluate the safety and efficacy of currently used SGLT-2I as an add-on to insulin therapy in the treatment of T2DM.

  10. Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency.

    Science.gov (United States)

    Moldovan, Dumitru; Bernstein, Jonathan A; Cicardi, Marco

    2015-01-01

    Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA. PMID:26250409

  11. Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency.

    Science.gov (United States)

    Moldovan, Dumitru; Bernstein, Jonathan A; Cicardi, Marco

    2015-01-01

    Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

  12. Unusual location of tuberculosis in the course of tumor necrosis factor α inhibitor therapy.

    Science.gov (United States)

    Bielewicz-Zielińska, Agnieszka; Brzezicki, Jan; Rymko, Marcin; Jeka, Sławomir

    2015-01-01

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex mycobacteria. Extrapulmonary tuberculosis usually develops more than two years after infection or many years later. Factors favoring onset of the disease are malnutrition, older age, renal failure, diabetes, cancer, immunosuppression and biological treatment, e.g. tumor necrosis factor α (TNF-α) inhibitors. The paper presents a case of a 56-year-old patient with ankylosing spondylitis treated with infliximab, diagnosed with tuberculosis of the spleen. The unusual location and uncharacteristic symptoms created a lot of diagnostic difficulties, particularly as during qualification for biological treatment tests are performed to exclude infection with Mycobacterium tuberculosis. Pharmacological treatment of tuberculosis is typical, but in the case of tuberculosis of the spleen, splenectomy also is a method of treatment. The decision was made to implement pharmacological treatment, which proved to be effective, so the patient avoided surgery.

  13. Development of antibody-based c-Met inhibitors for targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Lee D

    2015-02-01

    Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

  14. KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy.

    Science.gov (United States)

    Chen, Guojun; Jaskula-Sztul, Renata; Harrison, April; Dammalapati, Ajitha; Xu, Wenjin; Cheng, Yiqiang; Chen, Herbert; Gong, Shaoqin

    2016-08-01

    Neuroendocrine (NE) cancers can cause significant patient morbidity. Besides surgery, there are no curative treatments for NE cancers and their metastases, emphasizing the need for the development of other forms of therapy. In this study, multifunctional unimolecular micelles were developed for targeted NE cancer therapy. The unimolecular micelles were formed by multi-arm star amphiphilic block copolymer poly(amidoamine)-poly(valerolactone)-poly(ethylene glycol) conjugated with KE108 peptide and Cy5 dye (abbreviated as PAMAM-PVL-PEG-KE108/Cy5). The unimolecular micelles with a spherical core-shell structure exhibited a uniform size distribution and excellent stability. The hydrophobic drug thailandepsin-A (TDP-A), a recently discovered HDAC inhibitor, was physically encapsulated into the hydrophobic core of the micelles. KE108 peptide, a somatostatin analog possessing high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), commonly overexpressed in NE cancer cells, was used for the first time as an NE cancer targeting ligand. KE108 exhibited superior targeting abilities compared to other common somatostatin analogs, such as octreotide, in NE cancer cell lines. The in vitro assays demonstrated that the TDP-A-loaded, KE108-targeted micelles exhibited the best capabilities in suppressing NE cancer cell growth. Moreover, the in vivo near-infrared fluorescence imaging on NE-tumor-bearing nude mice showed that KE108-conjugated micelles exhibited the greatest tumor accumulation due to their passive targeting and active targeting capabilities. Finally, TDP-A-loaded and KE108-conjugated micelles possessed the best anticancer efficacy without detectable systemic toxicity. Thus, these novel TDP-A-loaded and KE108-conjugated unimolecular micelles offer a promising approach for targeted NE cancer therapy. PMID:27156249

  15. Take your PIK: PI-3-kinase inhibitors race through the clinic and towards cancer therapy

    OpenAIRE

    Ihle, Nathan T.; Powis, Garth

    2009-01-01

    The phosphatidylinositol-3-kinase / Akt signaling pathway is currently one of the most exciting drug targets in oncology. However only a short time ago, the paradigm existed that drugs targeted to the four PI3K class 1 isoforms would be too toxic for use in cancer therapy due to effects on physiological signaling. Since that time studies have delineated the roles of these four isoforms in non-pathological signaling as well as their roles in cancer. An extensive effort has gone into developing...

  16. Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial

    DEFF Research Database (Denmark)

    Yeni, P; Cooper, DA; Aboulker, J-P;

    2006-01-01

    antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received...... participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262...

  17. Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Thomsen, Frederik B; Brasso, Klaus; Christensen, Ib J;

    2015-01-01

    BACKGROUND: The optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is still an issue of debate. METHODS: A randomised, double-blind, parallel-group trial comparing bicalutamide 150mg once daily with placebo in addition to standard care in patients with hormone-naïve, non...... to receive bicalutamide in addition to their standard care and 611 to receive placebo. Median follow-up was 14.6years. Overall, 866 (71.1%) patients died, 428 (70.5%) in the bicalutamide arm and 438 (71.7%) in the placebo arm, p=0.87. Bicalutamide significantly improved OS in patient with locally advanced...... disease (HR=1.19 (95% CI: 1.00-1.43), p=0.056). However, a survival gain from bicalutamide therapy was present in patients with localised disease and a baseline PSA greater than 28ng/mL at randomisation. In multivariate Cox proportional hazard model, only including patients managed on watchful waiting...

  18. Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Nicolae-Catalin; Mechie; Christian; Rver; Silke; Cameron; Ahmad; Amanzada

    2014-01-01

    AIM: To investigate the predictability of interleukin-28 B single nucleotide polymorphism rs12979860 with respect to sustained virological response(SVR) in chronically hepatitis C virus(HCV) genotype-1 patients treated with a protease-inhibitor and pegylated interferon-α(Peg-INF-α) based triple-therapy. METHODS: We searched PubMed, the Cochrane Library and Web of Knowledge for studies regarding the interleukin 28B(IL-28B)-genotype and protease-inhibitor based triple-therapy. Ten studies with 2707 patients were included into this meta-analysis. We used regression methods in order to investigate determinants of SVR.RESULTS: IL-28B-CC-genotype patients achieved higher SVR rates(odds 5.34, 95%CI: 3.81-7.49) than IL-28B-non-CC-genotype patients(1.88, 95%CI: 1.43-2.48) receiving triple-therapy. The line of therapy(treatment-nave or-experienced for Peg-INF-α) did not affect the predictive value of IL-28B(P = 0.1). IL-28BCC-genotype patients treated with protease inhibitorbased triple-therapy consisting of Boceprevir, Simeprevir, Telaprevir or Vaniprevir showed odds of 3.38, 14.66, 7.84 and 2.91, respectively. The odds for CC genotype patients treated with Faldaprevir cannot be quantified, as only a single study with a 100% SVR rate was available.CONCLUSION: IL-28B-SNP predicts the outcome for chronic HCV genotype-1 patients receiving protease inhibitor-based triple-therapy. The predictive value varies between the different protease inhibitors.

  19. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

  20. Receptor Tyrosine Kinase and Tyrosine Kinase Inhibitors: New Hope for Success in Multiple Sclerosis Therapy.

    Science.gov (United States)

    Mirshafiey, Abbas; Ghalamfarsa, Ghasem; Asghari, Babak; Azizi, Gholamreza

    2014-07-01

    Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate cell-to-cell communication and their function as relay points for signaling pathways. They have a key role in numerous processes that control cellular proliferation and differentiation, regulate cell growth and cellular metabolism, and promote cell survival and apoptosis. Recently, the role of RTKs including TCR, FLT-3, c-Kit, c-Fms, PDGFR, ephrin, neurotrophin receptor, and TAM receptor in autoimmune disorder, especially rheumatoid arthritis and multiple sclerosis has been suggested. In multiple sclerosis pathogenesis, RTKs and their tyrosine kinase enzymes are selective important targets for tyrosine kinase inhibitor (TKI) agents. TKIs, compete with the ATP binding site of the catalytic domain of several tyrosine kinases, and act as small molecules that have a favorable safety profile in disease treatment. Up to now, the efficacy of TKIs in numerous animal models of MS has been demonstrated, but application of these drugs in human diseases should be tested in future clinical trials.

  1. Computational design of apolipoprotein E4 inhibitors for Alzheimer's disease therapy from traditional Chinese medicine.

    Science.gov (United States)

    Huang, Hung-Jin; Chen, Hsin-Yi; Lee, Cheng-Chun; Chen, Calvin Yu-Chian

    2014-01-01

    Apolipoprotein E4 (Apo E4) is the major genetic risk factor in the causation of Alzheimer's disease (AD). In this study we utilize virtual screening of the world's largest traditional Chinese medicine (TCM) database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD) simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB) penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.

  2. Real life Dosages and Costs of TNFα inhibitor therapy for RA patients in Denmark

    DEFF Research Database (Denmark)

    Hostenkamp, Gisela; Sørensen, Jan; Hetland, Merete Lund

    2009-01-01

    an average dosage per kg body weight ratio was calculated from non-missing observations for reduced, standard and increased treatment regimes respectively and applied to patients with missing data on dosage. The annual dosage, duration and treatment costs were analysed at the end of each treatment line using...... of treatment. Cost estimates based on short term observational data or on instruction leaflets from manufacturers may provide wrong cost assessments of TNF-alpha therapy. It is important to take the long term cost structure into account to arrive at unbiased treatment cost estimates.......Background: When estimating the cost of biological treatment many analyses rely on cross sectional data or standard consumption patterns indicated in the manufacturers' instruction leaflet. Unless such consumption patterns truly reflect routine clinical practice they may result in wrong assumptions...

  3. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Krauze, Andra V. [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States); Myrehaug, Sten D. [Department of Radiation Oncology, Lakeridge Health Durham Regional Cancer Centre, Oshawa, Ontario (Canada); Chang, Michael G.; Holdford, Diane J. [Massey Cancer Center Virginia Commonwealth University, Richmond, Virginia (United States); Smith, Sharon; Shih, Joanna; Tofilon, Philip J. [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States); Fine, Howard A. [New York University Langone Medical Center, New York, New York (United States); Camphausen, Kevin, E-mail: camphauk@mail.nih.gov [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States)

    2015-08-01

    Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

  4. IMPACT OF THE THERAPY WITH TUMOR NECROSIS FACTOR α INHIBITORS ON THE FREQUENCY OF UVEITIS EXACERBATIONS IN PATIENTS WITH ANKYLOSING SPONDYLITIS

    Directory of Open Access Journals (Sweden)

    Alla A Godzenko

    2014-01-01

    Full Text Available The course of uveitis in patients with ankylosing spondylitis (AS does not always correlate with inflammation in the axial skeleton and peripheral joints. Effect of tumor necrosis factor α (TNFα inhibitors on uveitis has been insufficiently studied yet, unlike their effect on the peripheral joints and spine.Objective. To compare the frequency of uveitis attacks in patients with AS during treatment with TNFα inhibitors and the conventional anti-inflammatory therapy.Materials and Methods. The study included 48 patients with AS and recurrent uveitis treated with TNFα inhibitors: 25 – infliximab, 15 – adalimumab, 9 – etanercept; 7 patients received two or more drugs sequentially. Median [25th, 75th percentiles] of the treatment duration was 3 [3.5; 5] years. The duration of treatment since the first attack of uveitis until administration of TNFα inhibitors was 5 [5; 9.7] years. Eighteen patients received only nonsteroidal anti-inflammatory drugs (NSAIDs, 30 patients received NSAIDs and basic anti-inflammatory drugs (DMARDs, including sulfasalazine (n = 23, methotrexate (n = 4, and cyclosporine (n = 4.Results. The median number of uveitis exacerbations during the standard anti-inflammatory therapy was 1 [0.4; 3] per year; during treatment with TNFα inhibitors – 0 [0; 0.5] per year (p = 0.0007. In 19 of 48 patients (40%, no exacerbations of uveitis were registered during therapy with these drugs. The frequency of uveitis attacks in patients treated with infliximab decreased from 1 [0.2; 2.75] to 0.1 [0; 0.8] episodes per year (p = 0.002, adalimumab – from 1.75 [1; 4.5] to 0 [0; 0.07] (p = 0.04, etanercept – from 0.95 [0.5; 1.75] to 0 [0; 0.07] (p = 0.001.Conclusion. Administration of TNFα inhibitors significantly reduces the frequency of uveitis attacks in patients with AS.

  5. Oral versus intravenous proton pump inhibitors in preventing re-bleeding for patients with peptic ulcer bleeding after successful endoscopic therapy

    Directory of Open Access Journals (Sweden)

    Yen Hsu-Heng

    2012-06-01

    Full Text Available Abstract Background High dose intravenous proton pump inhibitor after endoscopic therapy for peptic ulcer bleeding has been recommended as adjuvant therapy. Whether oral proton pump inhibitor can replace intravenous proton pump inhibitor in this setting is unknown. This study aims to compare the clinical efficacy of oral and intravenous proton pump inhibitor after endoscopic therapy. Methods Patients with high-risk bleeding peptic ulcers after successful endoscopic therapy were randomly assigned as oral lansoprazole or intravenous esomeprazole group. Primary outcome of the study was re-bleeding rate within 14 days. Secondary outcome included hospital stay, volume of blood transfusion, surgical intervention and mortality within 1 month. Results From April 2010 to Feb 2011, 100 patients were enrolled in this study. The re-bleeding rates were 4% (2/50 in the intravenous group and 4% (2/50 in the oral group. There was no difference between the two groups with regards to the hospital stay, volume of blood transfusion, surgery or mortality rate. The mean duration of hospital stay was 1.8 days in the oral lansoprazole group and 3.9 days in the intravenous esomeprazole group (p > 0.01. Conclusion Patients receiving oral proton pump inhibitor have a shorter hospital stay. There is no evidence of a difference in clinical outcomes between oral and intravenous PPI treatment. However, the study was not powered to prove equivalence or non-inferiority. Future studies are still needed. Trial registration NCT01123031

  6. Switching to Letrozole Versus Continued Tamoxifen Therapy in Treatment of Postmenopausal Women with Early Breast Cancer

    International Nuclear Information System (INIS)

    Tamoxifen has been the mainstay of breast cancer therapy. Over time, resistance to tamoxifen may develop. The aromatase inhibitors have proven to be a powerful drug for use in hormone-sensitive early breast cancer. The switching strategy was designed to combine the apparent superior efficacy of aromatase inhibitors with tamoxifen favourable effects. Methods: This study was performed on 120 postmenopausal women with histologically confirmed, hormone receptor-positive, operable invasive breast carcinoma who remained free of disease after 2 years of adjuvant tamoxifen therapy. They were randomized to receive either letrozole 2.5 mg/day (60 patients) or to continue 20 mg/day tamoxifen for 5 years (60 patients). Results: The treatment groups were well balanced in terms of age, tumor size, nodal status, oestrogen and progesterone receptor status, and previous surgery. The disease recurred in 10 patients in the group receiving tamoxifen and 3 patients in the same group switched to letrozole. There were 8 deaths in the group receiving tamoxifen and 3 deaths in the group of patients who switched to letrozole. Disease-free survival was higher in the group of patients who switched to letrozole compared to the group of patients who received tamoxifen (p=0.04), while the overall survival was not statistically significantly different in the two groups. Letrozole was associated with a significantly lower rate of vaginal bleeding and thromboembolic events. However, bone fractures and adverse cardiovascular events were more frequent in the arm receiving letrozole than in the arm receiving tamoxifen but these differences were not statistically significant. Conclusion: Switching to letrozole after 2 years of tamoxifen may be better than continuing five years of tamoxifen therapy as regard efficacy and tolerability. Further study is recommended on a larger group of patients to verify this finding

  7. Proton Pump Inhibitor Therapy Is Associated With Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation

    Science.gov (United States)

    Kang, Seong Hee; Yim, Hyung Joon; Kim, Seung Young; Suh, Sang Jun; Hyun, Jong Jin; Jung, Sung Woo; Jung, Young Kul; Koo, Ja Seol; Lee, Sang Woo

    2016-01-01

    Abstract Endoscopic variceal band ligation (EVL) is an effective procedure to control and prevent variceal bleeding in patients with liver cirrhosis, but it can be complicated by bleeding from post-EVL ulcers. Several studies have reported that proton pump inhibitors (PPIs) decrease the size of post-EVL ulcers. However, evidence are limited as to whether PPIs actually reduce the risk of bleeding after EVL. This study aimed to analyze the factors associated with bleeding after prophylactic EVL and to assess the effect of PPI therapy. Five hundred and five cirrhotic patients with high risk esophageal varices who received primary prophylactic EVL were included for this retrospective cohort study. Post-EVL bleeding was defined as bleeding after prophylactic EVL within 8 weeks evidenced by the occurrence of melena or hematemesis, or by a decrease of hemoglobin by >2.0 g/dL. If evidence of bleeding from ulceration of the EVL sites was confirmed by endoscopy, we defined it as post-EVL ulcer bleeding. Fourteen patients developed bleeding after prophylactic EVL. Factors associated with post-EVL bleeding included alcohol as etiology, low albumin, high total bilirubin, high Child-Pugh score, high MELD score, coexistence of gastric varices, and not administrating PPI medication by univariate analysis. In multivariate logistic analysis, Co-existing gastric varix (odds ratio [OR] 5.680, P = 0.005] and not administrating PPIs (OR 8.217, P = 0.002) were associated with bleeding after prophylactic EVL. In the subgroup analysis excluding patients whose gastric varices were treated, not administering PPI medication (OR 8.827, P = 0.008) was the sole factor associated with post-EVL bleeding. We suggest that PPI therapy needs to be considered in patients receiving prophylactic EVL to reduce the risk of bleeding after prophylactic EVL. PMID:26937932

  8. Plasma tissue inhibitor of matrix metalloproteinase-1 (TIMP-1): an independent predictor of poor response to cardiac resynchronization therapy

    Science.gov (United States)

    Tolosana, Jose María; Mont, Lluís; Sitges, Marta; Berruezo, Antonio; Delgado, Victoria; Vidal, Bàrbara; Tamborero, David; Morales, Manel; Batlle, Montserrat; Roig, Eulalia; Castel, M. Angeles; Pérez-Villa, Félix; Godoy, Miguel; Brugada, Josep

    2010-01-01

    Aims Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors of poor response to cardiac resynchronization therapy (CRT). Methods and results A cohort of 42 CRT patients from our centre was prospectively evaluated at baseline and after 12-month follow-up. MMP-2 and TIMP-1 assays were performed prior to CRT implant. Cardiac resynchronization therapy responders were defined as patients who survived, were not transplanted, and increased their basal 6 min walking distance test (6MWDT) by ≥10% or improved their NYHA functional class. Overall, 25 patients (60%) were classed as responders. At 12-month follow-up, six patients (14.2%) had died and one (2.4%) patient had been transplanted. Compared with responders, non-responders had higher levels of TIMP-1 (277 ± 59 vs. 216 ± 46 ng/mL, P = 0.001), MMP-2 (325 ± 115 vs. 258 ± 56 ng/mL, P = 0.02), and creatinine (1.76 ± 0.8 vs. 1.25 ± 0.3 mg/dL, P = 0.01). In a multivariate analysis, TIMP-1 was the only independent predictor of non-response to CRT [OR 0.97, 95% (CI 0.96–0.99) P = 0.005]. TIMP-1≥248 ng/mL predicted non-response with 71% sensitivity and 72% specificity. Conclusion TIMP-1 is an independent predictor of non-response in patients treated with CRT. PMID:20360066

  9. Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy.

    Science.gov (United States)

    Ali, Mohamed A M

    2016-08-01

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q-. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms-either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling-have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs. PMID:27220498

  10. Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Imad M Tleyjeh

    Full Text Available INTRODUCTION: Emerging epidemiological evidence suggests that proton pump inhibitor (PPI acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI. METHODS: Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. RESULTS: We identified 47 eligible citations (37 case-control and 14 cohort studies with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85, I(2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26-1.83. In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. CONCLUSIONS: In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class for an association between PPI use and CDI that does not support a cause-effect relationship.

  11. Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer.

    Science.gov (United States)

    Yang, Shih-Hung; Kuo, Ting-Chun; Wu, Hsu; Guo, Jhe-Cyuan; Hsu, Chiun; Hsu, Chih-Hung; Tien, Yu-Wen; Yeh, Kun-Huei; Cheng, Ann-Lii; Kuo, Sung-Hsin

    2016-08-28

    Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to co-administration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA double-strand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer. PMID:27621574

  12. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis: A Meta-Analysis.

    Science.gov (United States)

    Liang, Hui; Li, Wen-Rong; Zhang, Hua; Tian, Xu; Wei, Wei; Wang, Chun-Mei

    2015-12-01

    Since the use of tumor necrosis factor (TNF) inhibitor therapy is becoming wider, the effects of concurrent intervention with exercises and stabilized TNF inhibitors therapy in patients with ankylosing spondylitis (AS) are different. The study aimed to objectively evaluate whether concurrent intervention with exercises and stabilized TNF inhibitors can reduce the disease activity in patients with AS. A search from PubMed, Web of Science, EMBASE, and the Cochrane Library was electronically performed to collect studies which compared concurrent intervention with exercise and TNF inhibitor to conventional approach in terms of disease activity in patients with AS published from their inception to June 2015. Studies that measured the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), and chest expansion as outcomes were included. Two independent investigators screened the identified articles, extracted the data, and assessed the methodological quality of the included studies. Quantitative analysis was performed with Review Manager (RevMan) software (version 5.3.0). A total of 5 studies comprising 221 participants were included in the study. Meta-analyses showed that concurrent intervention with exercises and stabilized TNF inhibitors therapy significantly reduced the BASMI scores (MD, -0.99; 95% CI, -1.61 to -0.38) and BASDAI scores (MD, -0.58; 95% CI, -1.10 to -0.06), but the BASFI scores (MD, -0.31; 95% CI, -0.76 to 0.15) was not reduced, and chest expansion (MD, 0.80; 95% CI, -0.18 to 1.78) was not increased. Concurrent intervention with exercises and stabilized TNF inhibitors therapy can reduce the disease activity in patients with AS. More randomized controlled trials (RCTs) with high-quality, large-scale, and appropriate follow-up are warranted to further establish the benefit of concurrent intervention with exercises and TNF inhibitors for

  13. Effects of aromatase inhibition on spatial working memory and hippocampal astrocyte numbers

    OpenAIRE

    José I. Arias; Héctor González-Pardo; Nélida M. Conejo; Jorge L. Arias

    2012-01-01

    Sex hormones are known to induce the sexual differentiation of the brain during early development in mammals. Testosterone secreted by males already during gestation is classically believed to contribute to brain and behavioural sexual differentiation thanks to its conversion to estradiol by the enzyme aromatase. However, there is evidence suggesting that aromatase inhibition may also impair cognitive functions in women receiving hormonal treatment for breast cancer. In order to evaluate the ...

  14. Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis

    Directory of Open Access Journals (Sweden)

    Maia Jr H

    2012-02-01

    Full Text Available Hugo Maia Jr1,2, Clarice Haddad1,2, Julio Casoy11CEPARH, 2Itaigara Memorial Day Hospital, Salvador, Bahia, BrazilObjective: To investigate whether aromatase expression in the eutopic endometrium correlates with the presence and severity of endometriosis in patients with infertility and/or dysmenorrhea undergoing laparoscopy and hysteroscopy.Patients: The study involved 106 patients of reproductive age with symptoms of dysmenorrhea and infertility. Sixteen endometriosis-free asymptomatic patients were used as a control group.Methods: Concomitant laparoscopy and hysteroscopy was carried out in all cases. An endometrial biopsy was taken to determine aromatase p450 expression by immunohistochemistry. Endometriosis was staged according to the American Society of Reproductive Medicine classification.Results: Endometriosis was diagnosed by laparoscopy in 92/106 symptomatic patients. In this group, aromatase expression was detected in the eutopic endometrium of 66/92 patients with endometriosis (72% and in 13/14 (95% patients in the symptomatic, endometriosis-free group (P = 0.09. Aromatase expression was not detected in any patients from the control group. In the endometriosis group, aromatase expression was detected in the eutopic endometrium of 28/45 patients (62% with American Society of Reproductive Medicine classification stage 1 of the disease, in 11/14 patients (78% with stage II, 14/20 patients (70% with stage III, and in 12/13 patients (92% with stage IV; however, the difference was only statistically significant between stages I and IV (P = 0.04.Conclusion: Aromatase expression in the endometrium was associated with the presence of dysmenorrhea and infertility irrespective of the presence of endometriosis. When endometriosis was present, however, there was a tendency for aromatase expression to be positively correlated with dysmenorrhea severity.Keywords: aromatase, endometrium, endometriosis, Cox-2, dysmenorrhea

  15. Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk

    OpenAIRE

    Siegelmann-Danieli, N; Buetow, K H

    1999-01-01

    The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat...

  16. SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives

    Science.gov (United States)

    Gurgle, Holly E; White, Karen; McAdam-Marx, Carrie

    2016-01-01

    Controversy exists regarding the selection of second-line therapy for patients with type 2 diabetes mellitus (T2DM) who are unable to achieve glycemic control with metformin therapy alone. Newer pharmacologic treatments for T2DM include glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors. Both the classes of medication are efficacious, exhibit positive effects on weight, and are associated with minimal risk of hypoglycemia. The purpose of this review is to compare the clinical trial and real-world effectiveness data of glucagon-like peptide-1 receptor agonists versus sodium–glucose cotransporter 2 inhibitors related to A1c reduction, weight loss, cost-effectiveness, cardiovascular outcomes, and safety in patients with T2DM. This review summarizes comparative evidence for providers who are determining which of the two classes may be the most appropriate for a specific patient. PMID:27350752

  17. HORMONE THERAPY IN ADVANCED ER+/HER2- NEGATIVE BREAST CANCER WITH PI3K INHIBITORS: A REVIEW OF THE LITERATURE

    Directory of Open Access Journals (Sweden)

    Ivan Inkov

    2016-08-01

    Full Text Available Breast cancer is a heterogenous disease, showing as several different clinical and histologic types. Most of breast cancers express hormone receptors for estrogen and progesterone, which are considered as estrogen receptor-positive and progesterone-receptor-positive, respectively. Endocrine therapy was the first class of target-directed therapy approved for treating breast cancer and is still very important for the treatment of HR+ breast cancer because of its effectiveness and good toxicity profile. It targets receptor-mediated signaling pathways implicated in cell survival and proliferation, such as those mediated by hormone receptors. Although these approaches have improved the management of advanced breast cancer, many patients either fail to respond to initial therapy (primary or de novo resistance or eventually become resistant to treatment (secondary or acquired resistance. To expand the use of existing endocrine treatments and their efficiency, new methods are needed. Such new approaches would boost the benefit of existing endocrine therapy by extending time to disease progression, avoiding or overcoming resistance to endocrine treatment, and delaying the use of chemotherapy. This article will review the central role of the PI3K inhibitors in driving ER+/HER2- breast tumors. Also, schemes to combine pathway inhibitors with endocrine therapy for better patient outcome, and approaches to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway will be assessed.

  18. Sodium–glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin–metformin

    Science.gov (United States)

    Schwartz, Stanley S; Katz, Arie

    2016-01-01

    In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium–glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy. PMID:27042132

  19. Sodium-glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin-metformin.

    Science.gov (United States)

    Schwartz, Stanley S; Katz, Arie

    2016-01-01

    In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy. PMID:27042132

  20. Clinical Characteristics and Metabolic Predictors of Rapid Responders to Dipeptidyl Peptidase-4 Inhibitor as an Add-on Therapy to Sulfonylurea and Metformin

    Directory of Open Access Journals (Sweden)

    Ye An Kim

    2015-12-01

    Full Text Available BackgroundDipeptidyl peptidase-4 (DPP-4 inhibitor add-on therapy is a new option for patients with inadequately controlled type 2 diabetes who are taking combined metformin and sulfonylurea (SU. We evaluated the efficacy and safety of this triple therapy and the characteristics of rapid responders and hypoglycemia-prone patients.MethodsWe included 807 patients with type 2 diabetes who were prescribed a newly added DPP-4 inhibitor to ongoing metformin and SU in 2009 to 2011. Glycemia and other metabolic parameters at baseline, 12, 24, and 52 weeks, as well as episodes of hypoglycemia were analyzed. Rapid responders were defined as patients with ≥25% reduction in glycosylated hemoglobin (HbA1c within 12 weeks.ResultsAt baseline, while on the submaximal metformin and SU combination, the mean HbA1c level was 8.4%. Twelve weeks after initiation of DPP-4 inhibitor add-on, 269 patients (34.4% achieved an HbA1c level ≤7%. Sixty-six patients (8.2%, 47 men were rapid responders. The duration of diabetes was shorter in rapid responders, and their baseline fasting plasma glucose (FPG, HbA1c, C-peptide, and homeostasis model assessment of insulin resistance were significantly higher. Patients who experienced hypoglycemia after taking DPP-4 inhibitor add-on were more likely to be female, to have a lower body weight and lower triglyceride and FPG levels, and to have higher homeostasis model assessment of β-cells.ConclusionAn oral hypoglycemic triple agent combination including a DPP-4 inhibitor was effective in patients with uncontrolled diabetes. Proactive dose reduction of SU should be considered when a DPP-4 inhibitor is added for rapid responders and hypoglycemia-prone patients.

  1. Aromatase expression is linked to estrogenic sensitivity of periurethral muscles in female rabbits.

    Science.gov (United States)

    de los Ángeles Carrasco-Ruiz, María; García-Villamar, Verónica; López-García, Kenia; Sánchez-García, Octavio; Pacheco, Pablo; Cuevas, Estela; Martínez-Gómez, Margarita; Castelán, Francisco

    2015-06-01

    Beyond its role in the conversion of androgens to estrogens, the expression of aromatase could influence on the estrogenic signalling in targeted tissues. Considering the well-defined biochemical and physiological differences between the pubococcygeus (Pcm) and bulbospongiosus (Bsm) muscles in female rabbits, it is presently hypothesized that the aromatase expression is differentially linked to the estrogen sensitivity of each muscle. To this end, serum estradiol levels and the aromatase expression, presence of ERα and ERβ and morphometry were evaluated in the Pcm and Bsm of female rabbits allocated in control, ovariectomized (OVX) and OVX treated with estradiol benzoate (OVX + EB) groups. Aromatase expression was high in the Pcm. Independently to serum estradiol, ovariectomy increased aromatase expression in the Pcm while decreased it in the Bsm. The EB treatment avoided the effect of ovariectomy only in the Pcm. The number of immunoreactive nuclei anti-ERα and anti-ERβ was high in the Pcm of OVX and OVX + EB rabbits, while those in the Bsm remained unchanged. The number of peripheral nuclei per fibre and the cross-sectional area-to-myonucleus ratio were modified only in the Pcm. Our findings support aromatase expression in the Pcm, and Bsm of rabbits is differentially linked to estrogenic sensitivity of each muscle.

  2. Overexpression of aromatase alone is sufficient for ovarian development in genetically male chicken embryos.

    Directory of Open Access Journals (Sweden)

    Luke S Lambeth

    Full Text Available Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterised steroidogenic pathway, which is a multi-step process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1 is expressed female-specifically from the time of gonadal sex differentiation. To further explore the role of aromatase in sex determination, we ectopically delivered this enzyme using the retroviral vector RCASBP in ovo. Aromatase overexpression in male chicken embryos induced gonadal sex-reversal characterised by an enlargement of the left gonad and development of ovarian structures such as a thickened outer cortex and medulla with lacunae. In addition, the expression of key male gonad developmental genes (DMRT1, SOX9 and Anti-Müllerian hormone (AMH was suppressed, and the distribution of germ cells in sex-reversed males followed the female pattern. The detection of SCP3 protein in late stage sex-reversed male embryonic gonads indicated that these genetically male germ cells had entered meiosis, a process that normally only occurs in female embryonic germ cells. This work shows for the first time that the addition of aromatase into a developing male embryo is sufficient to direct ovarian development, suggesting that male gonads have the complete capacity to develop as ovaries if provided with aromatase.

  3. A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy

    OpenAIRE

    Wattmo, Carina

    2013-01-01

    Carina Wattmo, Elisabeth Paulsson, Lennart Minthon, Elisabet LondosClinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, SwedenBackground: To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer’s disease (AD).Methods: This 3-year, prospective, multicenter study ...

  4. A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy

    OpenAIRE

    Wattmo C; Paulsson E; Minthon L; Londos E

    2013-01-01

    Carina Wattmo, Elisabeth Paulsson, Lennart Minthon, Elisabet LondosClinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, SwedenBackground: To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer’s disease (AD).Methods: This 3-year, prospective, multicenter study ...

  5. In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy

    OpenAIRE

    Craveiro, Rogerio B.; Ehrhardt, Michael; Holst, Martin I.; Pietsch, Thorsten; Dilloo, Dagmar

    2014-01-01

    Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the o...

  6. Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Anna Maria Geretti

    Full Text Available BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption. METHODS: Resistance-associated mutations (RAMs and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography. RESULTS: Four weeks after NNRTI interruption, 19/31 (61.3% and 34/39 (87.2% patients showed measurable nevirapine (>0.25 ng/ml or efavirenz (>5 ng/ml concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8% patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01 with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(tide reverse transcriptase inhibitors (NRTIs were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03. After restarting NNRTI-based ART (n = 90, virologic suppression rates <400 copies/ml were 8/13 (61.5% with NNRTI-RAMs, 7/11 (63.6% with NRTI-RAMs only, and 51/59 (86.4% without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89 and 0.17 (95% CI 0.03, 1.15 for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04. CONCLUSIONS

  7. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer

    DEFF Research Database (Denmark)

    Mouridsen, H.; Giobbie-Hurder, A.; Goldhirsch, A.;

    2009-01-01

    BACKGROUND: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone. METHODS......: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment...... with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women. RESULTS: At a median follow-up of 71 months after randomization, disease-free survival...

  8. Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

    Directory of Open Access Journals (Sweden)

    Podda Mauro

    2010-05-01

    Full Text Available Abstract Introduction A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. Case presentation We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. Conclusion We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

  9. The Comparison of Acceptance and Commitment Therapy with Selective Serotonin Reuptake Inhibitors in the Treatment of Obsessive-Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    Yaghoob Vakili

    2014-08-01

    Full Text Available Background: The aim of this study was to compare the effectiveness of acceptance and commitment therapy (ACT, selective serotonin reuptake inhibitors (SSRIs, and the combination of ACT and SSRIs in the treatment of adults with obsessive-compulsive disorder (OCD. Materials and Methods: In This experimental study 32 outpatients meeting DSM-IV-TR criteria for OCD were randomly assigned to one of three treatment conditions: ACT, SSRIs, and combined treatment. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS, Beck Depression Inventory-II-Second edition (BDI-II, and Beck Anxiety Inventory (BAI were administered at pre- and post-treatment. Twenty-seven patients completed the study. Data were analyzed by one-way analysis of variance (ANOVAs and one - way analysis of covariance (ANCOVAs, clinically significant change, and complete remission status. Results: Analyses with ANCOVA revealed that the patients treated with ACT and combined treatment experienced a significantly greater improvement in obsessive- compulsive symptoms at post-treatment as compared to those treated with SSRIs alone. However, there were no significant differences between ACT and combined treatment on OC symptoms. In addition, no significant differences were found between all the 3 treatment groups regarding reduction in the BDI-II and BAI scores at post-treatment. Clinically significant change and complete remission status results also showed that, unlike the SSRI, the ACT and combined treatment lead to more improvement in OC symptoms. Conclusion: ACT and combined treatment are more effective than SSRIs alone in treating OC symptoms. However, it seems that adding SSRIs to ACT does not increase the effectiveness of ACT in the treatment of adults with OCD in the short-term.

  10. The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression.

    Science.gov (United States)

    Traish, Abdulmaged M; Mulgaonkar, Ashwini; Giordano, Nicholas

    2014-06-01

    With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy. PMID:24955220

  11. Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy.

    Science.gov (United States)

    Karamchand, Sumanth; Leisegang, Rory; Schomaker, Michael; Maartens, Gary; Walters, Lourens; Hislop, Michael; Dave, Joel A; Levitt, Naomi S; Cohen, Karen

    2016-03-01

    Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged. PMID:26945366

  12. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    C. Wang

    2013-03-01

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  13. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    C. Wang

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  14. Long-Term Drug Survival of TNF Inhibitor Therapy in RA Patients: A Systematic Review of European National Drug Registers

    OpenAIRE

    Arora, Anamika; Mahajan, Anadi; Spurden, Dean; Boyd, Helen; Porter, Duncan

    2013-01-01

    Objective. The present systematic review of RA registry data was undertaken to analyse the time on treatment of licensed TNF inhibitors in patients with RA in Europe. Methods. English language European registry studies comparing TNF inhibitors were searched using MEDLINE, Embase, Cochrane, and WHO: ICTRP up to 16 April 2012 and proceedings of three selected conferences held between 2010 and 2012. Pooled analysis was performed to determine drug survival rates for each TNF inhibitor. Results. S...

  15. Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes

    OpenAIRE

    Shapiro, Amy D.; Hedner, Ulla

    2011-01-01

    In the past, patients with hemophilia and inhibitors have had less-than-optimal treatment and have experienced more orthopedic complications than patients without inhibitors. Bypassing agents offer the potential to close treatment gaps between inhibitor and noninhibitor patients by helping the former better attain key treatment goals, including: facilitating early initiation of treatment and hemostatic control in hemarthroses; providing effective treatment in serious hemorrhagic episodes; and...

  16. Fueling the engine and releasing the break:combinational therapy of cancer vaccines and immune checkpoint inhibitors

    Institute of Scientific and Technical Information of China (English)

    Jennifer Kleponis; Richard Skelton; Lei Zheng

    2015-01-01

    Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-inifltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.

  17. Scleroderma renal crisis during intravenous cyclophosphamide pulse therapy for complicated interstitial lung disease was successfully treated with angiotensin converting enzyme inhibitor and plasma exchange.

    Science.gov (United States)

    Nagamura, Norihiro; Kin, Seikon

    2016-08-01

    Systemic sclerosis (SSc) is a multiorgan disorder involving the skin, heart, lungs, kidneys, and intestines. Progressive interstitial lung disease (ILD) is a serious complication in SSc patients, and cyclophosphamide (CYC) is the only recommended therapy for this condition;(1)) however, its clinical effectiveness is not sufficient. Scleroderma renal crisis (SRC) is a rare complication, characterized by acute renal failure and progressive hypertension. Angiotensin-converting-enzyme inhibitor (ACE-i) is a widely accepted therapy for SRC. We report an SSc patient with SRC and progressive ILD who underwent treatment with CYC and successful treatment with ACE-i and plasma exchange (PE). SRC and ILD are significant contributors to morbidity and mortality among SSc patients, and the therapy for these disorders is of great interest to rheumatologists. This study presents the possibility of favorable effects of PE for SSc-associated ILD and SRC. PMID:27578917

  18. P450-aromatase activity and expression in human testicular tissues with severe spermatogenic failure.

    Science.gov (United States)

    Lardone, M C; Castillo, P; Valdevenito, R; Ebensperger, M; Ronco, A M; Pommer, R; Piottante, A; Castro, A

    2010-08-01

    There is evidence that impaired spermatogenesis is associated with an imbalance in the oestradiol/testosterone ratio and with Leydig cell (LC) dysfunction. In testis, P450-aromatase, encoded by CYP19, is responsible for the conversion of testosterone to oestradiol. The aims of this study were to quantify CYP19 mRNA expression, aromatase activity and protein localization, and to measure the oestradiol to testosterone ratio in testicular tissues of men with spermatogenic impairment. Twenty-four men with complete Sertoli cell-only syndrome (SCOS), 14 with focal SCOS, 14 with maturation arrest (MA), 8 with mixed atrophy and 30 controls with normal spermatogenesis were subjected to testicular biopsy. All subjects underwent a physical examination, cytogenetic and serum hormonal studies. Testicular CYP19 mRNA was quantified using real time RT-PCR. Testicular aromatase activity was measured using the (3)H(2)0 assay and protein expression was evaluated using immunohistochemistry. In cases, serum testosterone and oestradiol were normal, but the testosterone/LH ratio was lower compared with controls (p < 0.05). Aromatase was localized in the Leydig, Sertoli and germ cells of all tissues, although stronger intensity was observed in LC. Aromatase mRNA and activity were not altered in cases and correlated positively with LC number (r = 0.516 and r = 0.369; p < 0.008). The intratesticular oestradiol/testosterone ratio was elevated (p = 0.005) in complete SCOS patients compared with controls. In conclusion, testicular aromatase seems to be normal in most subjects with impaired spermatogenesis. However, an altered intratesticular oestradiol/testosterone ratio in some patients with complete SCOS suggests that aromatase is increased, which might contribute to Leydig cell dysfunction.

  19. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anti-cancer therapies

    Science.gov (United States)

    Matthews, Thomas P; Jones, Alan M; Collins, Ian

    2014-01-01

    Introduction Checkpoint kinase inhibitors offer the promise of enhancing the effectiveness of widely prescribed cancer chemotherapies and radiotherapy by inhibiting the DNA damage response, as well as the potential for single agent efficacy. Areas covered This article surveys structural insights into the checkpoint kinases CHK1 and CHK2 that have been exploited to enhance the selectivity and potency of small molecule inhibitors. The use of mechanistic cellular assays to guide the optimisation of inhibitors is reviewed. The status of the current clinical candidates and emerging new clinical contexts for CHK1 and CHK2 inhibitors are discussed, including the prospects for single agent efficacy. Expert opinion Protein bound water molecules play key roles in structural features that can be targeted to gain high selectivity for either enzyme. The results of early phase clinical trials of checkpoint inhibitors have been mixed, but significant progress has been made in testing the combination of CHK1 inhibitors with genotoxic chemotherapy. Second generation CHK1 inhibitors are likely to benefit from increased selectivity and oral bioavailability. While the optimum therapeutic context for CHK2 inhibition remains unclear, the emergence of single agent preclinical efficacy for CHK1 inhibitors in specific tumour types exhibiting constitutive replication stress represents exciting progress in exploring the therapeutic potential of these agents. PMID:23594139

  20. ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN ACUTE MYOCARDIAL INFARCTION: WHEN TO START THERAPY AND WHICH DRUG TO USE?

    OpenAIRE

    S. Y. Martsevich; S. N. Tolpygina

    2015-01-01

    Data of studies devoted to application of angiotensin converting enzyme (ACE) inhibitors in acute myocardial infarction are reviewed. The reasons of ambiguous results are discussed. A point of view that different ACE inhibitors may have the various efficacy and safety in patients with acute myocardial infarction is suggested.

  1. Sodium–glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin–metformin

    Directory of Open Access Journals (Sweden)

    Schwartz SS

    2016-03-01

    Full Text Available Stanley S Schwartz,1,2 Arie Katz3 1University of Pennsylvania, Philadelphia, PA, USA; 2Main Line Health System, Ardmore, PA, USA; 3AstraZeneca, Fort Washington, PA, USA Abstract: In type 2 diabetes (T2D, early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium–glucose cotransporter-2 (SGLT-2 inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy. Keywords: combination therapy, dapagliflozin, metformin

  2. 哺乳动物雷帕霉素靶蛋白抑制剂与肿瘤治疗%Mammalian target of rapamycin inhibitors and tumor therapy

    Institute of Scientific and Technical Information of China (English)

    李欣; 杨作成

    2012-01-01

    Mammalian target of rapamycin(mTOR) inhibitors have the anti-tumor ettect,which have been known early.The traditional mTOR inhibitors include rapamycin and its derivatives,which have been applied in clinical use early.Nowadays,some new small molecule inhibitors such as the PI3K/mTOR duel inhibitor,Torinl,one after another are found to play a unique role in the tumor therapy.%哺乳类动物雷帕霉素靶蛋白(mTOR)抑制剂的抗肿瘤作用已被熟知,传统的mTOR抑制剂包括雷帕霉素及其衍生物,早期已应用于临床.目前mTOR小分子抑制剂如磷脂酰肌醇激酶3-激酶(PI3K)/mTOR双重抑制剂、Torinl等陆续被发现在肿瘤治疗中有着独特的作用.

  3. Does the Angiotensin-converting enzyme (ACE gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

    Directory of Open Access Journals (Sweden)

    Perna Annalisa

    2005-10-01

    Full Text Available Abstract Background Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease. Methods Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality. Results Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes. Conclusion Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers.

  4. Long-Term Drug Survival of TNF Inhibitor Therapy in RA Patients: A Systematic Review of European National Drug Registers

    Directory of Open Access Journals (Sweden)

    Anamika Arora

    2013-01-01

    Full Text Available Objective. The present systematic review of RA registry data was undertaken to analyse the time on treatment of licensed TNF inhibitors in patients with RA in Europe. Methods. English language European registry studies comparing TNF inhibitors were searched using MEDLINE, Embase, Cochrane, and WHO: ICTRP up to 16 April 2012 and proceedings of three selected conferences held between 2010 and 2012. Pooled analysis was performed to determine drug survival rates for each TNF inhibitor. Results. Sixteen studies met the inclusion criteria, of which 11 studies assessed biologic-naive patients and five studies included a mixed population of biologic-naive and biologic pretreated patients. The overall effectiveness of TNF inhibitors diminished with time, leading to decreased drug survival rates. Pooled drug survival rates after 60 months follow-up were 37% (infliximab, 48% (adalimumab, and 52% (etanercept. Further, in an observational study, when TNF inhibitors were used in combination with methotrexate, a longer drug survival was observed compared to TNF inhibitors alone. Conclusion. The findings of this systematic review indicated numerically lower drug discontinuation rates with etanercept than adalimumab, whereas infliximab had the highest rate. Further research is needed to understand the underlying mechanisms of treatment discontinuation with TNF inhibitors.

  5. Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization

    International Nuclear Information System (INIS)

    A simple and efficient method is described for the purification of microsomal aromatase cytochrome P-450 from human placenta. The enzyme was solubilized with Emulgen 913 and sodium cholate and subjected to chromatography on a column of Sepharose 4B couples with a specific monoclonal antibody, followed by hydroxyapatite column chromatography. The specific cytochrome P-450 content of purified aromatase was 13.1 (12-14.8) nmol/mg of protein. Aromatase assays were carried out with reconstituted systems of bovine liver P-450 reductase and dilauroyl-L-α-phosphatidylcholine with [1β-3H,4-14C]androstenedione as substrate. The total recovery of purified aromatase activity was 32.2%, and P-450 recovery was 17.6%. The very high Km value for 16α-hydroxytestosterone aromatization gives a reasonable indication that estriol is not the directly aromatized product in the fetoplacental unit of human pregnancy. The aromatase P-450 was subjected to SDS-polyacrylamide gel electrophoresis in increasing quantities. Silver stain detection techniques indicated a single band having a molecular mass of 55 kDa with greater than 97% purity. The stability analysis showed a half-life of over 4 years on storage at -80C

  6. The use of fractal dimension analysis in estimation of blood vessels shape in transplantable mammary adenocarcinoma in Wistar rats after photodynamic therapy combined with cysteine protease inhibitors.

    Science.gov (United States)

    Jurczyszyn, Kamil; Osiecka, Beata J; Ziółkowski, Piotr

    2012-01-01

    Fractal dimension analysis (FDA) is modern mathematical method widely used to describing of complex and chaotic shapes when classic methods fail. The main aim of this study was evaluating the influence of photodynamic therapy (PDT) with cystein proteases inhibitors (CPI) on the number and morphology of blood vessels inside tumor and on increase of effectiveness of combined therapy in contrast to PDT and CPI used separately. Animals were divided into four groups: control, treated using only PDT, treated using only CPI and treated using combined therapy, PDT and CPI. Results showed that time of animal survival and depth of necrosis inside tumor were significantly higher in CPI+PDT group in contrast to other groups. The higher value of fractal dimension (FD) was observed in control group, while the lowest value was found in the group which was treated by cystein protease inhibitors. The differences between FD were observed in CPI group and PDT+CPI group in comparison to control group. Our results revealed that fractal dimension analysis is a very useful tool in estimating differences between irregular shapes like blood vessels in PDT treated tumors. Thus, the implementation of FDA algorithms could be useful method in evaluating the efficacy of PDT.

  7. Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1

    DEFF Research Database (Denmark)

    Schmitt, Manfred; Harbeck, Nadia; Brünner, Nils;

    2011-01-01

    and III breast cancer therapy trials (Chemo-N0, NNBC-3 and Plan B), and introduces ongoing clinical trials targeting uPA in advanced cancers of the breast and pancreas, employing synthetic small-size drugs to counteract uPA activity (WX-UK1, Mesupron(®)). The therapeutic effect of a uPA-derived small......Clinical research on cancer biomarkers is essential in understanding recent discoveries in cancer biology and heterogeneity of the cancer disease. However, there are only a few examples of clinically useful studies that have identified cancer biomarkers with clinical benefit. Urokinase......-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) are two of the few tumor tissue-associated cancer biomarkers that have been evaluated successfully and extensively in many preclinical and clinical studies for their clinical utility. Most of the studies have been...

  8. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment.

    Science.gov (United States)

    Graff, Jochen; Harder, Sebastian

    2013-04-01

    The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration-time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with

  9. Adalimumab (TNFα Inhibitor) Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient

    OpenAIRE

    Wei, S. S.; Sinniah, R.

    2013-01-01

    Adalimumab (Humira) is a tumour necrosis factor α (TNF α ) inhibitor that is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ankylosing spondylitis, and juvenile idiopathic arthritis (Sullivan and Preda (2009), Klinkhoff (2004), and Medicare Australia). Use of TNF α inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, and sarcoidosis or sarcoid-like granulomas) (Ramos-Casals et al. (2010)). ...

  10. Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy

    OpenAIRE

    Eric K Hoobler; Ganesha Rai; Warrilow, Andrew G. S.; Perry, Steven C; Smyrniotis, Christopher J.; Ajit Jadhav; Anton Simeonov; Parker, Josie E.; Kelly, Diane E.; Maloney, David J.; Kelly, S. L.; Holman, Theodore R.

    2013-01-01

    We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, ...

  11. Quality of life and depression among HIV-infected patients receiving efavirenz- or protease inhibitor-based therapy in Senegal

    OpenAIRE

    Poupard, M.; Gueye, N. F. N.; Thiam, D.; Ndiaye, B.; Girard, P. M.; Delaporte, Eric; Sow, P. S.; Landman, R.

    2007-01-01

    Background Efavirenz has been associated with neuropsychiatric disorders, but little is known about depression and quality of life in sub-Saharan Africa, where nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are still the first-line treatment recommended by the World Heath Organization (WHO) and are widely prescribed. Methods In a cross-sectional study, we evaluated quality of life and depression among Senegalese patients receiving efavirenz- or protease inhibitor (PI)-ba...

  12. Patient preference and satisfaction in erectile dysfunction therapy: a comparison of the three phosphodiesterase-5 inhibitors sildenafil, vardenafil and tadalafil

    Directory of Open Access Journals (Sweden)

    Amr Abdel Raheem

    2009-04-01

    Full Text Available Amr Abdel Raheem1, Philip Kell21St. Peter’s Andrology Department, The Institute of Urology, London, and Cairo University, Egypt; 2St. Peter’s Andrology Department, The Institute of Urology, London, UKAbstract: Erectile dysfunction (ED is a problem that may affect up to 52% of men between the ages of 40 and 70. It can be distressing because of its negative effect on self-esteem, quality of life, and interpersonal relationships. Oral phosphodiesterase-5 inhibitors (PDE5 inhibitors are now the first choice of treatment in ED. The availability of three (sildenafil citrate, tadalafil, and vardenafil well tolerated and effective oral PDE5 inhibitors gives treatment options for men with ED. Although the mechanism of action is the same for the three drugs, they differ in their pharmacokinetics. Several preference studies were conducted between the three PDE5 inhibitors but they were not free from bias. Because of the lack of overwhelming reliable data showing that one PDE5 inhibitor is superior to another, current opinion is that the individual patient should have the opportunity to test all three drugs and then select the one that best suits him and his partner.Keywords: erectile dysfunction, PDE5 inhibitors, patient preference

  13. Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors

    Directory of Open Access Journals (Sweden)

    Samuel K Houston

    2011-01-01

    Full Text Available Samuel K Houston1, Yolanda Piña1, Timothy G Murray1, Hinda Boutrid1, Colleen Cebulla2, Amy C Schefler1, Wei Shi1, Magda Celdran1, William Feuer1, Jaime Merchan3, Ted J Lampidis41Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Ophthalmology, The Ohio State University, Columbus, OH, USA; 3Division of Hematology/Oncology, Department of Medicine, 4Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USAPurpose: The purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.Methods: LHBETATAG mice (n = 30 were evaluated. Mice were divided into 5 groups (n = 6 and received injections at 16 weeks of age (advanced tumors with a saline, b anecortave acetate (AA, c 2-deoxyglucose (2-DG, d AA + 2-DG (1 day post-AA treatment, or e AA + 2-DG (1 week post-AA treatment. Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.Results: Eyes treated with 2-DG 1 day post-AA injection showed a 23% (P = 0.03 reduction in tumor burden compared with 2-DG alone and a 61% (P < 0.001 reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone (P = 0.21 and a 56% (P < 0.001 decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001, but did not affect the density of mature vasculature.Conclusions: Combination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment

  14. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors

    Directory of Open Access Journals (Sweden)

    Sacco AG

    2016-04-01

    Full Text Available Assuntina G Sacco,1 Francis P Worden2 1Department of Internal Medicine, Division of Hematology/Oncology, University of California at San Diego Moores Cancer Center, La Jolla, CA, USA; 2Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System, Ann Arbor, MI, USA Abstract: The majority of patients with head and neck squamous cell carcinoma (HNSCC present with locally advanced disease, which requires site-specific combinations of surgery, radiation, and chemotherapy. Despite aggressive therapy, survival outcomes remain poor, and treatment-related morbidity is not negligible. For patients with recurrent or metastatic disease, therapeutic options are further limited and prognosis is dismal. With this in mind, molecularly targeted therapy provides a promising approach to optimizing treatment efficacy while minimizing associated toxicity. The ErbB family of receptors (ie, epidermal growth factor receptor [EGFR], ErbB2/human epidermal growth factor receptor [HER]-2, ErbB3/HER3, and ErbB4/HER4 is known to contribute to oncogenic processes, such as cellular proliferation and survival. EGFR, specifically, is upregulated in more than 90% of HNSCC, has been implicated in radiation resistance, and correlates with poorer clinical outcomes. The central role of EGFR in the pathogenesis of HNSCC suggests that inhibition of this pathway represents an attractive treatment strategy. As a result, EGFR inhibition has been extensively studied, with the emergence of two classes of drug therapy: monoclonal antibodies and tyrosine kinase inhibitors. While the monoclonal antibody cetuximab is currently the only US Food and Drug Administration–approved EGFR inhibitor for the treatment of HNSCC, numerous investigational drugs are being evaluated in clinical trials. This paper will review the role of the ErbB family in the pathogenesis of HNSCC, as well as the evidence-based data for the use of ErbB family inhibition in clinical

  15. Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

    Science.gov (United States)

    Rios, Adan; Hsu, Sigmund H.; Blanco, Angel; Buryanek, Jamie; Day, Arthur L.; McGuire, Mary F.; Brown, Robert E.

    2016-01-01

    Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID:27489862

  16. Systematic Review and Meta-Analysis of Combination Therapy with Cholinesterase Inhibitors and Memantine in Alzheimer’s Disease and Other Dementias

    Directory of Open Access Journals (Sweden)

    Taim Muayqil

    2012-11-01

    Full Text Available Background:N-methyl-D-aspartic acid antagonists (memantine and cholinesterase inhibitors (ChEIs are the only two approved classes of drugs to treat dementia; this paper explores the evidence for using these two treatments in combination. Objective: To determine the efficacy and safety of using combination therapy with memantine and a ChEI to treat dementia in comparison to monotherapy with either memantine or a ChEI. Methods: In March 2012, we systematically searched MEDLINE/PubMed, EMBASE, Cochrane library, and grey literature databases. All study types were included, except for case series or reports, which looked at combination therapy versus monotherapy in various dementing disorders. Data was pooled for blinded randomized controlled trials (RCTs only; mean differences and standardized mean differences were used to determine effect sizes. Results: Thirteen studies were included in this review; 3 were blinded RCTs, with a total of 971 Alzheimer’s disease (AD patients, which were included into the meta-analysis. No papers were found that primarily addressed combination therapy in other dementias. In the meta-analysis, small but statistically significant effect sizes were seen in favor of combination therapy among patients with moderate to severe AD on the scales of cognition (0.45–0.52; p Conclusion: Although there were statistically significant changes in favor of combination therapy in moderate to severe AD, heterogeneity in scales and patient characteristics exists. However, it is unclear if clinically significant outcomes can be achieved using the combination therapy. More studies are required before a recommendation for combination therapy can be made.

  17. Transgenic Chickens Overexpressing Aromatase Have High Estrogen Levels but Maintain a Predominantly Male Phenotype.

    Science.gov (United States)

    Lambeth, Luke S; Morris, Kirsten R; Wise, Terry G; Cummins, David M; O'Neil, Terri E; Cao, Yu; Sinclair, Andrew H; Doran, Timothy J; Smith, Craig A

    2016-01-01

    Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterized steroidogenic pathway, which is a multistep process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation. PMID:26556534

  18. Sex differences in brain aromatase activity: genomic and non-genomic controls

    Directory of Open Access Journals (Sweden)

    Jacques eBalthazart

    2011-09-01

    Full Text Available Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months, brain aromatase activity and transcription are markedly (4-6 fold increased by genomic actions of sex steroids. Initial work indicated that the preoptic aromatase activity is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of aromatase activity, immunoreactivity and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. Aromatase activity in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in aromatase activity have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral

  19. Transgenic Chickens Overexpressing Aromatase Have High Estrogen Levels but Maintain a Predominantly Male Phenotype.

    Science.gov (United States)

    Lambeth, Luke S; Morris, Kirsten R; Wise, Terry G; Cummins, David M; O'Neil, Terri E; Cao, Yu; Sinclair, Andrew H; Doran, Timothy J; Smith, Craig A

    2016-01-01

    Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterized steroidogenic pathway, which is a multistep process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation.

  20. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    DEFF Research Database (Denmark)

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.;

    2000-01-01

    range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [H-3](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon tall fungicides), and dicofol tan...... acaricide) gave rise to a statistically significant inhibition of aromatase activity. The IC(50)s of prochloraz, imazalil, propioconazole fenarimol, triadimenol, and triadimefon were calculated from dose-response curves to be 0.04, 0.34, 6.5, 10, 21 and 32 mu M, respectively, The IC50 Of dicofol was greater...

  1. Xanthones from the Botanical Dietary Supplement Mangosteen (Garcinia mangostana) with Aromatase Inhibitory Activity

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    Twelve xanthone constituents of the botanical dietary supplement, mangosteen (the pericarp of Garcinia mangostina) were screened using a non-cellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5)α-mangostin (8), and γ-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was γ-mangosti...

  2. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

    Science.gov (United States)

    Nauck, M

    2016-03-01

    Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

  3. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial

    DEFF Research Database (Denmark)

    Hansen, Ab; Obel, N; Nielsen, Henrik Ib;

    2011-01-01

    -naïve patients were randomized to zidovudine/lamivudine+efavirenz or lopinavir/ritonavir+efavirenz. We performed dual energy X-ray absorptiometry (DEXA) at baseline and at weeks 24, 48, 96 and 144 to evaluate lumbar spine and femoral neck (hip) BMD. Results At baseline, 33 patients (55.9%) had low BMD (T......-score stabilizing. In the NRTI-sparing arm, the mean percentage change from baseline was -2.7% [95% confidence interval (CI) -3.9 to -1.4] at week 24 and -2.5% (95% CI -5.4 to 0.3) at week 144......, compared with -3.2% (95% CI -4.4 to -2.1) and -1.9% (95% CI -3.5 to -0.3) in the protease inhibitor-sparing arm. Hip BMD declined until week 48 before stabilizing. In the NRTI-sparing arm, BMD had decreased by -5.1% (95% CI -7.1 to -3.1) at week 48 and -4.5% (95% CI -6.9 to -2.1) at week 144, compared...

  4. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: misleading analysis and doubtful methodology

    OpenAIRE

    Guo WQ; Li L

    2015-01-01

    Wenqin Guo, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaZhao et al have presented the result of the relative cardiovascular safety profile in using anastrozole, letrozole, and exemestane to treat the postmenopausal estrogen receptor-positive breast cancer, in which fatal or nonfatal myocardial infarction is the outcome measure and ten randomized controlled trials are used as the data sources.1 We cong...

  5. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: misleading analysis and doubtful methodology

    OpenAIRE

    Guo, Wenqin; Li, Lang

    2015-01-01

    Wenqin Guo, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaZhao et al have presented the result of the relative cardiovascular safety profile in using anastrozole, letrozole, and exemestane to treat the postmenopausal estrogen receptor-positive breast cancer, in which fatal or nonfatal myocardial infarction is the outcome measure and ten randomized controlled trials are used as the data sources.1 We ...

  6. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: misleading analysis and doubtful methodology

    Directory of Open Access Journals (Sweden)

    Guo WQ

    2015-11-01

    Full Text Available Wenqin Guo, Lang Li Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaZhao et al have presented the result of the relative cardiovascular safety profile in using anastrozole, letrozole, and exemestane to treat the postmenopausal estrogen receptor-positive breast cancer, in which fatal or nonfatal myocardial infarction is the outcome measure and ten randomized controlled trials are used as the data sources.1 We congratulate and applaud their important work, but there are some issues of concern.  View original article by Zhao et al 

  7. Investigation of adaptive responses in fathead minnows (Pimephales promelas) exposed to the model aromatase inhibitor fadrozole

    Science.gov (United States)

    The vertebrate hypothalamic-pituitary-gonadal (HPG) axis is a highly dynamic system, which, through various feedback mechanisms, strives to maintain physiological conditions conducive to reproduction even in potentially stressful situations. The development of useful predictive m...

  8. Influence of different chromosomal abnormalities in Ph-positive bone marrow cells on the chronic myeloid leukemia course during tyrosine kinase inhibitors therapy

    Directory of Open Access Journals (Sweden)

    O. Yu. Vinogradova

    2014-07-01

    Full Text Available The additional molecular and chromosomal abnormalities (ACA in Phositive cells usually considered as a genetic marker of chronic myeloid leukemia (CML progression. 457 patients in different CML phases received tyrosine kinase inhibitors (1st and 2nd generation were studied. During therapy 50 cases with additional chromosomal abnormalities in Ph+ clone (22 of them in chronic CML phase were revealed (median follow-up from CML diagnosis – 117 months, median imatinib therapy – 62 months. 86 % of patients in chronic phase with Ph+- cell abnormalities were cytogenetic resistance, and their 5-years overall survival was 80 % which was significantly lower than in patients without ACA (p < 0.005. The treatment results depend on chromosomal abnormalities detected. In patients with additional chromosome 8 imatinib therapy is effective, although complete cytogenetic response (CCR is achieved only in the later therapy stages. In patients with additional translocations CCR also achieved with imatinib or 2nd generation TKI. Only a third of patients with additional Ph-chromosome or BCR/ABL amplification achieved complete suppression of Ph+ clone using 2nd generation TKI. The presence of additional chromosome 7 abnormalities and complex karyotype disorders involving isochromosome i(17(q10 are poor prognostic factors of TKI treatment failures.

  9. Influence of different chromosomal abnormalities in Ph-positive bone marrow cells on the chronic myeloid leukemia course during tyrosine kinase inhibitors therapy

    Directory of Open Access Journals (Sweden)

    O. Yu. Vinogradova

    2012-01-01

    Full Text Available The additional molecular and chromosomal abnormalities (ACA in Phositive cells usually considered as a genetic marker of chronic myeloid leukemia (CML progression. 457 patients in different CML phases received tyrosine kinase inhibitors (1st and 2nd generation were studied. During therapy 50 cases with additional chromosomal abnormalities in Ph+ clone (22 of them in chronic CML phase were revealed (median follow-up from CML diagnosis – 117 months, median imatinib therapy – 62 months. 86 % of patients in chronic phase with Ph+- cell abnormalities were cytogenetic resistance, and their 5-years overall survival was 80 % which was significantly lower than in patients without ACA (p < 0.005. The treatment results depend on chromosomal abnormalities detected. In patients with additional chromosome 8 imatinib therapy is effective, although complete cytogenetic response (CCR is achieved only in the later therapy stages. In patients with additional translocations CCR also achieved with imatinib or 2nd generation TKI. Only a third of patients with additional Ph-chromosome or BCR/ABL amplification achieved complete suppression of Ph+ clone using 2nd generation TKI. The presence of additional chromosome 7 abnormalities and complex karyotype disorders involving isochromosome i(17(q10 are poor prognostic factors of TKI treatment failures.

  10. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

    Science.gov (United States)

    Moilanen, Anu-Maarit; Riikonen, Reetta; Oksala, Riikka; Ravanti, Laura; Aho, Eija; Wohlfahrt, Gerd; Nykänen, Pirjo S; Törmäkangas, Olli P; Palvimo, Jorma J; Kallio, Pekka J

    2015-07-03

    Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

  11. The relationship between tyrosine kinase inhibitor therapy and overall survival in patients with non-small cell lung cancer carrying EGFR mutations

    Institute of Scientific and Technical Information of China (English)

    Hidekazu Suzuki; Tomonori Hirashima; Norio Okamoto; Tadahiro Yamadori; Motohiro Tamiya; Naoko Morishita; Takayuki Shiroyama

    2013-01-01

    For patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer,the relationship between the dose or duration of treatment with tyrosine kinase inhibitor (TKI) and overall survival remains unclear.Here,we analyzed clinical data of 39 patients who were diagnosed with EGFR mutation-positive non-small cell lung cancer and treated with TKI,but subsequently died.Several parameters were measured in this study:overall survival; first,second,and overall TKI therapy durations;first TKI intensity (actual dose/normal dose); and TKI rate (overall TKI therapy duration/overall survival).The response rate to TKI therapy was 50%,and the median survival was 553 days.After TKI therapy failed,38.5% patients were re-challenged with TKI.We observed a moderate relationship [r =0.534,95%confidential interval (CI) =0.263 to 0.727,P < 0.001] between overall TKI therapy duration and overall survival.However,we found no relationship between overall survival and first TKI intensity (r =0.073,95%CI =-0.380 to 0.247,P =0.657) or TKI rate (r =0.0345,95% CI =-0.284 to 0.346,P =0.835).Nonsmall cell lung cancer patients with mutation-positive tumors remained on TKI therapy for,on average,33% of the overall survival time.These findings suggest that patients with EGFR mutation-positive tumors should not stick to using TKIs.

  12. BRAF inhibitor therapy-associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression.

    Science.gov (United States)

    Mudaliar, Kumaran; Tetzlaff, Michael T; Duvic, Madeleine; Ciurea, Ana; Hymes, Sharon; Milton, Denái R; Tsai, Kenneth Y; Prieto, Victor G; Torres-Cabala, Carlos A; Curry, Jonathan L

    2016-04-01

    Newly appearing or changing melanocytic lesions (MLs) are a recently reported toxicity of BRAF inhibitor (BRAFi) therapy. Morphologically, MLs associated with BRAFi therapy (BRAFi-MLs) may demonstrate alarming features of melanoma with an epithelioid cell phenotype with notable cytologic atypia. We sought to characterize the clinicopathological and molecular features of BRAFi-MLs. A retrospective review over a 4-year period revealed 20 patients in which 44 MLs (including 11 control nevi) were characterized by histopathology, review of clinical medical records, and immunohistochemical (IHC) studies (with anti-BRAF V600E, anti-BAP1, anti-cyclin D1, and anti-p16); the percentage of IHC+ cells was scored. Of the 20 patients, 3 (15%) whose BRAFi-MLs were biopsied had a second primary cutaneous melanoma. Of the 44 BRAFi-MLs tested, 37 (100%) of 37 MLs available for BRAF V600E testing lacked expression in contrast to 1 (9%) of 11 control nevi (lesions not associated with targeted therapy). A significantly higher level of cyclin D1 expression (>50% IHC+ cells) was more commonly seen in BRAFi-MLs (44%) than in control nevi (9%). No difference in p16 expression in melanocytes was seen between the 2 groups. BRAF mutation status distinctly differs between BRAFi-MLs from melanomas and nevi biopsied in patients who do not receive BRAFi therapy. Morphologically, BRAFi-MLs demonstrate a greater degree of atypia than do control nevi. Furthermore, BRAFi-MLs with coexisting cutaneous keratinocyte toxicity developed during fewer days of targeted therapy. Paradoxical activation of the MAPK pathway in BRAF(WT) melanocytes may account for ~15% to 21% of patients developing a second new primary melanoma within a year of starting BRAFi therapy; thus, close clinical surveillance is warranted.

  13. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer.

    Science.gov (United States)

    Nakagawa, Takayuki; Takeuchi, Shinji; Yamada, Tadaaki; Nanjo, Shigeki; Ishikawa, Daisuke; Sano, Takako; Kita, Kenji; Nakamura, Takahiro; Matsumoto, Kunio; Suda, Kenichi; Mitsudomi, Tetsuya; Sekido, Yoshitaka; Uenaka, Toshimitsu; Yano, Seiji

    2012-10-01

    Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. PMID:22844075

  14. Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy

    DEFF Research Database (Denmark)

    Glintborg, Bente; Østergaard, Mikkel; Krogh, Niels Steen;

    2013-01-01

    OBJECTIVE: To investigate frequencies and reasons for switching, treatment responses and drug survival in patients with ankylosing spondylitis (AS) switching tumour-necrosis-factor-α inhibitor (TNFi) treatment in routine clinical care. METHODS: AS patients were identified in the Danish nationwide...

  15. Discovery of a novel dual fungal CYP51/human 5-lipoxygenase inhibitor: implications for anti-fungal therapy.

    Directory of Open Access Journals (Sweden)

    Eric K Hoobler

    Full Text Available We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11 and human 5-lipoxygenase (5-LOX with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM and CYP51 (IC50 = 43 nM in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component.

  16. Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis.

    Science.gov (United States)

    Krishnan, Asha; Stobaugh, Derrick J; Deepak, Parakkal

    2015-04-01

    The association between inhibition of tumor necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and the onset of inflammatory bowel disease (IBD) is unclear. We sought to evaluate this association by analyzing adverse events (AEs) reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) with a standardized scoring tool for drug-induced AEs. A search of the FAERS for RA or JRA (January 2003-December 2011) reported with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab was performed. This dataset was then queried for cases indicating IBD. Full-length reports were accessed using the Freedom of Information Act and organized by age, sex, concomitant medications, co-morbidities, type of TNF-α inhibitor used, and diagnosis/treatment details. The Naranjo score was used to determine whether the drug-induced AEs were definite, probable, possible, or doubtful. There were 158 cases of IBD after TNF-α inhibitor exposure in RA or JRA patients. Use of the Naranjo score revealed that, in a majority of the cases (71.5 %), TNF-α inhibitor exposure was considered a 'possible' cause. A majority of the 'probable cases' in JRA were reported with etanercept (40 patients, 90.91 %). There were no 'definite' cases of anti-TNF-induced IBD. After applying the Naranjo scale, a weak association between new-onset IBD and TNF-α inhibitor therapy in RA patients and a moderately strong association especially with etanercept exposure in JRA patients was observed. However, causality cannot be determined due to limitations of the FAERS and the Naranjo score.

  17. Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes.

    Science.gov (United States)

    Shapiro, Amy D; Hedner, Ulla

    2011-10-01

    In the past, patients with hemophilia and inhibitors have had less-than-optimal treatment and have experienced more orthopedic complications than patients without inhibitors. Bypassing agents offer the potential to close treatment gaps between inhibitor and noninhibitor patients by helping the former better attain key treatment goals, including: facilitating early initiation of treatment and hemostatic control in hemarthroses; providing effective treatment in serious hemorrhagic episodes; and performance of major surgery. Effective treatment with a bypassing agent minimizes joint and/or muscle damage and potentially can serve as an effective prophylactic agent to minimize the number of hemarthroses experienced per year, thereby mitigating the development of arthropathy. The reported efficacy of the currently available bypassing agents ranges from approximately 50-80% (50-64% in controlled studies) for plasma-derived activated prothrombin complex concentrate (pd-aPCC) and 81-91% (in controlled studies) for recombinant activated factor VII (rFVIIa), including use in major orthopedic surgery. Both bypassing agents have undergone key improvements in their formulation and/or properties in recent years. The nanofiltered, vapor-heated formulation of pd-aPCC has diminished the risk of acquiring blood-borne viral infections and the room temperature stable formulation of rFVIIa allows more convenient storage, increased ease to dissolve and inject, and smaller volumes, thereby increasing overall ease of administration. Use of recommended dosing has been demonstrated to provide effective hemostasis with a minimal number of injections for both agents. In this paper, we review the individual characteristics of pd-aPCC and rFVIIa and discuss clinical data from studies conducted in inhibitor patients that demonstrate the potential benefits of these bypassing agents in this difficult-to-treat population, and underscore the potential opportunities to close the gap in care between

  18. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    Science.gov (United States)

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors. PMID:26899138

  19. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    Science.gov (United States)

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors.

  20. Clinical relevance of "withdrawal therapy" as a form of hormonal manipulation for breast cancer

    Directory of Open Access Journals (Sweden)

    Robertson John FR

    2011-09-01

    Full Text Available Abstract Background It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of "withdrawal therapy". Methods Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1 estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years, locally advanced or metastatic breast cancer; (2 disease deemed suitable for treatment by hormonal manipulation; (3 disease assessable by UICC criteria; (4 received "withdrawal" from a prior endocrine agent as a form of therapy; (5 on "withdrawal therapy" for ≥ 6 months unless they progressed prior. Results Seventeen patients with median age of 84.3 (53.7-92.5 had "withdrawal therapy" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10, an aromatase inhibitor (n = 5, megestrol acetate (n = 1 or fulvestrant (n = 1. Ten patients (58.8% had clinical benefit (CB (complete response/partial response/stable disease ≥ 6 months with a median duration of Clinical Benefit (DoCB of 10+ (7-27 months. Two patients remain on "withdrawal therapy" at the time of analysis. Conclusion "Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients. This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. "Withdrawal" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy.

  1. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain.

    Science.gov (United States)

    Biegon, Anat; Alia-Klein, Nelly; Fowler, Joanna S

    2012-01-01

    Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking and many effects of nicotine are sexually dimorphic (reviewed by Pogun and Yararbas, 2009). Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product). Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine, and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

  2. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain

    Directory of Open Access Journals (Sweden)

    Anat eBiegon

    2012-11-01

    Full Text Available Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking are sexually dimorphic. Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product. Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

  3. Is aromatase cytochrome P450 involved in the pathogenesis of endometrioid endometrial cancer?

    NARCIS (Netherlands)

    Jongen, VHWM; Thijssen, JHH; Hollema, H; Donker, GH; Santema, JG; Van Der Zee, AGJ; Heineman, MJ

    2005-01-01

    Prospectively, the relationship between androgen levels in the utero-ovarian circulation, aromatase activity in endometrial and body fat tissue, and the presence or absence of endometrioid endometrial cancer was studied in postmenopausal women. In 43 women with endometrioid endometrial cancer and 8

  4. Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome

    Science.gov (United States)

    Grindstad, Thea; Skjefstad, Kaja; Andersen, Sigve; Ness, Nora; Nordby, Yngve; Al-Saad, Samer; Fismen, Silje; Donnem, Tom; Khanehkenari, Mehrdad Rakaee; Busund, Lill-Tove; Bremnes, Roy M.; Richardsen, Elin

    2016-01-01

    Androgens are considered important in normal prostate physiology and prostate cancer (PCa) pathogenesis. However, androgen-targeted treatment preventing PCa recurrence is still lacking. This indicates additional mediators contributing to cancer development. We sought to determine the prognostic significance of estrogen receptors, ERα and -β, and the aromatase enzyme in PCa. Tissue microarrays were created from 535 PCa patients treated with radical prostatectomy. Expression of ERα, ERβ and aromatase were evaluated using immunohistochemistry. Representative tumor epithelial (TE) and tumor stromal (TS) areas were investigated separately. Survival analyses were used to evaluate the markers correlation to PCa outcome. In univariate analyses, ERα in TS was associated with delayed time to clinical failure (CF) (p = 0.042) and PCa death (p = 0.019), while ERβ was associated with reduced time to biochemical failure (BF) (p = 0.002). Aromatase in TS and TE was associated with increased time to BF and CF respectively (p = 0.016, p = 0.046). Multivariate analyses supported these observations, indicating an independent prognostic impact of all markers. When stratifying the analysis according to different surgical centers the results were unchanged. In conclusion, significant prognostic roles of ERα, ERβ and aromatase were discovered in the in PCa specimens of our large multicenter cohort. PMID:27610593

  5. Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kharofa, Jordan [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI (United States); Cohen, Eric P. [Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI (United States); Tomic, Rade [Department of Medicine, Division of Pulmonology, Medical College of Wisconsin, Milwaukee, WI (United States); Xiang Qun [Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI (United States); Gore, Elizabeth, E-mail: Egore@mcw.edu [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI (United States)

    2012-09-01

    Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or

  6. The efficacy of therapy with DPP-4 inhibitors combined with insulin in patients with type 2 diabetes mellitus

    OpenAIRE

    Alesandr Sergeevich Ametov; Ekaterina Vladimirovna Karpova

    2011-01-01

    Recently, researchers started to pay increasingly more attention to the role of gastrointestinal hormones in regulation of insulin secretion, i.e. glucose homeostasis. To-day, there are two approaches to the treatment of DM based on the use of GLP-1 effects. One takes advantage of DPP-4 inhibitors the other is combination of these agents with various drugs necessitated by heterogeneity of pathophysiological factors responsible for the development of DM2. The latter approach ensures m...

  7. The PI3K inhibitor GDC-0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy

    OpenAIRE

    Ehrhardt, Michael; Craveiro, Rogerio B.; Holst, Martin I.; Pietsch, Torsten; Dilloo, Dagmar

    2014-01-01

    Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good ...

  8. Product of aromatase activity in intact LNCaP and MCF-7 human cancer cells.

    Science.gov (United States)

    Castagnetta, L A; Granata, O M; Bellavia, V; Amodio, R; Scaccianoce, E; Notarbartolo, M; Follari, M R; Miceli, M D; Carruba, G

    1997-04-01

    We investigated conversion rates of androgens to estrogens in cultured, hormone-responsive prostate (LNCaP) and breast (MCF-7) human cancer cells. For this purpose, we adopted an intact cell analysis, whereby cells were incubated for different incubation times in the presence of close-to-physiological (1 nM) or supraphysiological (1 microM) concentrations of labelled androgen precursors, i.e. testosterone (T) and androstenedione (delta4Ad). The aromatase activity, as measured by estrogen formation, was detected in LNCaP cells (0.5 pmol/ml), even though to a significantly lower extent than in MCF-7 cells (5.4 pmol/ml), using 1 microM T after 72 h incubation. Surprisingly, LNCaP cells displayed a much higher aromatase activity when T was used as a substrate with respect to delta4Ad. In either cell line, T transformation to delta4Ad was relatively low, attaining only 2.8% in LNCaP and 7.5% MCF-7 cells. However, T was mostly converted to conjugates (over 95%), glucuronides and some sulphates, in LNCaP cells, whereas it was only partly converted to sulphates (<10%) in MCF-7 cells. Aromatase activity seems to be inconsistent in LNCaP cells, being strongly affected by culture conditions, especially by fetal calf serum (FCS). Further studies should assess the regulation of aromatase expression by serum or growth factors in different human cancer cells, also using anti-aromatase and/or anti-estrogen compounds, in different culture conditions.

  9. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies

    International Nuclear Information System (INIS)

    Highlights: → Intrinsic trastuzumab resistance occurs in ∼70% of metastatic HER2 + breast carcinomas (BC). → Approximately 15% of early HER2 + BC relapse in spite of treatment with trastuzumab-based therapies. → HER2-independent downstream pro-survival pathways might underlie trastuzumab refractoriness. → Survivin is indispensable for proliferation and survival of HER2 + BC unresponsive to HER2-targeted therapies ab initio. → Survivin antagonists may clinically circumvent the occurrence of de novo resistance to HER2-directed drugs. -- Abstract: Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC50 values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naive SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed ∼4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated ∼10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely suppressed in JIMT-1 cells. Our current findings may

  10. Hedgehog pathway inhibitor in combination with radiation therapy for basal cell carcinomas of the head and neck. First clinical experience with vismodegib for locally advanced disease

    Energy Technology Data Exchange (ETDEWEB)

    Schulze, Bjoern; Roedel, Claus; Balermpas, Panagiotis [University Hospital Johann Wolfgang Goethe University, Department of Radiation Oncology, Frankfurt (Germany); Meissner, Markus [University Hospital Johann Wolfgang Goethe University, Department of Dermatology, Frankfurt (Germany); Ghanaati, Shahram [University Hospital Johann Wolfgang Goethe University, Department of Craniofacial and Plastic Surgery, Frankfurt (Germany); Burck, Iris [University Hospital Johann Wolfgang Goethe University, Department of Diagnostic and Interventional Radiology, Frankfurt (Germany)

    2016-01-15

    Definitive radiotherapy and vismodegib, an oral inhibitor of the hedgehog pathway, are both established treatment options for locally advanced basal cell carcinomas (BCC). Both have shown good results in local tumor control; however, the effects concerning advanced tumors are often not of a lasting nature and to date no systematic data about the combination of the two modalities are available. We retrospectively analyzed four patients who received vismodegib and radiotherapy in combination. Radiation doses varied between 50.4 Gy and 66.0 Gy. Three patients had recurrent BCC. One patient had locoregional lymph node involvement. Vismodegib was taken once a day (150 mg) during the entire time of irradiation and beyond upon instructions of the attending dermatologist. In three cases a persistent complete response was observed, in one case the tumor remained stable for approximately 6 months until further tumor progression was documented. The combined therapy was well tolerated in all cases. No exceptional side effects pointing at a drug-radiation interaction were observed. The combination of vismodegib and radiation seems feasible and the initial results are promising. In our cohort, there was no increase in unexpected side effects. Further research is needed to evaluate the significance of this combined therapy. (orig.) [German] Sowohl definitive Radiotherapie als auch Vismodegib, ein oraler Inhibitor der Hedgehog-Signalkaskade, sind etablierte Behandlungsoptionen fuer lokal fortgeschrittene Basalzellkarzinome (BCC). Beide Therapien zeigen fuer sich gute Ansprechraten, aber die lokale Tumorkontrolle ist oft nicht dauerhaft und bis heute existieren kaum Daten ueber eine Kombination der beiden Modalitaeten. Wir analysierten retrospektiv vier Patientenfaelle nach simultaner Applikation von Vismodegib und Bestrahlung. Die Bestrahlungsdosis variierte zwischen 50,4 Gy und 66,0 Gy. Drei der Patienten hatten ein rezidiviertes BCC. Ein Patient hatte einen befallenen regionalen

  11. Personalized therapy with TNF-inhibitors in Crohn's disease: optimizing treatment outcomes by monitoring drug levels and anti-drug antibodies.

    Science.gov (United States)

    Steenholdt, Casper

    2016-08-01

    Therapeutic monoclonal antibodies (Abs) targeting the proinflammatory cytokine, TNF-α have revolutionized the treatment of inflammatory bowel disease (IBD), and raised treatment goals from symptom control to maintenance of clinical remission with mucosal healing. However, clinicians are challenged by a significant proportion of patients not responding to TNF-inhibitors or losing effect over time, and by the high costs of these drugs along with their potential side effects. The aim of this dissertation was therefore to examine if anti-TNF treatment outcomes can be improved by tailoring therapy on an individual patient basis by considering relevant prognostic variables. The main finding is that personalized treatment with TNF-inhibitors by use of an algorithm defined by measurements of anti-TNF drug and anti-drug Abs to guide interventions at therapeutic failure can be useful to secure optimal clinical, economic, and patient reported outcomes. Furthermore, the present studies have documented the key role of measurements of anti-TNF drug and anti-drug Abs to elucidate conditions related to pharmacokinetics and pharmacodynamics of these agents in individual patients, and to serve as prognostic markers of anti-TNF treatment outcomes. In addition, knowledge has been provided on how to interpret and integrate measurements of anti-TNF drug and anti-drug Abs in the clinical management of individual IBD patients taking into account potential pit-falls and biases. Hence, the studies forming the basis for this dissertation have yielded novel insights into the technical, temporal, and methodological complexities and challenges related to application of personalized anti-TNF treatment strategies based on measurements of anti-TNF drug and anti-drug Abs, and established measures to proactively address and accommodate these - both technically and clinically. Although not yet completely resolved, this dissertation has also laid a foundation for individually tailored anti

  12. Risk of hormone escape in a human prostate cancer model depends on therapy modalities and can be reduced by tyrosine kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Charlotte Guyader

    Full Text Available Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR antagonists (bicalutamide or flutamide. Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration, but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR as compared to continuous castration (RR(intermittent: 14.5, RR(complete blockade: 6.5 and 1.35. All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17 and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent

  13. Comparison of health care resource utilization and costs among patients with GERD on once-daily or twice-daily proton pump inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Mody R

    2013-04-01

    Full Text Available Reema Mody,1 Debra Eisenberg,2 Likun Hou,2 Siddhesh Kamat,2 Joseph Singer,2 Lauren B Gerson3 1Takeda Pharmaceuticals International Inc, Deerfield, IL, 2HealthCore Inc, Wilmington, DE, 3Stanford University School of Medicine, Stanford, CA, USA Background: The purpose of this study was to assess differences in health care resource utilization and costs associated with once-daily and twice-daily proton pump inhibitor (PPI therapy. Most patients with gastroesophageal reflux disease (GERD achieve symptom control on once-daily PPI therapy, but approximately 20%–30% require twice-daily dosing. Methods: Patients were ≥18 years of age with at least one medical claim for GERD and at least two PPI claims from HealthCore's Integrated Research Database (HIRDSM during 2004–2009. Patients were continuously eligible for 12 months before and after the index date (date of first PPI claim. Based on PPI dosing throughout the post-index period (quantity of medication dispensed/number of days supply, patients were classified as once-daily (dose ≤ 1.5 pills per day or twice-daily (≥1.5 PPI users. Results: The study cohort included 248,386 patients with GERD (mean age 52.8 ± 13.93 years, 56% females of whom 90% were once-daily and 10% were twice-daily PPI users. The Deyo-Charlson Comorbidity Index for once-daily and twice-daily PPI users was 0.70 ± 1.37 and 0.89 ± 1.54, respectively (P < 0.05. More once-daily patients had claims for Barrett's esophagus (5% versus 2%, P < 0.0001 than twice-daily patients. Post-index, higher proportions of twice-daily patients had at least one GERD-related inpatient visit (7% versus 5%, outpatient visit (60% versus 49%, and office visit (48% versus 38% versus once-daily patients (P < 0.0001. Mean total GERD-related health care costs were $2065 ± $6636 versus $3749 ± $11,081 for once-daily and twice-daily PPI users, respectively (P < 0.0001. Conclusion: Patients receiving twice-daily PPI therapy were likely to have more

  14. Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation

    Science.gov (United States)

    Chomel, Jean Claude; Bonnet, Marie Laure; Sorel, Nathalie; Sloma, Ivan; Bennaceur-Griscelli, Annelise; Rea, Delphine; Legros, Laurence; Marfaing-Koka, Anne; Bourhis, Jean-Henri; Ame, Shanti; Guerci-Bresler, Agnès; Rousselot, Philippe; Turhan, Ali G.

    2016-01-01

    During the last decade, the use of tyrosine kinase inhibitor (TKI) therapy has modified the natural history of chronic myeloid leukemia (CML) allowing an increase of the overall and disease-free survival, especially in patients in whom molecular residual disease becomes undetectable. However, it has been demonstrated that BCR-ABL1- expressing leukemic stem cells (LSCs) persist in patients in deep molecular response. It has also been shown that the discontinuation of Imatinib leads to a molecular relapse in the majority of cases. To determine a possible relationship between these two phenomena, we have evaluated by clonogenic and long-term culture initiating cell (LTC-IC) assays, the presence of BCR-ABL1-expressing LSCs in marrow samples from 21 patients in deep molecular response for three years after TKI therapy (mean duration seven years). LSCs were detected in 4/21 patients. Discontinuation of TKI therapy in 13/21 patients led to a rapid molecular relapse in five patients (4 without detectable LSCs and one with detectable LSCs). No relapse occurred in the eight patients still on TKI therapy, whether LSCs were detectable or not. Thus, this study demonstrates for the first time the in vivo efficiency of TKIs, both in the progenitor and the LSC compartments. It also confirms the persistence of leukemic stem cells in patients in deep molecular response, certainly at the origin of relapses. Finally, it emphasizes the difficulty of detecting residual LSCs due to their rarity and their low BCR-ABL1 mRNA expression. PMID:27167108

  15. Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation.

    Science.gov (United States)

    Chomel, Jean Claude; Bonnet, Marie-Laure; Sorel, Nathalie; Sloma, Ivan; Bennaceur-Griscelli, Annelise; Rea, Delphine; Legros, Laurence; Marfaing-Koka, Anne; Bourhis, Jean-Henri; Ame, Shanti; Guerci-Bresler, Agnès; Rousselot, Philippe; Turhan, Ali G

    2016-06-01

    During the last decade, the use of tyrosine kinase inhibitor (TKI) therapy has modified the natural history of chronic myeloid leukemia (CML) allowing an increase of the overall and disease-free survival, especially in patients in whom molecular residual disease becomes undetectable. However, it has been demonstrated that BCR-ABL1- expressing leukemic stem cells (LSCs) persist in patients in deep molecular response. It has also been shown that the discontinuation of Imatinib leads to a molecular relapse in the majority of cases. To determine a possible relationship between these two phenomena, we have evaluated by clonogenic and long-term culture initiating cell (LTC-IC) assays, the presence of BCR-ABL1-expressing LSCs in marrow samples from 21 patients in deep molecular response for three years after TKI therapy (mean duration seven years). LSCs were detected in 4/21 patients. Discontinuation of TKI therapy in 13/21 patients led to a rapid molecular relapse in five patients (4 without detectable LSCs and one with detectable LSCs). No relapse occurred in the eight patients still on TKI therapy, whether LSCs were detectable or not. Thus, this study demonstrates for the first time the in vivo efficiency of TKIs, both in the progenitor and the LSC compartments. It also confirms the persistence of leukemic stem cells in patients in deep molecular response, certainly at the origin of relapses. Finally, it emphasizes the difficulty of detecting residual LSCs due to their rarity and their low BCR-ABL1 mRNA expression. PMID:27167108

  16. Myocarditis in CD8-depleted SIV-infected rhesus macaques after short-term dual therapy with nucleoside and nucleotide reverse transcriptase inhibitors.

    Directory of Open Access Journals (Sweden)

    Lakshmanan Annamalai

    Full Text Available BACKGROUND: Although highly active antiretroviral therapy (HAART has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs. Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed. METHODOLOGY/PRINCIPAL FINDINGS: We examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine (PMPA and (+/--beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine (RCV] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p<0.05, but significantly greater quantities of TNF-α mRNA than either SIV-positive untreated animals or uninfected controls (p<0.05. Interferon-γ (IFN-γ, IL-1β and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART. CONCLUSIONS/SIGNIFICANCE: These results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful

  17. Effects of Pharmaceuticals Used for Breast Cancer Treatment on Reproduction and Aromatase Activity in a Marine Fish

    Science.gov (United States)

    Laboratory experiments were conducted with the marine fish cunner (Tautogolabrus adspersus) to evaluate whether four pharmaceuticals used in breast cancer treatment have an impact on reproduction or aromatase activity. Tamoxifen binds to estrogen receptors, while anastrozole, let...

  18. EFFECTS OF INCUBATION TEMPERATURE AND ESTROGEN EXPOSURE ON AROMATASE ACTIVITY IN THE BRAIN AND GONADS OF EMBRYONIC ALLIGATORS

    Science.gov (United States)

    During embryogenesis, incubation temperature and the hormonal environment influence gonadal differentiation of some reptiles, including all crocodilians. Current evidence suggests that aromatase, the enzyme that converts androgens to estrogens, has a role in sexual differentiatio...

  19. Symptomatic benign prostatic hyperplasia: the role of 5-alpha-reductase inhibitors in the prevention of acute urinary retention and surgical therapy

    Directory of Open Access Journals (Sweden)

    Norma Marigliano

    2012-01-01

    Full Text Available Benign prostatic hyperplasia (BPH is a disease that affects over 50% of males aged 50 years or older. In men aged >80 years, the incidence is 90%. BPH occurs in 9-25% of males aged 40 to 79 years. Fifty percent of patients with BPH are symptomatic. The symptoms include reduced urinary flow, nocturia, defective bladder emptying, urinary hesitancy, and dysuria. Disease progression can be associated with acute urinary retention (AUR. Prostatic obstruction includes mechanical and dynamic components, the latter mediated by alpha-muscarinic receptors. Treatment with alpha-1-blockers (alfuzosin, doxazosin, tamsulosin, and terazosin leads to rapid amelioration of symptoms and urinary flow, usually within one or two weeks. The 5-alpha reductase inhibitors (5-ARIs are “disease-modifying drugs.” They control the growth of the prostate by blocking the conversion of testosterone into dihydrotestosterone (DHT. Finasteride is a 5–ARI that is selective for type 2 receptors. Dutasteride is a powerful inhibitor of both 5- alpha reductase isoforms (type 1 and 2 and produces more complete suppression of DHT synthesis than finasteride. Dutasteride also has a much longer half-life than finasteride (five weeks versus five to six hours. The authors review the results of clinical trials involving finasteride and dutasteride, with and without alpha-1-blockers, highlighting the important role of dutasteride in improving acute urinary retention and eliminating the need for surgical therapy.

  20. Post-proliferative immature radial glial cells female-specifically express aromatase in the medaka optic tectum.

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    Akio Takeuchi

    Full Text Available Aromatase, the key enzyme responsible for estrogen biosynthesis, is present in the brain of all vertebrates. Much evidence has accumulated that aromatase is highly and exclusively expressed in proliferating mature radial glial cells in the brain of teleost fish even in adulthood, unlike in other vertebrates. However, the physiological significance of this expression remains unknown. We recently found that aromatase is female-specifically expressed in the optic tectum of adult medaka fish. In the present study, we demonstrated that, contrary to the accepted view of the teleost brain, female-specific aromatase-expressing cells in the medaka optic tectum represent a transient subset of post-proliferative immature radial glial cells in the neural stem cell lineage. This finding led us to hypothesize that female-specific aromatase expression and consequent estrogen production causes some sex difference in the life cycle of tectal cells. As expected, the female tectum exhibited higher expression of genes indicative of cell proliferation and radial glial maturation and lower expression of an anti-apoptotic gene than did the male tectum, suggesting a female-biased acceleration of the cell life cycle. Complicating the interpretation of this result, however, is the additional observation that estrogen administration masculinized the expression of these genes in the optic tectum, while simultaneously stimulating aromatase expression. Taken together, these results provide evidence that a unique subpopulation of neural stem cells female-specifically express aromatase in the optic tectum and suggest that this aromatase expression and resultant estrogen synthesis have an impact on the life cycle of tectal cells, whether stimulatory or inhibitory.

  1. Adalimumab (TNFα Inhibitor Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient

    Directory of Open Access Journals (Sweden)

    S. S. Wei

    2013-01-01

    Full Text Available Adalimumab (Humira is a tumour necrosis factor α (TNFα inhibitor that is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ankylosing spondylitis, and juvenile idiopathic arthritis (Sullivan and Preda (2009, Klinkhoff (2004, and Medicare Australia. Use of TNFα inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, and sarcoidosis or sarcoid-like granulomas (Ramos-Casals et al. (2010. We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab. He has renal biopsy proven IgA nephritis instead. Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure. He made a remarkable recovery after adalimumab cessation and steroid treatment. To our knowledge, this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab.

  2. Incidence and influencing factors of aldosterone breakthrough during therapy with angiotensin Ⅱ receptor bockers alone,or combined with angiotensin-converting enzyme inhibitors in patients with non-diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    梁敏

    2013-01-01

    Objective To investigate the incidence and influen-cing factors of aldosterone breakthrough during therapy with angiotensin Ⅱ receptor blockers(ARB) alone,or combined with angiotensin-converting enzyme inhibitors(ACEI) in Chinese patients with non-diabetic

  3. Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

    OpenAIRE

    Randhawa Jasleen; Ostojic Alen; Vrhovac Radovan; Atallah Ehab; Verstovsek Srdan

    2012-01-01

    Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in redu...

  4. Short term adherence tool predicts failure on second line protease inhibitor-based antiretroviral therapy: an observational cohort study

    OpenAIRE

    Court, Richard; Leisegang, Rory; Stewart, Annemie; Sunpath, Henry; Murphy, Richard; Winternheimer, Philip; Ally, Mashuda; Maartens, Gary

    2014-01-01

    Background Most patients who experience virologic failure (VF) on second line antiretroviral therapy (ART) in low-middle income countries fail due to poor adherence rather than antiretroviral resistance. A simple adherence tool designed to detect VF would conserve resources by rationally limiting need for viral load (VL) testing and, in those countries with access to third line ART, the need for resistance testing. Methods We conducted an observational cohort study of patients who initiated s...

  5. Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase.

    Science.gov (United States)

    Colombo, Riccardo; Caldarelli, Marina; Mennecozzi, Milena; Giorgini, Maria Laura; Sola, Francesco; Cappella, Paolo; Perrera, Claudia; Depaolini, Stefania Re; Rusconi, Luisa; Cucchi, Ulisse; Avanzi, Nilla; Bertrand, Jay Aaron; Bossi, Roberto Tiberio; Pesenti, Enrico; Galvani, Arturo; Isacchi, Antonella; Colotta, Francesco; Donati, Daniele; Moll, Jürgen

    2010-12-15

    MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.

  6. Xanthones from the botanical dietary supplement mangosteen (Garcinia mangostana) with aromatase inhibitory activity.

    Science.gov (United States)

    Balunas, Marcy J; Su, Bin; Brueggemeier, Robert W; Kinghorn, A Douglas

    2008-07-01

    Twelve xanthone constituents of the botanical dietary supplement mangosteen (the pericarp of Garcinia mangostana) were screened using a noncellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5), alpha-mangostin (8), and gamma-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was gamma-mangostin (9). Because xanthones may be consumed in substantial amounts from commercially available mangosteen products, the consequences of frequent intake of mangosteen botanical dietary supplements require further investigation to determine their possible role in breast cancer chemoprevention.

  7. Adenoviral delivery of pan-caspase inhibitor p35 enhances bystander killing by P450 gene-directed enzyme prodrug therapy using cyclophosphamide+

    International Nuclear Information System (INIS)

    Cytochrome P450-based suicide gene therapy for cancer using prodrugs such as cyclophosphamide (CPA) increases anti-tumor activity, both directly and via a bystander killing mechanism. Bystander cell killing is essential for the clinical success of this treatment strategy, given the difficulty of achieving 100% efficient gene delivery in vivo using current technologies. Previous studies have shown that the pan-caspase inhibitor p35 significantly increases CPA-induced bystander killing by tumor cells that stably express P450 enzyme CYP2B6 (Schwartz et al, (2002) Cancer Res. 62: 6928-37). To further develop this approach, we constructed and characterized a replication-defective adenovirus, Adeno-2B6/p35, which expresses p35 in combination with CYP2B6 and its electron transfer partner, P450 reductase. The expression of p35 in Adeno-2B6/p35-infected tumor cells inhibited caspase activation, delaying the death of the CYP2B6 'factory' cells that produce active CPA metabolites, and increased bystander tumor cell killing compared to that achieved in the absence of p35. Tumor cells infected with Adeno-2B6/p35 were readily killed by cisplatin and doxorubicin, indicating that p35 expression is not associated with acquisition of general drug resistance. Finally, p35 did not inhibit viral release when the replication-competent adenovirus ONYX-017 was used as a helper virus to facilitate co-replication and spread of Adeno-2B6/p35 and further increase CPA-induced bystander cell killing. The introduction of p35 into gene therapeutic regimens constitutes an effective approach to increase bystander killing by cytochrome P450 gene therapy. This strategy may also be used to enhance other bystander cytotoxic therapies, including those involving the production of tumor cell toxic protein products

  8. Impact of statin therapy on plasma levels of plasminogen activator inhibitor-1. A systematic review and meta-analysis of randomised controlled trials.

    Science.gov (United States)

    Sahebkar, Amirhossein; Catena, Cristiana; Ray, Kausik K; Vallejo-Vaz, Antonio J; Reiner, Željko; Sechi, Leonardo A; Colussi, GianLuca

    2016-07-01

    Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I² test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and "trim and fill" tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: -15.72 ng/ml, 95 % confidence interval [CI]: -25.01, -6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: -21.32 ng/ml, 95 % CI: -32.73, -9.91, I²=99 %) and particularly atorvastatin (WMD: -20.88 ng/mL, 95 % CI: -28.79, -12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations. PMID:27009446

  9. Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder

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    María Eugenia Hernandez

    2013-01-01

    Full Text Available Major depressive disorder (MDD is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator—human dialyzable leukocyte extract (hDLE—on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1β, IL-2, and IFN-γ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone.

  10. Oncological Impact of M-Tor Inhibitor Immunosuppressive Therapy after Liver Transplantation for Hepatocellular Carcinoma: Review of the Literature

    Science.gov (United States)

    Tarantino, Giuseppe; Magistri, Paolo; Ballarin, Roberto; Di Francia, Raffaele; Berretta, Massimiliano; Di Benedetto, Fabrizio

    2016-01-01

    Background: Hepatocellular Carcinoma (HCC) represents the fifth most common malignancy and the third cancer-related cause of death worldwide. Hepatitis B (HBV) and C (HCV) viral infections and alcohol abuse are the principal etiological factors for HCC. Liver transplantation (LT) is oncologically the preferable approach to HCC, as it can remove all the intrahepatic tumor foci, and also the oncogenic cirrhotic liver. The use of mTOR inhibitors (mTORi) for immunosuppression after LT for HCC has been proposed due to rapamycin antitumor activity. We decided to review the literature to clarify the oncological role of mTORi after liver transplantation for HCC, analyzing both present condition and future perspectives. Material and Methods: A systematic literature search was performed using PubMed, EMBASE, Scopus, and the Cochrane Library Central. The search was limited to studies in humans and to those reported in the English language in the period of time between January 2005 and December 2015. Results: The literature search yielded 93 articles; after duplicates were removed, 77 titles and abstracts were reviewed. Most relevant data and papers are herein reported and discussed. Conclusions: So far, the use of mTORi is encouraging in terms of oncological outcomes for patients underwent LT for HCC, both for prevention and treatment of HCC recurrence although definitive data are still awaited.

  11. C1-inhibitor therapy for hereditary angioedema attacks: prospective patient assessments of health-related quality of life.

    Science.gov (United States)

    Bewtra, Againdra K; Levy, Robyn J; Jacobson, Kraig W; Wasserman, Richard L; Machnig, Thomas; Craig, Timothy J

    2012-01-01

    C1-inhibitor (INH) concentrate, which is recommended as first-line treatment for acute hereditary angioedema (HAE) attacks in many countries, was recently approved in the United States. We sought to solicit patients' feedback about their health-related quality of life (HRQoL) while being treated with C1-INH concentrate for acute HAE attacks under real-world conditions, as well as the personal impact of the availability of C1-INH on lifestyle and mental health domains. Subjects enrolled in an open-label study of C1-INH at 20 U/kg for acute HAE attacks were invited to participate in a prospectively designed survey to solicit "real-time" patient responses that were collected via an interactive voice response service or online with a personal computer. Eighteen subjects submitted 60 quarterly HRQoL and treatment impact survey responses over 29 months. Seventeen of 18 patients responding reported mean short form 12 HRQoL scores that were within a normal range. More than one-half indicated that C1-INH availability made them feel somewhat or much better, and >80% reported having a better outlook on the future and feeling more secure about the danger of life-threatening attacks. These data confirm a high level of HRQoL and a positive impact in lifestyle and emotional domains among patients who were treated for acute attacks of HAE with C1-INH concentrate.

  12. Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer’s Disease Therapy from Traditional Chinese Medicine

    Directory of Open Access Journals (Sweden)

    Hung-Jin Huang

    2014-01-01

    Full Text Available Apolipoprotein E4 (Apo E4 is the major genetic risk factor in the causation of Alzheimer’s disease (AD. In this study we utilize virtual screening of the world’s largest traditional Chinese medicine (TCM database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.

  13. Brown Recluse spider bite mediated hemolysis: clinical features, a possible role for complement inhibitor therapy, and reduced RBC surface glycophorin A as a potential biomarker of venom exposure.

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    Eric A Gehrie

    Full Text Available BACKGROUND: The venom of Loxosceles reclusa (Brown Recluse spider can cause a severe, life-threatening hemolysis in humans for which no therapy is currently available in the USA beyond supportive measures. Because this hemolysis is uncommon, relatively little is known about its clinical manifestation, diagnosis, or management. Here, we aimed to clarify the clinical details of envenomation, to determine the efficacy of the complement inhibitor eculizumab to prevent the hemolysis in vitro, and to investigate markers of exposure to Brown Recluse venom. STUDY DESIGN AND METHODS: We performed a 10-year chart review of cases of Brown Recluse spider bite-mediated hemolysis at our institution. We also designed an in vitro assay to test the efficacy of eculizumab to inhibit hemolysis of venom exposed red blood cells. Finally, we compared levels of CD55, CD59 and glycophorin A on venom exposed versus venom-naïve cells. RESULTS: Most victims of severe Brown Recluse spider mediated hemolysis at our institution are children and follow an unpredictable clinical course. Brown Recluse spider bite mediated hemolysis is reduced by 79.2% (SD=18.8% by eculizumab in vitro. Erythrocyte glycophorin A, but not CD55 or CD59, is reduced after red blood cells are incubated with venom in vitro. CONCLUSION: Taken together, our laboratory data and clinical observations indicate that L. reclusa venom exposure results in non-specific antibody and complement fixation on red blood cells, resulting in complement mediated hemolysis that is curtailed by the complement inhibitor eculizumab in vitro. Glycophorin A measurement by flow cytometry may help to identify victims of L. reclusa envenomation.

  14. Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults

    Science.gov (United States)

    Barbour, Jason D.; Wrin, Terri; Grant, Robert M.; Martin, Jeffrey N.; Segal, Mark R.; Petropoulos, Christos J.; Deeks, Steven G.

    2002-01-01

    Continued use of antiretroviral therapy despite the emergence of drug-resistant human immunodeficiency virus (HIV) has been associated with the durable maintenance of plasma HIV RNA levels below pretherapy levels. The factors that may account for this partial control of viral replication were assessed in a longitudinal observational study of 20 HIV-infected adults who remained on a stable protease inhibitor-based regimen despite ongoing viral replication (plasma HIV RNA levels consistently >500 copies/ml). Longitudinal plasma samples (n = 248) were assayed for drug susceptibility and viral replication capacity (measured by using a single-cycle recombinant-virus assay). The initial treatment-mediated decrease in plasma viremia was directly proportional to the reduction in replicative capacity (P = 0.01). Early virologic rebound was associated the emergence of a virus population exhibiting increased protease inhibitor phenotypic resistance, while replicative capacity remained low. During long-term virologic failure, plasma HIV RNA levels often remained stable or increased slowly, while phenotypic resistance continued to increase and replicative capacity decreased slowly. The emergence of primary genotypic mutations within protease (particularly V82A, I84V, and L90M) was temporally associated with increasing phenotypic resistance and decreasing replicative capacity, while the emergence of secondary mutations within protease was associated with more-gradual changes in both phenotypic resistance and replicative capacity. We conclude that HIV may be constrained in its ability to become both highly resistant and highly fit and that this may contribute to the continued partial suppression of plasma HIV RNA levels that is observed in some patients with drug-resistant viremia. PMID:12368352

  15. Ligula intestinalis infection is associated with alterations of both brain and gonad aromatase expression in roach (Rutilus rutilus).

    Science.gov (United States)

    Boulange-Lecomte, C; Geraudie, P; Forget-Leray, J; Gerbron, M; Minier, C

    2011-09-01

    The tapeworm Ligula intestinalis commonly infests roach (Rutilus rutilus) and is responsible for the inhibition of gonad development. In order to better understand the effect of the plerocercoid on fish physiology, and to discriminate parasitization effects from those of endocrine-disrupting compounds (EDC), Cyp19b and Cyp19a aromatase expression was investigated by real-time quantitative polymerase chain reaction (PCR) in brain and gonads of ligulosed roach, caught from a reference site. Data were compared to reproductive and endocrine endpoints previously reported in a larger cohort study (including the sampled population of the present one), such as gonadosomatic index, Fulton index, gonadal histology, plasma sex steroid levels and brain aromatase activity. A decrease in Cyp19b expression in the brain of infected fish was demonstrated, in agreement with the reduction of aromatase activity previously described. In contrast, Cyp19a expression in the gonads appeared to be enhanced in ligulosed fish, in accordance with the presence of immature but differentiated sexual tissues. Together these results show that: (1) L. intestinalis infestation results in an alteration of aromatase expression which, in particular, may have profound effects on the fish brain; and (2) L. intestinalis infection must be considered as a major confounding factor in ecotoxicological studies using aromatase expression as an EDC biomarker. Moreover, the concordance between activity and expression--investigated for the first time in the same population--gives a functional relevance to the transcript aromatase dosage in the brain. Finally, quantitative PCR was confirmed as a sensitive approach, enabling aromatase status to be defined in the poorly developed gonads of ligulosed individuals. PMID:21062527

  16. The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy.

    Directory of Open Access Journals (Sweden)

    Mauro Savino

    Full Text Available Recent evidence points to Myc--a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers--as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule--instead--appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc.

  17. The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

    Science.gov (United States)

    Savino, Mauro; Annibali, Daniela; Carucci, Nicoletta; Favuzzi, Emilia; Cole, Michael D.; Evan, Gerard I.; Soucek, Laura; Nasi, Sergio

    2011-01-01

    Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc. PMID:21811581

  18. Combination therapy with the histone deacetylase inhibitor LBH589 and radiation is an effective regimen for prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Weiwei Xiao

    Full Text Available Radiation therapy (RT continues to be one of the most popular treatment options for localized prostate cancer (CaP. The purpose of the study was to investigate the in vitro effect of LBH589 alone and in combination with RT on the growth and survival of CaP cell lines and the possible mechanisms of radiosensitization of this combination therapy. The effect of LBH589 alone or in combination with RT on two CaP cell lines (PC-3 and LNCaP and a normal prostatic epithelial cell line (RWPE-1 was studied by MTT and clonogenic assays, cell cycle analysis, western blotting of apoptosis-related and cell check point proteins, and DNA double strand break (DSB repair markers. The immunofluorescence staining was used to further confirm DSB expression in treated CaP cells. Our results indicate that LBH589 inhibited proliferation in both CaP and normal prostatic epithelial cells in a time-and-dose-dependent manner; low-dose of LBH589 (IC20 combined with RT greatly improved efficiency of cell killing in CaP cells; compared to RT alone, the combination treatment with LBH589 and RT induced more apoptosis and led to a steady increase of sub-G1 population and abolishment of RT-induced G2/M arrest, increased and persistent DSB, less activation of non-homologous end joining (NHEJ/homologous recombination (HR repair pathways and a panel of cell cycle related proteins. These results suggest that LBH589 is a potential agent to increase radiosensitivity of human CaP cells. LBH589 used either alone, or in combination with RT is an attractive strategy for treating human CaP.

  19. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs)

    International Nuclear Information System (INIS)

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC50 values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent Ki/Ki' of 7.68/0,02 μM and 5.01/0.04 μM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a wide range of

  20. Neural stem cell sex dimorphism in aromatase (CYP19 expression: a basis for differential neural fate

    Directory of Open Access Journals (Sweden)

    Jay Waldron

    2010-11-01

    Full Text Available Jay Waldron1, Althea McCourty1, Laurent Lecanu1,21The Research Institute of the McGill University Health Centre, Montreal, Canada; 2Department of Medicine, McGill University, Quebec, CanadaPurpose: Neural stem cell (NSC transplantation and pharmacologic activation of endogenous neurogenesis are two approaches that trigger a great deal of interest as brain repair strategies. However, the success rate of clinical attempts using stem cells to restore neurologic functions altered either after traumatic brain injury or as a consequence of neurodegenerative disease remains rather disappointing. This suggests that factors affecting the fate of grafted NSCs are largely understudied and remain to be characterized. We recently reported that aging differentially affects the neurogenic properties of male and female NSCs. Although the sex steroids androgens and estrogens participate in the regulation of neurogenesis, to our knowledge, research on how gender-based differences affect the capacity of NSCs to differentiate and condition their neural fate is lacking. In the present study, we explored further the role of cell sex as a determining factor of the neural fate followed by differentiating NSCs and its relationship with a potential differential expression of aromatase (CYP19, the testosterone-metabolizing enzyme.Results: Using NSCs isolated from the subventricular zone of three-month-old male and female Long-Evans rats and maintained as neurospheres, we showed that differentiation triggered by retinoic acid resulted in a neural phenotype that depends on cell sex. Differentiated male NSCs mainly expressed markers of neuronal fate, including ßIII-tubulin, microtubule associated protein 2, growth-associated protein 43, and doublecortin. In contrast, female NSCs essentially expressed the astrocyte marker glial fibrillary acidic protein. Quantification of the expression of aromatase showed a very low level of expression in undifferentiated female NSCs

  1. Tumor necrosis factor inhibitor therapy in ankylosing spondylitis: differential effects on pain and fatigue and brain correlates.

    Science.gov (United States)

    Wu, Qi; Inman, Robert D; Davis, Karen D

    2015-02-01

    Ankylosing spondylitis is associated with back pain and fatigue and impacts mobility but can be treated with tumor necrosis factor inhibitors (TNFi). The differential effects of TNFi treatment on multiple symptoms and the brain is not well delineated. Thus, we conducted a 2-part study. In study 1, we conducted a retrospective chart review in 129 ankylosing spondylitis patients to assess TNFi effects on pain, fatigue, motor function, mobility, and quality of life (QoL). After at least 10 weeks of TNFi treatment, patients had clinically significant improvements (>30%) in pain (including neuropathic pain), most disease and QoL factors, and normalized sensory detection thresholds. However, residual fatigue (mean = 5.3) was prominent. Although 60% of patients had significant relief of pain, only 22% of patients had significant relief of both pain and fatigue. Therefore, the preferential TNFi treatment effect on pain compared with fatigue could contribute to suboptimal effects on QoL. Part 2 was a prospective study in 14 patients to identify TNFi treatment effects on pain, fatigue, sensory and psychological factors, and brain cortical thickness based on 3T magnetic resonance imaging. Centrally, TNFi was associated with statistically significant cortical thinning of motor, premotor, and posterior parietal regions. Pain intensity reduction was associated with cortical thinning of the secondary somatosensory cortex, and pain unpleasantness reduction was associated with the cortical thinning of motor areas. In contrast, fatigue reduction correlated with cortical thinning of the insula, primary sensory cortex/inferior parietal sulcus, and superior temporal polysensory areas. This indicates that TNFi treatment produces changes in brain areas implicated in sensory, motor, affective, and cognitive functions.

  2. A Rapid Screening Assay Identifies Monotherapy with Interferon-ß and Combination Therapies with Nucleoside Analogs as Effective Inhibitors of Ebola Virus.

    Directory of Open Access Journals (Sweden)

    Stephen D S McCarthy

    2016-01-01

    Full Text Available To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD. While a number of candidate drugs have shown limited efficacy in vitro and/or in non-human primate studies, differences in experimental methodologies make it difficult to compare their therapeutic effectiveness. Using an in vitro model of Ebola Zaire replication with transcription-competent virus like particles (trVLPs, requiring only level 2 biosafety containment, we compared the activities of the type I interferons (IFNs IFN-α and IFN-ß, a panel of viral polymerase inhibitors (lamivudine (3TC, zidovudine (AZT tenofovir (TFV, favipiravir (FPV, the active metabolite of brincidofovir, cidofovir (CDF, and the estrogen receptor modulator, toremifene (TOR, in inhibiting viral replication in dose-response and time course studies. We also tested 28 two- and 56 three-drug combinations against Ebola replication. IFN-α and IFN-ß inhibited viral replication 24 hours post-infection (IC50 0.038μM and 0.016μM, respectively. 3TC, AZT and TFV inhibited Ebola replication when used alone (50-62% or in combination (87%. They exhibited lower IC50 (0.98-6.2μM compared with FPV (36.8μM, when administered 24 hours post-infection. Unexpectedly, CDF had a narrow therapeutic window (6.25-25μM. When dosed >50μM, CDF treatment enhanced viral infection. IFN-ß exhibited strong synergy with 3TC (97.3% inhibition or in triple combination with 3TC and AZT (95.8% inhibition. This study demonstrates that IFNs and viral polymerase inhibitors may have utility in EVD. We identified several 2 and 3 drug combinations with strong anti-Ebola activity, confirmed in studies using fully infectious ZEBOV, providing a rationale for testing combination therapies in animal models of lethal Ebola challenge. These studies open up new possibilities for novel therapeutic options, in particular combination therapies, which could prevent and treat Ebola infection and potentially reduce drug

  3. Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART vs. continuous therapy for HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Cynthia Firnhaber

    Full Text Available BACKGROUND: The clinical outcomes of short interruptions of PI-based ART regimens remains undefined. METHODS: A 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load 450 cells/µl on stavudine (or zidovudine, lamivudine and lopinavir/ritonavir. Subjects were randomized to a sequential 2, 4 and 8-week ART interruptions or b continuous ART (cART. Primary analysis was based on the proportion of CD4 count >350 cells(c/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints. RESULTS: The proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: -0.16, 23.1. No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm. CONCLUSION: We are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur. TRIAL REGISTRATION: ClinicalTrials.gov NCT00100646.

  4. Factors that influence fatigue status in patients with severe rheumatoid arthritis (RA) and good disease outcome following 6 months of TNF inhibitor therapy: a comparative analysis.

    LENUS (Irish Health Repository)

    Minnock, Patricia

    2015-11-01

    The objective of the present study is to determine the factors associated with persistent fatigue in patients with severe rheumatoid arthritis (RA) and good disease response to 6 months of tumour necrosis factor inhibitor therapy. Eligible patients with either persistent (PF) or no fatigue (NF) were compared. Using validated questionnaires and bivariate analysis, this cross-sectional survey explored if clinical characteristics, pain, self-efficacy, sleep and mood\\/depression differed between groups. Patients with PF (PF; NF) (n = 28; 28) reported significantly more overall pain (11.3 ± 9.4 (0-33); 6.9 ± 8.9 (0-33)), more recent and current pain intensity (41.4 ± 26.6 (0-80) 24.4 ± 26.6 (0-100) and depression (11.8 ± 7.5 (1-35); 8.2 ± 6.6 (0-26)), than the NF group. There was no significant difference between groups in self-efficacy and both groups experienced poor sleep quality (Pittsburgh Sleep Quality Index >5). Despite having good disease response, the PF group had significantly higher rheumatoid factor incidence, disease activity score-28, early morning stiffness duration and lower incidence of ever-failing disease-modifying anti-rheumatic drugs than the NF group. These findings enhance the fatigue literature in patients with RA prescribed tumour necrosis factor (TNF) inhibition therapy, identifying the potentially modifiable factors of pain and depression, previously demonstrated to be strongly associated with fatigue in non-biologic populations. In addition, this study highlights the association between persistent fatigue and an on-going state of low disease activity. This infers that more judicious disease management could minimise the symptom burden of pain and depression and consequentially fatigue.

  5. Impact of Dual Antiplatelet Therapy with Proton Pump Inhibitors on the Outcome of Patients with Acute Coronary Syndrome Undergoing Drug-Eluting Stent Implantation

    Science.gov (United States)

    Macaione, Francesca; Montaina, Carla; Evola, Salvatore; Novo, Giuseppina; Novo, Salvatore

    2012-01-01

    This study aimed to assess if proton pump inhibitors (PPIs) may reduce the effectiveness of clopidogrel, than H2 antagonist (anti-H2) in order to determine rehospitalization for acute coronary syndrome (re-ACS), target vessel revascularization (TVR) and cardiac death. This case-control study included 176 patients with ACS undergoing angioplasty (PCI) with drug-eluting stent implantation. The population was divided into two groups: PPI group (n = 121) consisting of patients receiving at discharge dual antiplatelet therapy (DAT) plus PPI and anti-H2 group (n = 55), consisting of patients receiving at discharge DAT + H2 receptor antagonist (H2RA). In a followup of 36 months the prevalence of ACS event (P = 0.014), TVR (P = 0.031) was higher in the PPI group than in the anti-H2 group; instead there was no statistically significant difference between groups for death. The variables independently associated with ACS were the diabetes, omeprazole, and esomeprazole; instead the variables independently associated with TVR were only omeprazole. Our data shows that the use of omeprazole and esomeprazole, with clopidogrel, is associated with increased risk of adverse outcomes after PCI with drug-eluting stent implantation. PMID:22792485

  6. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Science.gov (United States)

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  7. Does fasting during Ramadan trigger non-adherence to oral hormonal therapy in breast cancer patients?

    International Nuclear Information System (INIS)

    Purpose: To estimate the effect of fasting during Ramadan (the ninth lunar month) on adherence to oral hormonal therapies (OHT) among breast cancer (BC) patients. Patients and Methods: During Ramadan 2010, 139 BC patients were interviewed at the Egyptian National Cancer Institute. They were asked about fasting as well as intake of OHT in Ramadan and in the preceding month. Results: The median age was 50 years and most patients were postmenopausal with good performance status and non-metastatic disease. The median number of fasting days was 18% and 93% of patients were fasting 80% or more of Ramadan. Tamoxifen and aromatase inhibitors were used in 64% and 36%, respectively. Adherence to OHT during Ramadan and its preceding month were 94.2% and 95.7%, respectively (p = 0.77). In univariate analysis, non-adherence prior to Ramadan and shorter duration of OHT were predictors of non-adherence during Ramadan (P < 0.001, 0.003, respectively). Fasting, age, performance status, presence of metastases and type of hormonal therapy were not good predictors of adherence. Conclusions: While most of patients receiving OHT for BC are fasting during Ramadan, this does not negatively impact compliance with treatment

  8. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.

    Directory of Open Access Journals (Sweden)

    Datsen George Wei

    2014-04-01

    Full Text Available Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD, a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM compared with vorinostat (VOR; EC50 = 3,950 nM and other histone deacetylase (HDAC inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM. The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART, a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.

  9. Rapid CD4 decline after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy in a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Watcharananan Siriorn

    2007-11-01

    Full Text Available Abstract Background Non-nucleoside reverse transcriptase inhibitor (NNRTI with stavudine and lamivudine is widely used as the first-line antiretroviral therapy (ART in resource-limited settings. Lipodystrophy is common and options for switching ART regimen are limited; this situation can lead to patients' poor adherence and antiretroviral resistance. Treatment interruption (TI in patients with high CD4 cell counts, lipodystrophy, and limited options may be an alternative in resource-limited settings. This study aimed to determine time to resume ART after TI and predictors for early resumption of ART in a resource-limited setting. Methods A prospective study was conducted in January 2005 to December 2006 and enrolled HIV-infected patients with HIV-1 RNA 350 cells/mm3, and willing to interrupt ART. CD4 cell count, HIV-1 RNA, lipid profile, and lipodystrophy were assessed at baseline and every 3 months. ART was resumed when CD4 declined to 3 or developed HIV-related symptoms. Patients were grouped based on ART regimens [NNRTI or protease inhibitor (PI] prior to TI. Results There were 99 patients, 85 in NNRTI group and 14 in PI group. Mean age was 40.6 years; 46% were males. Median duration of ART was 47 months. Median nadir CD4 and baseline CD4 were 151 and 535 cells/mm3, respectively. Median CD4 change at 3 months after TI were -259 (NNRTI and -105 (PI cells/mm3 (p = 0.038. At 13-month median follow-up, there was no AIDS-defining illness; 38% (NNRTI and 29% (PI of patients developed HIV-related symptoms. ART was resumed in 51% (NNRTI and 36% (PI of patients (p = 0.022. By Kaplan-Meier analysis, median time to resume ART was 5.5 (NNRTI and 14.2 (PI months (log rank test, p = 0.026. By Cox's regression analysis, NNRTI-based ART (HR 4.9; 95%CI, 1.5–16.3, nadir CD4 3 (HR 2.7; 95%CI 1.4–5.3 and baseline CD4 3 (HR 1.6; 95%CI, 1.2–3.1 were predictors for early ART resumption. Conclusion TI of NNRTI-based ART leads to rapid CD4 decline and high

  10. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    International Nuclear Information System (INIS)

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [3H]2O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks. - Highlights:

  11. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [{sup 3}H]{sub 2}O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks

  12. Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect.

    Science.gov (United States)

    Bougioukli, Sofia; Jain, Ashish; Sugiyama, Osamu; Tinsley, Brian A; Tang, Amy H; Tan, Matthew H; Adams, Douglas J; Kostenuik, Paul J; Lieberman, Jay R

    2016-03-01

    Recombinant human BMP-2 (rhBMP-2) is a potent osteoinductive agent, but has been associated not only with bone formation, but also osteoclastogenesis and bone resorption. Osteoprotegerin (OPG) is a RANKL inhibitor that blocks differentiation and function of osteoclasts. We hypothesized that the combination of local BMP-2 (recombinant protein or a product of gene therapy) plus systemic OPG-Fc is more effective than BMP-2 alone in promoting bone repair. To test this hypothesis we used a mouse critical-sized femoral defect model. Col2.3eGFP (osteoblastic marker) male mice were treated with rhBMP-2 (group I), rhBMP-2 and systemic OPG (group II), rhBMP-2 and delayed administration of OPG (group III), mouse BM cells transduced with a lentiviral vector containing the BMP-2 gene (LV-BMP-2; group IV), LV-BMP-2 and systemic OPG (group V), a carrier alone (group VI) and administration of OPG alone (group VII). All bone defects treated with BMP-2 (alone or combined with OPG) healed, whereas minimal bone formation was noted in animals treated with the carrier alone or OPG alone. MicroCT analysis showed that bone volume (BV) in rhBMP-2+OPG and LV-BMP-2+OPG groups was significantly higher compared to rhBMP-2 alone (p<0.01) and LV-BMP-2 alone (p<0.001). Similar results were observed in histomorphometry, with rhBMP-2 alone defects exhibiting significantly lower bone area (B.Ar) compared to rhBMP-2+OPG defects (p<0.005) and LV-BMP-2 defects having a significantly lower B.Ar compared to all BMP-2+OPG treated groups (p≤0.01). TRAP staining demonstrated a major osteoclast response in the groups that did not receive OPG (rhBMP-2, LV-BMP-2 and sponge alone) beginning as early as 7days post-operatively. In conclusion, we demonstrated that locally delivered BMP-2 (recombinant protein or gene therapy) in combination with systemically administered OPG improved bone healing compared to BMP-2 alone in a mouse critical-sized bone defect. These data indicate that osteoclasts can diminish

  13. Sporadic fundic gland polyps are not associated with proton pump inhibitors therapy but negatively correlate with Helicobacter pylori infection in China

    Institute of Scientific and Technical Information of China (English)

    Cao Hailong; Qu Rui; Zhang Zhihua; Kong Xinyue; Wang Shan; Jiang Kui; Wang Bangmao

    2014-01-01

    Background Sporadic fundic gland polyps (FGPs) are common gastric polyps.Some studies reported that FGPs dramatically increased due to proton pump inhibitors (PPIs) use and a decreased prevalence of Helicobacter pylori (H.pylon) infection in Western countries.However,data are still controversial.This study aimed to identify the relationships between these two factors and FGPs in China.Methods Consecutive patients with FGPs detected were retrospectively analyzed.Data including patients' age,sex,symptoms,H.pylori infection,history of PPIs use,and the polyps were documented.Each patient was compared with two randomly selected age-and sex-matched controls with similar symptoms in the same period.Results During the period from March 2011 to March 2012,a total of 328 patients were diagnosed as FGPs in 23 047 patients who underwent routine esophagogastroduodenoscopy and 656 patients without FGPs as controls.The mean age was (55.12±12.61) years,and 75.91% were women.The prevalence of H.pylori in patients with FGPs was significantly lower than in those without FGPs (22.30% (64/287) vs.42.26% (224/530),P <0.001,OR 0.392,95% Cl 0.283-0.544).Overall,a total of 54 patients with FGPs (54/328,16.46%) and 136 patients without FGPs (136/656,20.73%) received PPIs therapy (P=0.110).According to the different duration of PPIs use,no significant differences of PPIs use were found between the cases and controls among all subgroups.Moreover,the PPIs use was also similar,regardless of age,sex,H.pylori infection,and the number of polyps.Conclusion Sporadic FGPs may not be induced by PPIs therapy but negatively correlate with H.pylori infection in China,which is not the same with the data in Western countries.

  14. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

    Science.gov (United States)

    Berenguer-Daizé, Caroline; Astorgues-Xerri, Lucile; Odore, Elodie; Cayol, Mylène; Cvitkovic, Esteban; Noel, Kay; Bekradda, Mohamed; MacKenzie, Sarah; Rezai, Keyvan; Lokiec, François; Riveiro, Maria E; Ouafik, L'Houcine

    2016-11-01

    Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies. PMID:27388964

  15. A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Wattmo C

    2013-03-01

    Full Text Available Carina Wattmo, Elisabeth Paulsson, Lennart Minthon, Elisabet LondosClinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, SwedenBackground: To investigate the long-term effects of cholinesterase inhibitor (ChEI therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS by patients with Alzheimer’s disease (AD.Methods: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL, and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.Results: During the study, 332 patients (38% used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.Conclusions: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.Keywords: cognition, activities of daily living, treatment effect, gender, predictors

  16. Dual roles of NF-κB in cell survival and implications of NF-κB inhibitors in neuroprotective therapy

    Institute of Scientific and Technical Information of China (English)

    Zheng-hong QIN; Lu-yang TAO; Xin CHEN

    2007-01-01

    NF-κB is a well-characterized transcription factor with multiple physiological and pathological functions. NF-κB plays important roles in the development and maturation of lymphoids, regulation of immune and inflammatory response, and cell death and survival. The influence of NF-κB on cell survival could be protec- tive or destructive, depending on types, developmental stages of cells, and patho- logical conditions. The complexity of NF-rd3 in cell death and survival derives from its multiple roles in regulating the expression of a broad array of genes involved in promoting cell death and survival. The activation of NF-κB has been found in many neurological disorders, but its actual roles in pathogenesis are still being debated. Many compounds with neuroprotective actions are strongly as- sociated with the inhibition of NF-r,B, leading to speculation that blocking the pathological activation of NF-κB could offer neuroprotective effects in certain neurodegenerative conditions. This paper reviews the recent developments in understanding the dual roles of NF-κB in cell death and survival and explores its possible usefulness in treating neurological diseases. This paper will summarize the genes regulated by NF-κB that are involved in cell death and survival to elucidate why NF-r,B promotes cell survival in some conditions while facilitating cell death in other conditions. This paper will also focus on the effects of various NF-κB inhibitors on neuroprotection in certain pathological conditions to specu- late if NF-κB is a potential target for neuroprotective therapy.

  17. Histone deacetylase inhibitors in cancer therapy%组蛋白脱乙酰基酶抑制剂在肿瘤治疗中的应用

    Institute of Scientific and Technical Information of China (English)

    李媛媛; 张斌; 曹旭晨

    2011-01-01

    组蛋白的乙酰化状态调控DNA转录从而影响基因的表达水平.组蛋白脱乙酰基酶(HDAC)可降低组蛋白乙酰化,引起DNA-组蛋白复合物压缩.这种压缩可以阻碍基因转录,抑制细胞分化.HDAC抑制剂可以解除DNA-组蛋白复合物压缩,从而促进肿瘤细胞生长停滞、分化及凋亡.在此过程中,HDAC抑制剂也影响非组蛋白的乙酰化状态和功能.HDAC抑制剂在多种肿瘤中不仅单独使用具有显著的抗肿瘤效应,在联合应用中也具有重大意义.%The acetylation status of histories regulates access of transcription factors to DNA and influences levels of gene expression.Histone deacetylase(HDAC)activity diminishes acctylation of histones,causing compaction of the DNA-histone complex.This compaction blocks gene transcription and inhibits cell differentiation.HDAC inhibitom decompact the DNA-histone complex and promote cell growth arrest,differentiation,and apoptosis of tumor cells.Meantime,HDAC inhibition also affects acetylation status and function of non-histone proteins.HDAC inhibitors not only possess significant anti-tumor effects with single use,but also has great significance in combined therapy with other drugs.

  18. Kinetics and Molecular Docking Study of an Anti-diabetic Drug Glimepiride as Acetylcholinesterase Inhibitor: Implication for Alzheimer's Disease-Diabetes Dual Therapy.

    Science.gov (United States)

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Naaz, Deeba; Shakil, Shazi; Ahmad, Adnan; Haneef, Mohd; Abuzenadah, Adel M

    2016-06-01

    At the present time, treatment of two most common degenerative disorders of elderly population i.e., Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) is a major concern worldwide. As there are several evidences that proved strong linkages between these two disorders, the idea of using dual therapeutic agent for both the diseases might be considered as a good initiative. Earlier reports have revealed that oral anti-diabetic drugs such as peroxisome proliferator activated receptor γ (PPARγ) agonists (thiazolidinediones) when used in T2DM patients suffering from AD showed improved memory and cognition. However, the underlying mechanism still needs to be deciphered. Therefore, the present study was carried out to find whether glimepiride, an oral antidiabetic drug which is a PPARγ agonist could inhibit the activity of acetylcholine esterase (AChE) enzyme. Actually, AChE inhibitors seize the breakdown of acetylcholine which forms the main therapeutic strategy for AD. Here, glimepiride showed dose dependent inhibitory activity against AChE enzyme with IC50 value of 235 μM. Kinetic analysis showed competitive inhibition, which was verified by in silico docking studies. Glimepiride was found to interact with AChE enzyme at the same locus as that of substrate acetylcholine iodide (AChI). Interestingly, amino acid residues, Q71, Y72, V73, D74, W86, N87, Y124, S125, W286, F295, F297, Y337, F338 and Y341 of AChE were found to be common for 'glimepiride-AChE interaction' as well as 'AChI-AChE interaction'. Thus the present computational and kinetics study concludes that glimepiride and other thiazolidinediones derivatives could form the basis of future dual therapy against diabetes associated neurological disorders. PMID:26886763

  19. Treatment of depression in patients with temporal lobe epilepsy: A pilot study of cognitive behavioral therapy vs. selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Orjuela-Rojas, Juan Manuel; Martínez-Juárez, Iris E; Ruiz-Chow, Angel; Crail-Melendez, Daniel

    2015-10-01

    There is a high prevalence of depression in patients with epilepsy, which negatively impacts their quality of life (QOL) and seizure control. Currently, the first-line of treatment for depression in patients with epilepsy is based on selective serotonin reuptake inhibitors (SSRIs). The main objective of this pilot study was to compare cognitive behavioral therapy (CBT) versus SSRIs for the treatment of major depressive disorder (MDD) in patients with temporal lobe epilepsy (TLE). Seven patients who received group CBT were compared with eight patients treated with SSRIs. All were diagnosed with MDD and TLE. Patients were assessed at baseline before treatment and at six and 12weeks during treatment with the Quality of Life in Epilepsy Scale of 31 items (QOLIE 31), the Beck Depression Inventory (BDI), and the Hospital Anxiety and Depression Scale (HADS). Seizure records were also taken on a monthly basis. After 12weeks of treatment, both groups showed improved QOL and reduced severity of depression symptoms. There were no statistically significant group differences in the final scores for the BDI (p=0.40) and QOLIE 31 (p=0.72), although the effect size on QOL was higher for the group receiving CBT. In conclusion, the present study suggests that both CBT and SSRIs may improve MDD and QOL in patients with TLE. We found no significant outcome differences between both treatment modalities. These findings support further study using a double-blind controlled design to demonstrate the efficacy of CBT and SSRIs in the treatment of MDD and QOL in patients with TLE.

  20. An oral high dose of cholecalciferol restores vitamin D status in deficient postmenopausal HIV-1-infected women independently of protease inhibitors therapy: a pilot study.

    Science.gov (United States)

    Pepe, Jessica; Mezzaroma, Ivano; Fantauzzi, Alessandra; Falciano, Mario; Salotti, Alessandra; Di Traglia, Mario; Diacinti, Daniele; Biondi, Piergianni; Cipriani, Cristiana; Cilli, Mirella; Minisola, Salvatore

    2016-07-01

    The best repletion and maintenance dosing regimens with cholecalciferol in vitamin D-deficient HIV-1 patients remain unknown. Protease inhibitors (PIs) have been shown to inhibit vitamin D 1α- and 25α-hydroxylation in hepatocyte and monocyte cultures. We therefore evaluated the effect of a single high dose of cholecalciferol in vitamin D-deficient HIV-1 postmenopausal women undergoing treatment with highly active anti-retroviral therapy (cART), with and without PIs. Forty HIV-1 postmenopausal women treated with cART, with hypovitaminosis D (ng/ml), were enrolled. We measured serum changes of 25-hydroxyvitamin D [25(OH)D]; 1,25-dihydroxyvitamin D [1,25(OH)2D], parathyroid hormone (PTH), serum calcium, and urinary calcium excretion following a loading dose of 600,000 IU of cholecalciferol after 3, 30, 60, 90, and 120 days. Patients were divided into two groups, whether or not they were taking PI. A significant increase in mean 25(OH)D and 1,25(OH)2D levels at day 3 and throughout the entire observation period was found in both groups (p < 0.001). PTH levels concomitantly decreased in both groups (p < 0.001). Mean albumin-adjusted serum calcium increases with respect to baseline were significant only at day 3 and day 30 for both groups (p < 0.01). Considering remaining parameters, there were no significant differences between the groups at any time, by two-way RM ANOVA. An oral dose of 600,000 IU of cholecalciferol in HIV-1 postmenopausal women rapidly increases 25(OH)D and 1,25(OH)2D levels reducing PTH levels, regardless of the presence of PIs in the cART scheme. PMID:26254790

  1. Gossypol enantiomers potently inhibit human placental 3β-hydroxysteroid dehydrogenase 1 and aromatase activities.

    Science.gov (United States)

    Dong, Yaoyao; Mao, Baiping; Li, Linxi; Guan, Hongguo; Su, Ying; Li, Xiaoheng; Lian, Qingquan; Huang, Ping; Ge, Ren-Shan

    2016-03-01

    Gossypol is a chemical isolated from cotton seeds. It exists as (+) or (-) enantiomer and has been tested for anticancer, abortion-inducing, and male contraception. Progesterone formed from pregnenolone by 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) and estradiol from androgen by aromatase (CYP19A1) are critical for the maintenance of pregnancy or associated with some cancers. In this study we compared the potencies of (+)- and (-)-gossypol enantiomers in the inhibition of HSD3B1 and aromatase activities as well as progesterone and estradiol production in human placental JEG-3 cells. (+) Gossypol showed potent inhibition on human placental HSD3B1 with IC50 value of 2.3 μM, while (-) gossypol weakly inhibited it with IC50 over 100 μM. In contrast, (-) gossypol moderately inhibited CYP19A1 activity with IC50 of 23 μM, while (+) gossypol had no inhibition when the highest concentration (100 μM) was tested. (+) Gossypol enantiomer competitively inhibited HSD3B1 against substrate pregnenolone and showed mixed mode against NAD(+). (-) Gossypol competitively inhibited CYP19A1 against substrate testosterone. Gossypol enantiomers showed different potency related to their inhibition on human HSD3B1 and CYP19A1. Whether gossypol enantiomer is used alone or in combination relies on its application and beneficial effects. PMID:26709042

  2. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection.

    Science.gov (United States)

    Cohen, P G

    2001-06-01

    In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time. PMID:11399122

  3. Clinical Response, Drug Survival, and Predictors Thereof Among 548 Patients With Psoriatic Arthritis Who Switched Tumor Necrosis Factor α Inhibitor Therapy

    DEFF Research Database (Denmark)

    Glintborg, Bente; Ostergaard, Mikkel; Krogh, Niels Steen;

    2013-01-01

    To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care.......To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care....

  4. Neo-adjuvant endocrine therapy in breast cancer%乳腺癌新辅助内分泌治疗进展

    Institute of Scientific and Technical Information of China (English)

    刘倩

    2011-01-01

    针对局部晚期乳腺癌患者,尤其是绝经后内分泌反应型且不能耐受化疗的群体,新辅助内分泌治疗不失为一种选择方案.第三代芳香化酶抑制剂为绝经后患者首选药物,因其疗效显著优于他莫昔芬.同比新辅助化疗,在病例选择得当的前提下,新辅助内分泌治疗可获得相似的短期获益,由于长时间随访结果较少,总体预后尚不清楚.%Nco-adjuvant endocrine therapy has provided opened new alternatives for locally advanced breast cancer, especially for patient groups such as the elderly, those who are not suited for chemotherapy, and those whose response may not be optimal. The latest generation of endocrine therapy for breast cancer,aromatase inhibitors, has proved superior to tamoxifen in terms of toxicity and efficacy in the adjuvant setting.Compared with neo-adjuvant chemotherapy, the appropriate patients to receive nco-adjuvant endocrine therapy can achieve similar short-term benefit. However, because of fewer long-term follow up results, the overall prognosis is not clear.

  5. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL– and mutant FLT3-expressing cells

    Science.gov (United States)

    Weisberg, Ellen; Banerji, Lolita; Wright, Renee D.; Barrett, Rosemary; Ray, Arghya; Moreno, Daisy; Catley, Laurence; Jiang, Jingrui; Hall-Meyers, Elizabeth; Sauveur-Michel, Maira; Stone, Richard; Galinsky, Ilene; Fox, Edward; Kung, Andrew L.

    2008-01-01

    Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo. PMID:18184863

  6. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity.

    Science.gov (United States)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [(3)H](2)O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks.

  7. CREB-regulated transcription co-activator family stimulates promoter II-driven aromatase expression in preadipocytes.

    Science.gov (United States)

    Samarajeewa, Nirukshi U; Docanto, Maria M; Simpson, Evan R; Brown, Kristy A

    2013-08-01

    The dramatically increased prevalence of breast cancer after menopause is of great concern and is correlated with elevated local levels of estrogens. This is mainly due to an increase in aromatase expression driven by its proximal promoter II (PII). We have previously demonstrated that the CREB co-activator CRTC2 binds directly to PII and stimulates its activity via mechanisms involving LKB1-AMPK in response to prostaglandin E(2) (PGE(2)). There are three members of the CRTC family (CRTC1-3) and this study aimed to characterize the role of other CRTCs in the activation of aromatase PII. The expression and subcellular localization of CRTCs were examined in preadipocytes using qPCR and immunofluorescence. Under basal conditions, CRTC1 expression was the lowest, whereas CRTC3 transcripts were present at higher levels. Basally, CRTC2 and CRTC3 were mainly cytoplasmic and PGE(2) caused their nuclear translocation. Reporter assays and chromatin immunoprecipitation (ChIP) were performed to assess the effect of CRTCs on PII activity and binding. Basal PII activity was significantly increased with all CRTCs. Forskolin (FSK)/phorbol 12-myristate 13-acetate (PMA), to mimic PGE(2), resulted in a further significant increase in PII activity with all CRTCs, with CRTC2 and CRTC3 having greater effects. This was consistent with ChIP data showing an increased binding of CRTCs to PII with FSK/PMA. Moreover, gene silencing of CRTC2 and CRTC3 significantly reduced the FSK/PMA-mediated stimulation of aromatase activity. Interestingly, CRTCs acted cooperatively with CREB1 to increase PII activity, and both CREs were found to be essential for the maximal induction of PII activity by CRTCs. Phosphorylation of CRTC2 at its AMPK target site, Ser 171, dictated its subcellular localization, and the activation of aromatase PII in preadipocytes. In conclusion, this study demonstrates that aromatase regulation in primary human breast preadipocytes involves more than one CRTC.

  8. Cost-effectiveness of tipranavir versus comparator protease inhibitor regimens in HIV infected patients previously exposed to antiretroviral therapy in the Netherlands

    Directory of Open Access Journals (Sweden)

    Kappelhoff Bregt S

    2007-11-01

    Full Text Available Abstract Background This study compares the costs and effects of a regimen with ritonavir-boosted tipranavir (TPV/r to a physician-selected genotypically-defined standard-of-care comparator protease inhibitor regimen boosted with ritonavir (CPI/r in HIV infected patients that were previously exposed to antiretroviral therapy in the Netherlands. Methods We compared the projected lifetime costs and effects of two theoretical groups of 1000 patients, one receiving a standard of care regimen with TPV/r as a component and the other receiving a standard of care regimen with CPI/r. A 3-stage Markov model was formulated to represent three different consecutive HAART regimens. The model uses 12 health states based on viral load and CD4+ count to simulate disease progression. The transition probabilities for the Markov model were derived from a United States cohort of treatment experienced HIV patients. Furthermore, the study design was based on 48-week data from the RESIST-2 clinical trial and local Dutch costing data. Cost and health effects were discounted at 4% and 1.5% respectively according to the Dutch guideline. The analysis was conducted from the Dutch healthcare perspective using 2006 unit cost prices. Results Our model projects an accumulated discounted cost to the Dutch healthcare system per patient receiving the TPV/r regimen of €167,200 compared to €145,400 for the CPI/r regimen. This results in an incremental cost of €21,800 per patient. The accumulated discounted effect is 7.43 life years or 6.31 quality adjusted life years (QALYs per patient receiving TPV/r, compared to 6.91 life years or 5.80 QALYs per patient receiving CPI/r. This translates into an incremental effect of TPV/r over CPI/r of 0.52 life years gained (LYG or 0.51 QALYs gained. The corresponding incremental cost effectiveness ratios (iCERs are €41,600 per LYG and €42,500 per QALY. Conclusion We estimated the iCER for TPV/r compared to CPI/r at approximately €40

  9. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group

    DEFF Research Database (Denmark)

    Flather, M D; Yusuf, S; Køber, L;

    2000-01-01

    BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials enro...

  10. The interaction between aromatase, metalloproteinase 2,9 and cd44 in breast cancer A interação entre aromatase, metalloproteinase 2, 9 e cd44 no câncer de mama

    Directory of Open Access Journals (Sweden)

    Fábio Bagnoli

    2010-01-01

    Full Text Available OBJECTIVE: This study intends to verify the expression levels and correlation of aromatase, matrix metalloproteinase 2 (MMP-2, matrix metalloproteinase 9 (MMP-9 and CD44 in ductal carcinoma in situ (DCIS and infiltrating ductal carcinoma (IDC when both are found in the same breast. METHODS: One hundred and ten cases were evaluated by tissue microarray (TMA and immunohistochemically screened with anti-aromatase polyclonal antibodies, anti-MMP-2 monoclonal antibodies, anti-MMP-9 policlonal antibodies and anti-CD44 monoclonal antibodies. RESULTS: Aromatase was expressed in IDC and DCIS in 63 (57.3% and 60 (67% of the cases respectively; MMP-2 was similarly expressed in IDC and DCIS in 15 (13.60% cases; MMP-9 was positively expressed in IDC and DCIS in 83 (75.50% and 82 (74.50% cases, respectively; CD44 was positively expressed in IDC and DCIS in 49 (44.50% and 48 (42.60% of the cases, respectively; all of them were highly correlated (pOBJETIVO: O objetivo desse estudo é verificar as expressões e correlações da aromatase, metalloproteinase 2 da matriz (MMP2, metalloproteinase 9 da matriz (MMP-9 e CD44 no carcinoma ductal in situ (CDIS e carcinoma ductal infiltrativo (CDI quando ambos estão presentes simultaneamente na mesma mama. MÉTODOS: Foram avaliados 110 casos pelo método de tissue microarray (TMA e através da utilização de anticorpos policlonais antiaromatase, anticorpos monoclonais anti-MMP-2, anticorpos policlonais anti-MMP-9 e anticorpos monoclonais anti-CD44. RESULTADOS: A aromatase estava expressa de forma positiva no CDI e CDIS em 63 (57,3% e 60 (67% casos, respectivamente. A expressão de MMP-2 estava expressa de forma positiva em 15 (13,6% casos tanto no CDI, quanto no CDIS. A expressão da MMP-9 estava expressa de forma positiva em 83 (75,5% e 82 (74,5% casos de CDI e CDIS, respectivamente. A expressão de CD44 estava expressa de forma positiva em 49 (44,5% e 48 (42,6% casos de CDI e CDIS, respectivamente. Todos eles

  11. ACE INHIBITORS: A COMPREHENSIVE REVIEW

    Directory of Open Access Journals (Sweden)

    Pradeep Kumar Arora* and Ashish Chauhan

    2013-02-01

    Full Text Available Hypertension is a chronic increase in blood pressure, characterized as primary and secondary hypertension. The disorder is associated with various risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is being treated since ancient times by Ayurvedic, Chinese and Unani medicine. Now various allopathic drugs are available which include diuretics, calcium channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics and ACE-inhibitors. Non-pharmacological treatments include weight reduction, dietary sodium reduction, increased potassium intake and reduction in alcohol consumption. ACE-inhibitors are widely used in the treatment of hypertension by inhibiting the angiotensin converting enzyme responsible for the conversion of angiotensin I to angiotensin II (responsible for vasoconstriction. Various structure activity relationship studies led to the synthesis of ACE-inhibitors, some are under clinical development. This comprehensive review gives various guidelines on classification of hypertension, hypertension therapy including ancient, pharmacological, non-pharmacological therapies, pharmacoeconomics, historical perspectives of ACE, renin, renin angiotensin system (circulating vs local RAS, mechanism of ACE inhibitors, and development of ACE inhibitors. Review also emphasizes on the recent advancements on ACE inhibitors including drugs in clinical trials, computational studies on ACE-inhibitors, peptidomimetics, dual, natural, multi-functional ACE inhibitors, and conformational requirements for ACE-inhibitors.

  12. The Evolution of the Local and System Therapy of Breast Cancer Stage I: 27-Years’s Data Analysis

    Directory of Open Access Journals (Sweden)

    Kolyadina I.V.

    2014-03-01

    trastuzumab in adjuvant therapy — after 2005; about half of the women with HER2-positive breast cancer stage I (50.8% have received anti-HER2-therapy by trastuzumab. The proportion of patients receiving endocrine therapy by tamoxifen alone has decreased (from 84.2 to 52.4%, p < 0.05 in favor of other agents (aromatase inhibitors and sequential modes.

  13. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use.

    Science.gov (United States)

    McBride, J Abram; Coward, Robert M

    2016-01-01

    The use of testosterone replacement therapy (TRT) for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS) within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG) axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use. PMID:26908067

  14. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use

    Directory of Open Access Journals (Sweden)

    J Abram McBride

    2016-01-01

    Full Text Available The use of testosterone replacement therapy (TRT for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use.

  15. New insights about the evaluation of human sperm quality: the aromatase example.

    Directory of Open Access Journals (Sweden)

    A Saad

    2010-01-01

    Full Text Available Male contribution to the couple's infertility is at first evaluated by the routine examination of semen parameters upon optical microscopy providing valuable information for a rational initial diagnosis and for a clinical management of infertility. But the different forms of infertility defined according to the WHO criteria especially teratozoospermia are not always related to the chromatin structure or to the fertilization capacity. New investigations at the molecular level (transcript and protein could be developed in order to understand the nature of sperm malformation responsible of human infertility and thus to evaluate the sperm quality. The profile analysis of spermatozoal transcripts could be considered as a fingerprint of the past spermatogenic events. The selection of representative transcripts of normal spermatozoa remains complex because a differential expression (increased, decreased or not modified levels of specific transcripts has been revealed between immotile and motile sperm fractions issued from normozoospermic donors. Microarrays tests or real-time quantitative PCR could be helpful for the identification of factors involved in the male infertility. Differences in the expression of specific transcripts have been reported between normal and abnormal semen samples. With the aromatase example, we have noted a negative strong correlation between the amount of transcript and the percentage of abnormal forms especially in presence of head defects. Immunocytochemical procedures using fluorescent probes associated with either confocal microscopy or flow cytometry can be also helpful to proceed with further investigations about the localization of proteins in the compartmentalized spermatozoa or the acrosome reaction. The dual location of aromatase both in the equatorial segment, the mid-piece and the tail could explain the double role of this enzyme in acrosome reaction and motility.

  16. Frequency of Polymorphism in Aromatase Enzyme Coding Gene with Prostate Cancer Risk in North Indian Population

    Directory of Open Access Journals (Sweden)

    KH Onsory

    2015-10-01

    Full Text Available Background: A series of biochemical reactions are involved in the endogenous production of estrogens. Their final and rate-limiting step is catalyzed by aromatase belonging to the class XIX of cytochrome P450. CYP19 is a key enzyme for estrogen synthesis in males. It catalyzes the irreversible conversion of androstenedione and testosterone to estrone and estradiol-17β, respectively. Aromatase P450 is present in the endoplasmic reticulum of estrogen-reproducing cells in which it is expressed. The effects of the resulting estrogens are mediated through the estrogen receptor. One of the most important polymorphism, is a C to T variation in exon 7 resulting in an Arg264Cys amino acid exchange, has been shown to be very common in Asia. The purpose of this study was to determine the association of CYP19 gene polymorphism with the prostate cancer risk among the studied population. Methods: PCR-RFLP analysis of CYP19 gene was on 100 prostate cancer patients and an equal number of matching controls. The data was analyzed using the computer software SPSS for windows (version 19. Results: The frequency of CT genotype was higher in patients (37% as compared to controls (21.2% and this incidence was statistically significant (OR, 2.10; 95 % CI, 1.02-4.34; P=0.044. Stratification of patients according to the risk factors, resulted in a slightly improved OR in individuals carrying CT compared to CC genotype (OR, 2.35 95% CI, 1.11-4.96; P=0.024. The TT genotype was not significantly associated with prostate cancer risk (OR, 0.63; 95% CI, 0.16-2.50; P=0.519. Conclusion: It seems that CT genotype is more associated with cancer prostate compare with other genotypes. It appears to be an increased risk of prostate cancer associated with the Arg264Cys substitution in the CYP19 gene.

  17. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    OpenAIRE

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  18. Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

    International Nuclear Information System (INIS)

    In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC. An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011. A total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response. Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical

  19. Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival.

    Science.gov (United States)

    Ma, Yifei; Zhou, Wang; He, Shaohui; Xu, Wei; Xiao, Jianru

    2016-09-15

    Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy. PMID:27164264

  20. Prior EGFR tyrosine-kinase inhibitor therapy did not influence the efficacy of subsequent pemetrexed plus platinum in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Tseng JS

    2014-05-01

    Full Text Available Jeng-Sen Tseng,1,2 Tsung-Ying Yang,2 Kun-Chieh Chen,1,2 Kuo-Hsuan Hsu,1,3 Chong-Jen Yu,4 Wei-Yu Liao,4 Chi-Ren Tsai,5,6 Meen-Hsin Tsai,2,7 Sung-Liang Yu,8–11 Kang-Yi Su,8,12 Jeremy JW Chen,1 Hsuan-Yu Chen,7 Gee-Chen Chang1,2,13–151Institute of Biomedical Sciences, National Chung-Hsing University, 2Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, 3Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 4Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 5Department of Pediatrics, Taichung Veterans General Hospital, 6Institute of Molecular Biology, National Chung-Hsing University, Taichung, 7Institute of Statistical Science, Academia Sinica, 8Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, 9Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, 10Graduate Institute of Pathology, College of Medicine, National Taiwan University, 11Department of Laboratory Medicine, National Taiwan University Hospital, 12Center of Genomic Medicine, National Taiwan University, Taipei, 13School of Medicine, China Medical University, 14Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, 15Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, TaiwanBackground: Tumor cells before and after epidermal growth-factor receptor (EGFR tyrosine-kinase inhibitor (TKI therapy might display different characteristics. The aim of this study was to evaluate the influence of prior EGFR TKI therapy on the efficacy of subsequent pemetrexed plus platinum (PP in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma.Materials and methods: Advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma receiving PP as first

  1. Osteocompatibility of Biofilm Inhibitors

    OpenAIRE

    Rawson, Monica; Haggard, Warren; Jennings, Jessica A.

    2014-01-01

    The demand for infection prevention therapies has led to the discovery of several biofilm inhibitors. These inhibiting signals are released by bacteria, fungi, or marine organisms to signal biofilm dispersal or disruption in Gram-positive, Gram-negative, and fungal microorganisms. The purpose of this study was to test the biocompatibility of five different naturally-produced biofilm chemical dispersal and inhibition signals with osteoblast-like cells: D-amino acids (D-AA), lysostaphin (LS), f...

  2. Farnesoid X Receptor, through the Binding with Steroidogenic Factor 1-responsive Element, Inhibits Aromatase Expression in Tumor Leydig Cells*

    OpenAIRE

    Catalano, Stefania; Malivindi, Rocco; Giordano, Cinzia; Gu, Guowei; Panza, Salvatore; Bonofiglio, Daniela; Lanzino, Marilena; Sisci, Diego; Panno, Maria Luisa; Andò, Sebastiano

    2009-01-01

    The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. It is expressed in the liver and the gastrointestinal tract, but also in several non-enterohepatic tissues including testis. Recently, FXR was identified as a negative modulator of the androgen-estrogen-converting aromatase enzyme in human breast cancer cells. In the present study we detected the expression of FXR in Leydig normal and tumor cell lines and in rat testes tissue. ...

  3. Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner

    OpenAIRE

    Dickens, M.J.; Balthazart, J.; Cornil, C. A.

    2012-01-01

    Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with s...

  4. Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice

    OpenAIRE

    Subbaramaiah, Kotha; Sue, Erika; Bhardwaj, Priya; Du, Baoheng; Hudis, Clifford A.; Giri, Dilip; Kopelovich, Levy; Zhou, Xi Kathy; Dannenberg, Andrew J.

    2013-01-01

    In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose...

  5. Cost-effectiveness of ACE inhibitor therapy to prevent dialysis in nondiabetic nephropathy : Influence of the ACE insertion/deletion polymorphism

    NARCIS (Netherlands)

    Vegter, Stefan; Perna, A.; Hiddema, W.; Ruggenenti, P.; Remuzzi, G.; Navis, Ger Jan; Postma, Maarten

    2009-01-01

    Introduction End-stage renal disease is associated with high health-care costs and low quality of life compared with chronic kidney disease. The renoprotective effectiveness of angiotensin-converting enzyme inhibitors (ACEi) is largely determined by the ACE insertion/deletion (I/D) polymorphism. We

  6. Cost-effectiveness of tipranavir versus comparator protease inhibitor regimens in HIV infected patients previously exposed to antiretroviral therapy in the Netherlands

    NARCIS (Netherlands)

    Hubben, Gijs A A; Bos, Jasper M; Veltman-Starkenburg, Christa A; Stegmeijer, Simon; Finnern, Henrik W; Kappelhoff, Bregt S; Simpson, Kit N; Tramarin, Andrea; Postma, Maarten J

    2007-01-01

    BACKGROUND: This study compares the costs and effects of a regimen with ritonavir-boosted tipranavir (TPV/r) to a physician-selected genotypically-defined standard-of-care comparator protease inhibitor regimen boosted with ritonavir (CPI/r) in HIV infected patients that were previously exposed to an

  7. The rationale and design of the perindopril genetic association study (PERGENE): A pharmacogenetic analysis of angiotensin-converting enzyme inhibitor therapy in patients with stable coronary artery disease

    NARCIS (Netherlands)

    J.J. Brugts (Jasper); M.P.M. de Maat (Moniek); H. Boersma (Eric); J.C.M. Witteman (Jacqueline); C.M. van Duijn (Cock); A.G. Uitterlinden (André); M.E. Bertrand (Michel); W.J. Remme (Willem); K.M. Fox (Kim); R. Ferrari (Roberto); A.H.J. Danser (Jan); M.L. Simoons (Maarten)

    2009-01-01

    textabstractBackground: Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment

  8. Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: Overview of the primary results of the PERindopril GENEtic association (PERGENE) study

    NARCIS (Netherlands)

    J.J. Brugts (Jasper); M.P.M. de Maat (Moniek); A.H.J. Danser (Jan); H. Boersma (Eric); M.L. Simoons (Maarten)

    2012-01-01

    textabstractIn patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure resp

  9. A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults

    OpenAIRE

    Zheng, Yi

    2016-01-01

    Yong-hua Cui,1 Yi Zheng1,2 1Department of Pediatrics, Beijing An’ding Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Institutes of Brain Disorders, Beijing, People’s Republic of China Objective: The aim of the study was to investigate the efficacy and safety of St John’s wort extract and selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression.Methods: Databases were searched for studies compa...

  10. Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells.

    Science.gov (United States)

    Leung, Euphemia; Rewcastle, Gordon W; Joseph, Wayne R; Rosengren, Rhonda J; Larsen, Lesley; Baguley, Bruce C

    2012-12-01

    Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC(50) values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer.

  11. Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country, prospective cohort study.

    Directory of Open Access Journals (Sweden)

    Jeffrey S A Stringer

    2010-02-01

    Full Text Available BACKGROUND: Intrapartum and neonatal single-dose nevirapine (NVP reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART over the first 48 wk of therapy than would women without a prior exposure. METHODS AND FINDINGS: We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load >or=400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1% and 132 of 523 NVP-unexposed women (25.2% met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%-13.0%. The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women; 25 of 67 women in whom 7-12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women; and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women. Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval. CONCLUSIONS: Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this

  12. New Oral Therapies for Psoriasis

    Science.gov (United States)

    Lanoue, Julien; Dong, Joanna

    2016-01-01

    Conventional oral therapies for psoriasis, including methotrexate, cyclosporine, and acitretin, have generally unfavorable safety profiles and are not ideal for long-standing use. Thus, new oral therapies are necessary for patients with more moderate disease, patients who prefer oral treatments to injectable biologies, and patients who failed conventional therapies. The authors review here the clinical and safety evidence of phosphodiesterase 4 inhibitor, apremilast, janus kinase inhibitors, including tofacitinib, and fumarie acid esters as additional options in oral psoriasis therapy. PMID:27672415

  13. Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4 inhibitors and human glucagon-like peptide-1 (GLP-1 analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review.

    Directory of Open Access Journals (Sweden)

    Martin C S Wong

    Full Text Available The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4 inhibitors and the human glucagon-like peptide-1 (GLP-1 analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59-0.90% and 0.77-1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major

  14. The effect of liposome encapsulation on the pharmacokinetics of recombinant secretory leukocyte protease inhibitor (rSLPI) therapy after local delivery to a guinea pig asthma model.

    LENUS (Irish Health Repository)

    Gibbons, Aileen

    2011-09-01

    Inhaled recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) has shown potential for treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs have limited clinical efficacy. Encapsulation of rSLPI within 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]:Cholesterol liposomes (DOPS-rSLPI) protects rSLPI against Cat L inactivation in vitro. We aimed to determine the effect of liposomes on rSLPI pharmacokinetics and activity in vitro and after local delivery to the airways in vivo.

  15. Dose Adjustment of the Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) during Concurrent Rifampicin-Containing Tuberculosis Therapy: One Size does not Fit All

    Science.gov (United States)

    Kwara, Awewura; Ramachandran, Geetha; Swaminathan, Soumya

    2009-01-01

    Importance of the field HIV/TB coinfection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy (HAART) during TB treatment is associated with substantial survival benefit but drug-drug interactions complicate NNRTI dosing. Areas covered in this review We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. Pub Med database was searched from 1966 to July 2009, using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed. What the reader will gain A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies controlled for genetic factors and there was limited data on children. Take home message There was insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug-gene interactions. PMID:19968575

  16. Kinase inhibitors for advanced medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Martin Schlumberger

    2012-01-01

    Full Text Available The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

  17. Adalimumab (TNF α Inhibitor) Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient.

    Science.gov (United States)

    Wei, S S; Sinniah, R

    2013-01-01

    Adalimumab (Humira) is a tumour necrosis factor α (TNF α ) inhibitor that is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ankylosing spondylitis, and juvenile idiopathic arthritis (Sullivan and Preda (2009), Klinkhoff (2004), and Medicare Australia). Use of TNF α inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, and sarcoidosis or sarcoid-like granulomas) (Ramos-Casals et al. (2010)). We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab. He has renal biopsy proven IgA nephritis instead. Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure. He made a remarkable recovery after adalimumab cessation and steroid treatment. To our knowledge, this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab.

  18. The Place of protease inhibitors in antiretroviral treatment

    Directory of Open Access Journals (Sweden)

    S.B. Tenore

    2009-10-01

    Full Text Available With the introduction of highly active antiretroviral therapy, a number of drugs have been developed. The best choice concerning which antiretroviral analogs to start is always under discussion, especially in the choice between non-nucleoside reverse transcriptase inhibitors-based therapies and ritonavir-boosted protease inhibitors. Both are proven to control viral replication and lead to immunological gain. The choice between a non-nucleoside analog reverse transcriptase inhibitor and a protease inhibitor as a third antiretroviral drug in the therapy should consider factors related to the individual, as well as the inclusion of the best therapy in the patient's daily activities and potential adherence. The protease inhibitor-based therapies showed similar efficacy among the various inhibitors with characteristics concerning the adverse events from each medicine. For the treatment of protease-resistant patients, darunavir and tipranavir showed good efficacy with higher genetic barrier to resistance.

  19. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)

    Energy Technology Data Exchange (ETDEWEB)

    Conte, F.A.; Grumbach, M.M. [Univ. of California, San Francisco, CA (United States); Ito, Y.; Fisher, C.R.; Simpson, E.R. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

    1994-06-01

    The authors report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (<37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris has enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. 32 refs., 6 figs., 2 tabs.

  20. Proton pump inhibitors and gastroenteritis

    NARCIS (Netherlands)

    R.J. Hassing (Robert); A. Verbon (Annelies); H. de Visser (Herman); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2016-01-01

    textabstractAn association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study