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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. Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

    OpenAIRE

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

    There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative...

  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. PMID:27178335

  4. Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update.

    Science.gov (United States)

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

    There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2-3 years followed by exemestane or anastrozole for 2-3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2-3 years of tamoxifen. The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures. PMID:16981992

  5. Pharmacogenomics of tamoxifen and aromatase inhibitors.

    Science.gov (United States)

    Ingle, James N

    2008-02-01

    In selection of therapy for women with breast cancer, the focus has been almost exclusively on the characteristics of the tumor, eg, estrogen receptor (ER) and HER-2. Until recently, essentially no attention has been paid to the host and her genetic makeup as it relates to the metabolism of different drugs. The first real clinical application of pharmacogenetics in breast cancer management relates to tamoxifen's biotransformation to active anticancer metabolites. New information has arisen on the metabolism of tamoxifen to the active metabolite, 4 hydroxy-N-desmethyl-tamoxifen (endoxifen). Endoxifen is a metabolite with antitumor activity and affinity for the ER that is similar to 4-hydroxy-tamoxifen, but 1 that is normally present in substantially higher concentrations. CYP2D6 plays a central role in the metabolism to endoxifen and 1 published study shows that genotypic differences in CYP2D6 and use of CYP2D6 inhibitors has an impact on outcomes of women treated with tamoxifen. The aromatase inhibitors represent a major class of drugs in the armamentarium against breast cancer. The aromatase gene has been resequenced and functional genomics have been performed on the identified nonsynonymous coding single nucleotide polymorphisms showing significant decreases in levels of activity. These findings are consistent with a hypothesis that genetic variation in the CYP19 gene might be important in the activity of aromatase inhibitors. Currently, the emphasis is on examining multiple genes (thus pharmacogenomics) in pharmacodynamic and pharmacokinetic pathways in women receiving aromatase inhibitors for breast cancer. PMID:18072234

  6. 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.

  7. [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

    Science.gov (United States)

    Sakurai, Kenichi; Fujisaki, Shigeru; Suzuki, Shuhei; Adachi, Keita; Nagashima, Saki; Masuo, Yuki; Tomita, Ryouichi; Gonda, Kenji; Enomoto, Katsuhisa; Amano, Sadao; Matsuo, Sadanori; Umeda, Nao

    2015-10-01

    We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy. PMID:26489554

  8. 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

  9. 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...

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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...

  16. Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort

    Science.gov (United States)

    Castel, Liana D.; Hartmann, Katherine E.; Mayer, Ingrid A.; Saville, Benjamin R.; Alvarez, JoAnn; Boomershine, Chad S.; Abramson, Vandana G.; Chakravarthy, A. Bapsi; Friedman, Debra L.; Cella, David F.

    2013-01-01

    BACKGROUND More than 80,000 postmenopausal breast cancer patients in the US each year are estimated to begin a five-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. OBJECTIVES To describe one-year arthralgia trajectories and baseline covariates among AI patients and a postmenopausal comparison group. METHODS Patients initiating AIs (n=91) were surveyed at the time of AI initiation and at six repeated assessments over one year. A comparison group of postmenopausal women without breast cancer (n=177) completed concomitantly-timed surveys. Numeric rating scales (0–10) were used to measure pain in eight joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors. RESULTS By week six, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means=1.8, (95% CI 1.2–2.7, p=0.002), adjusting for baseline characteristics. Arthralgia then worsened further over a year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe longitudinal arthralgia. CONCLUSIONS Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia. PMID:23575918

  17. 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.

  18. Bilateral de quervain syndrome after aromatase inhibitor administration: a case report and review of the literature.

    Science.gov (United States)

    Papadimitriou, Konstantinos; Kountourakis, Panteleimon; Morakis, Emmanouil; Vassiliou, Vassilios; Barbounis, Vasileios; Ardavanis, Alexandros

    2012-01-01

    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. PMID:22567020

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

    OpenAIRE

    Vasileios Barbounis; Vassilios Vassiliou; Emmanouil Morakis; Panteleimon Kountourakis; Konstantinos Papadimitriou; Alexandros Ardavanis

    2012-01-01

    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 th...

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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...

  7. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation

    OpenAIRE

    Asadabadi, Ebrahim Barzegari; Chupani, Latifeh; Jamalan, Mostafa; Mirzaie, Sako; Shahverdi, Ahmad Reza

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of arom...

  8. 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

  9. 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...

  10. 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...

  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. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design

    OpenAIRE

    Mirzaie, Sako; Chupani, Latifeh; Asadabadi, Ebrahim Barzegari; Shahverdi, Ahmad Reza; Jamalan, Mostafa

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromata...

  13. Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer.

    Science.gov (United States)

    Abdalla, Mohamed M; Al-Omar, Mohamed A; Bhat, Mashooq A; Amr, Abdel-Galil E; Al-Mohizea, Abdullah M

    2012-05-01

    The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(®)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer. PMID:22361454

  14. Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats.

    Science.gov (United States)

    Yahr, Pauline

    2015-09-01

    Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens α-halogenated at carbon 6, e.g., 6α-bromoA, 6α-fluoroA and 6α-fluoroT. 6α-FluoroT is the only 6α-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it cannot be aromatized yet has the same A-ring as T. 6α-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6α-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6α-fluoroT on mating. Thus, 6α-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6α-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6α-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen. PMID:26232614

  15. 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

  16. 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. |

  17. 3H- and 14C-labelling of the aromatase inhibitor ZK 138723

    International Nuclear Information System (INIS)

    It has been known for several years that the growth of certain neoplastic disorders - especially breast cancer in women -depends on the serum level of estrogen. One strategy of lowering the estrogen formation is to inhibit the action of the enzyme aromatase, which catalyzes the final step in estrogen biosynthesis in humans. For this purpose nonsteroidal compounds seem to offer advantages as compared to the classical steroid derivatives regarding intensity and duration of effect as well as selectivity to other cytochrome P450 enzymes. The competitive aromatase inhibitor ZK138723 is such a nonsteroidal compound. It was labelled with 3H and 14C to be used for further pharmacological investigations. (author)

  18. 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

  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. Metastatic progression with resistance to aromatase inhibitors is driven by the steroid receptor coactivator SRC-1.

    Science.gov (United States)

    McBryan, Jean; Theissen, Sarah M; Byrne, Christopher; Hughes, Eamon; Cocchiglia, Sinead; Sande, Stephen; O'Hara, Jane; Tibbitts, Paul; Hill, Arnold D K; Young, Leonie S

    2012-01-15

    Aromatase inhibitors (AI) are a standard-of-care treatment for postmenopausal, estrogen receptor-positive breast cancers. Although tumor recurrence on AI therapy occurs, the mechanisms underlying acquired resistance to AIs remain unknown. In this study, we examined a cohort of endocrine-treated breast cancer patients and used a cell line model of resistance to the AI letrozole. In patients treated with a first-line AI, hormone receptor switching between primary and resistant tumors was a common feature of disease recurrence. Resistant cells exhibited a switch from steroid-responsive growth to growth factor-responsive and endocrine-independent growth, which was accompanied by the development of a more migratory and disorganized phenotype. Both the resistant cells and tumors from AI-resistant patients showed high expression of the steroid receptor coactivator SRC-1. Direct interactions between SRC-1 and the transcription factor Ets2 regulated Myc and MMP9. SRC-1 was required for the aggressive and motile phenotype of AI-resistant cells. Interestingly, SRC-1 expression in primary and/or recurrent tumors was associated with a reduction in disease-free survival in treated patients. Moreover, there was a significant association between SRC-1 and Ets2 in the recurrent tissue compared with the matched primary tumor. Together, our findings elucidate a mechanism of AI-specific metastatic progression in which interactions between SRC-1 and Ets2 promote dedifferentiation and migration in hormone-dependent breast cancer. PMID:22108824

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

    International Nuclear Information System (INIS)

    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 selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

  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. 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...

  4. 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

  5. Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons.

    Science.gov (United States)

    Robarge, Jason D; Duarte, Djane B; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A; Vasko, Michael R

    2016-07-01

    Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

  6. 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

  7. 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

  8. Management of adenomyosis in infertile women: comparison between laparotomic resection and administration of aromatase inhibitor (Experience in 55 cases

    Directory of Open Access Journals (Sweden)

    Rajuddin Rajuddin

    2006-03-01

    Full Text Available The objective of this study was to observe the results of adenomyosis mangement with resection and administration of aromatase inhibitor. Cases of ademyosis in infertile women were collected for three years (January 1999 to December 2001 and the diagnoses were confirmed using transvaginal USG. Cases were grouped into two groups, i.e. group 1 (undergoing laparotomic resection and group 2 (receiving treatment with aromatase inhibitor of anastrozole. Both groups were evaluated for changes in clinical symptoms, rate of successful pregnancy, and postoperative recurrency rate. During three years as many as 1619 infertility cases were managed, and among which 66 (4.07% cases of adenomyosis were diagnosed with transvaginal USG. As many as 55 cases were analyzed, i.e., 32 cases underwent resection and 23 cases received aromatase inhibitor. Of 32 cases of surgical resection, the histopathological results showed 30 (93.75% cases of adenomyosis and 2 (6.25% cases of uterus myoma. In the group undergoing resection three cases (9.4% were successfully pregnant, i.e., two cases had live birth, one case ended up with 6-week abortion. Moreover, 25 (78.1% cases were not pregnant and 4 (12.5% cases had recurrency, while 24 (75.35% cases experienced disappearance of symptoms yet not pregnant. On the other hand, of 23 cases in the group receiving aromatase inhibitor 2 (8.6% cases were able to be pregnant, one case had live birth and another case ended up with abortion, while 14 (59.1% cases had disappearance of symptoms yet not pregnant. During three months of treatment with aromatase inhibitor, a reduction in the lesion size between 7.31 mm3 and 25.90 mm3 were observed with CI 95% (p < 0.001. In conclusion, treatment with aromatase inihibitor did not heal lesions, but only reduced the size of adenomyosis lesions. On the other hand, resection could heal lesions, yet recurrency of disease may occur (12.5% after one postoperative year. (Med J Indones 2006; 15

  9. Aromatase inhibitors - a viable option for recurrent granulosa cell tumour of ovary: overview and case report

    International Nuclear Information System (INIS)

    Granulosa cell tumour of the ovary in adults is a rare tumour of low malignant potential affecting middle aged peri or post menopausal patients. These tumours are often diagnosed at an early stage, due to their hormonally active nature. They, however, have unique distinguishing histologic features and behaviour of frequent and late local or systemic relapses. The diagnosis can be challenging with unusual presentations. There is high association of endometrial carcinoma. Surgery is the mainstay of management in early low risk disease, while radiotherapy and systemic platinum based chemotherapy are employed in higher stage with poor prognostic indices. Survival is good in early stage disease. Recurrent, progressive, and treatment refractory disease is not infrequent and poses management challenge. Endocrine manipulation and hormone treatment are employed in few cases with equivocal results, as reported in literature. We present a case of recurrent and treatment refractory GCT in a postmenopausal patient, managed by aromatase inhibitor Anastrozole with reasonable efficacy. (author)

  10. 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.

  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

    2008-11-01

    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

  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. Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.

    Science.gov (United States)

    Ghosh, Debashis; Lo, Jessica; Egbuta, Chinaza

    2016-06-01

    Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enzyme's structure-function relationships. PMID:26689671

  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. New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

    Directory of Open Access Journals (Sweden)

    Roleira Fernanda MF

    2008-07-01

    Full Text Available Abstract Background Aromatase, the cytochrome P-450 enzyme (CYP19 responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI, which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. Results The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. Conclusion Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

  16. Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

    OpenAIRE

    Takagi, K.; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G.; Ebata, A.; Mori, N; Nakamura, Y.; Watanabe, M.; Amari, M; Ohuchi, N.; Sasano, H; Suzuki, T

    2013-01-01

    Background: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Methods: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by...

  17. Aromatase inhibitors in breast cancer: the discovery of new computational design and biochemical evaluation

    OpenAIRE

    Neves, Marco André Coelho das

    2009-01-01

    Continuous exposure to high levels of endogenous estrogens is associated with increased risks of developing breast cancer. In this sense, aromatase, the cytochrome P450 enzyme involved in the conversion of androgens, testosterone and androstenedione, into estrogens, estradiol and estrone, is an important target for the endocrine treatment of breast cancer in postmenopausal women. Aromatase inhibition is achieved either with compounds structurally related to the androstenedio...

  18. 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

    Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. RESULTS: Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from...... 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...... estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. TRIAL REGISTRATION: Sub-study of trial P025 for advanced breast cancer....

  19. 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

  20. 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

  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. 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

  3. 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.

  4. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    DEFF Research Database (Denmark)

    Løssl, Kristine; Andersen, A N; Loft, A; Freiesleben, N L C; Bangsbøll, S; Andersen, C Yding

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  5. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial

    DEFF Research Database (Denmark)

    Lossl, K; Andersen, C Yding; Loft, A; Freiesleben, N L C; Bangsbøll, S; Andersen, A Nyboe; Løssl, Kristine

    2008-01-01

    Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top...

  6. Aromatase: Contributions to Physiology and Disease in Women and Men.

    Science.gov (United States)

    Blakemore, Jennifer; Naftolin, Fredrick

    2016-07-01

    Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products. PMID:27252161

  7. 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

  8. Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet: A Systematic Review.

    Science.gov (United States)

    Ekpo, Ernest U; Brennan, Patrick C; Mello-Thoms, Claudia; McEntee, Mark F

    2016-06-01

    Background Lower breast density (BD) is associated with lower risk of breast cancer and may serve as a biomarker for the efficacy of chemopreventive strategies. This review explores parameters that are thought to be associated with lower BD. We conducted a systematic review of articles published to date using the PRISMA strategy. Articles that assessed change in BD with estrogen-receptor modulators (tamoxifene [TAM], raloxifene [RLX], and tibolone) and aromatase inhibitors (AIs), as well as cross-sectional and longitudinal studies (LSs) that assessed association between BD and physical activity (PA) or diet were reviewed. Results Ten studies assessed change in BD with TAM; all reported TAM-mediated BD decreases. Change in BD with RLX was assessed by 11 studies; 3 reported a reduction in BD. Effect of tibolone was assessed by 5 RCTs; only 1 reported change in BD. AI-mediated BD reduction was reported by 3 out of 10 studies. The association between PA and BD was assessed by 21 studies; 4 reported an inverse association. The relationship between diet and BD was assessed in 34 studies. All studies on calcium and vitamin D as well as vegetable intake reported an inverse association with BD in premenopausal women. Two RCTs demonstrated BD reduction with a low-fat, high-carbohydrate intervention. Conclusion TAM induces BD reduction; however, the effect of RLX, tibolone, and AIs on BD is unclear. Although data on association between diet and BD in adulthood are contradictory, intake of vegetables, vitamin D, and calcium appear to be associated with lower BD in premenopausal women. PMID:27130722

  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. 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...

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

    OpenAIRE

    Bauer M; Bryce J; Hadji P

    2012-01-01

    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 th...

  12. 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.

  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. 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.

  15. The time since last menstrual period is important as a clinical predictor for non-steroidal aromatase inhibitor-related arthralgia

    International Nuclear Information System (INIS)

    The clinical predictors of aromatase inhibitor-related arthralgia (AIA), a drug-related adverse reaction of aromatase inhibitors (AIs), remain unclear. AIA was prospectively surveyed every 4 months in 328 postmenopausal breast cancer patients administered a non-steroidal AI (anastrozole). Various clinicopathological parameters were recorded and analyzed (chi-square test, Fisher's exact test and logistic regression analysis). The mean observation period was 39.9 months. AIA manifested in 114 patients (34.8%), with peaks of onset at 4 (33.7%) and 8 months (11.4%) after starting AI administration. Some cases manifested even after 13 months. AIA tended to occur in younger patients (incidences of 46.3%, 37.4% and 28.0% for ages of < 55, 55-65 and > 65 years, respectively (p = 0.063)) and decreased significantly with the age at menarche (53.3%, 35.3% and 15.4% for < 12, 12-15 and > 15 years, respectively (p = 0.036)). The incidences were 45.1%, 46.3 and 25.1% for the time since the last menstrual period (LMP) < 5 years, 5-10 years and > 10 years, being significantly lower at > 10 years (p < 0.001). In logistic regression analysis, the AIA incidence was significantly lower in the time since LMP > 10-year group versus the < 5-year group (odds ratio 0.44, p = 0.002), but the age at menarche showed no association. AIA manifested significantly earlier (≤ 6 months) as the time since LMP became shorter (< 5 years). AIA tends to manifest early after starting AI, but some cases show delayed onset. The incidence was significantly lower in patients with a duration of > 10 years since LMP. When the time since LMP was short, the onset of AIA was significantly earlier after starting AI administration

  16. Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer

    International Nuclear Information System (INIS)

    After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function

  17. 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...

  18. 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

    shown to inhibit the aromatase enzyme in both types of aromatase assays. The IC50 values ranged from 3 to 600μM. All five SSRIs, were further investigated in the H295R cell line. All compounds altered the steroid secretion from the cells, the lowest observed effect levels were 0.9μM and 3.1μ...

  19. 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

  20. 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.

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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...

  6. 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. PMID:27190705

  7. 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.

  8. 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

  9. 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 ...

  10. 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 ...

  11. Inhibition of rainbow trout (Oncorhynchus mykiss) P450 aromatase activities in brain and ovarian microsomes by various environmental substances.

    Science.gov (United States)

    Hinfray, Nathalie; Porcher, Jean-Marc; Brion, François

    2006-11-01

    Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, represent a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on aromatase enzymes in fish. In this study, we first optimized a rainbow trout (Oncorhynchus mykiss) microsomal aromatase assay to measure the effects of 43 substances belonging to diverse chemical classes (steroidal and non steroidal aromatase inhibitors, pesticides, heavy metals, organotin compounds, dioxins, polycyclic aromatic hydrocarbons) on brain and ovarian aromatase activities in vitro. Our results showed that 12 compounds were able to inhibit brain and ovarian aromatase activities in a dose-dependent manner with IC50 values ranging from the low nM to the high microM range depending on the substance: steroidal and non steroidal inhibitors of aromatase (4-hydroxyandrostenedione, androstatrienedione, aminogluthethimide), imidazole fungicides (clotrimazole, imazalil, prochloraz), triazole fungicides (difenoconazole, fenbuconazole, propiconazole, triadimenol), the pyrimidine fungicide fenarimol and methylmercury. Overall, this study demonstrates that rainbow trout brain and ovarian microsomal aromatase assay is suitable for evaluating potential aromatase inhibitors in vitro notably with respect to environmental screening. The results highlight that methylmercury and some pesticides that are currently used throughout the world, have the potential to interfere with the biosynthesis of endogenous estrogens in fish. PMID:17081805

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

    International Nuclear Information System (INIS)

    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 (11C)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 (11C)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.

  13. 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.

  14. 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...

  15. 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

  16. CYP17 inhibitors for prostate cancer therapy.

    Science.gov (United States)

    Vasaitis, Tadas S; Bruno, Robert D; Njar, Vincent C O

    2011-05-01

    Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors. PMID:21092758

  17. Current feasibility of endocrine therapy for breast cancer

    Directory of Open Access Journals (Sweden)

    I. V. Vysotskaya

    2014-07-01

    Full Text Available The paper considers the current feasibility of endocrine therapy for breast cancer (BC. It presents trials of the efficacy of fulvestrant in the treatment of patients with BC. Practically all clinical trials have demonstrated that the drug is well tolerated, without causing any significant systemic estrogen-like effects, as well as complications associated with the use of aromatase inhibitors.

  18. Imaging of aromatase distribution in rat and rhesus monkey brains with [{sup 11}C]vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Kayo [Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala SE-75124 (Sweden); Uppsala Imanet, Uppsala SE-75109 (Sweden)]. E-mail: kayo.takahashi@uppsala.imanet.se; Bergstroem, Mats [Uppsala Imanet, Uppsala SE-75109 (Sweden); Department of Pharmaceutical Biosciences, Uppsala University, Uppsala SE-75124 (Sweden); Fraendberg, Pernilla [Uppsala Imanet, Uppsala SE-75109 (Sweden); Vesstroem, Eva-Lotta [Uppsala Imanet, Uppsala SE-75109 (Sweden); Watanabe, Yasuyoshi [Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585 (Japan); Langstroem, Bengt [Uppsala Imanet, Uppsala SE-75109 (Sweden)

    2006-07-15

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [{sup 11}C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K {sub d} of [{sup 11}C]vorozole binding to aromatase in MA was determined to be 0.60{+-}0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [{sup 11}C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.

  19. Imaging of aromatase distribution in rat and rhesus monkey brains with [11C]vorozole

    International Nuclear Information System (INIS)

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [11C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K d of [11C]vorozole binding to aromatase in MA was determined to be 0.60±0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [11C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons

  20. 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

  1. 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.

  2. Long-term maintenance therapy with calcineurin inhibitors: an update.

    Science.gov (United States)

    Campistol, J M

    2010-11-01

    Combination therapy with mammalian target of rapamycin (mTOR)-inhibitors and calcineurin inhibitors (CNIs) provides significant immunosuppressive efficacy. If the combination of these agents is not properly optimized, however, important risks for synergistic toxicity and long-term complications may result. The combination of a CNI and an mTOR-inhibitor is a potent immunosuppressive therapy that effectively prevents the incidence of acute rejection, although the potential nephrotoxic impact must be considered in the longer term. The trend has therefore been to use a low-dose CNI in combination with the mTOR-inhibitor sirolimus in order to reduce the risk of nephrotoxicity. Recent studies show that an mTOR-inhibitor/low-dose CNI combination is effective in the short term following transplantation, and over time, consideration should be given to the elimination of the CNI in order to preserve renal function. In the medium to long term, it is also possible to consider the elimination of steroids from such a protocol. Considering CNI dose minimization or elimination is an essential component of this approach, as is the optimal dose and level of both drugs when used in combination. PMID:21095445

  3. New targets for therapy in breast cancer: Farnesyltransferase inhibitors

    International Nuclear Information System (INIS)

    Current systemic therapies for breast cancer are often limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues, and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in development of various signal transduction inhibitor drugs as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines that contain wild-type ras, including breast cancer cells. Additive or synergistic effects were observed when FTIs were combined with cytotoxic agents (in particular the taxanes) or endocrine therapies (tamoxifen). Phase I trials with FTIs have explored different schedules for prolonged administration, and dose-limiting toxicities included myelosuppression, gastrointestinal toxicity and neuropathy. Clinical efficacy against breast cancer was seen for the FTI tipifarnib in a phase II study. Based on promising preclinical data that suggest synergy with taxanes or endocrine therapy, combination clinical studies are now in progress to determine whether FTIs can add further to the efficacy of conventional breast cancer therapies

  4. 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.

  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. 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.

  7. Mini-review: bmx kinase inhibitors for cancer therapy.

    Science.gov (United States)

    Jarboe, John S; Dutta, Shilpa; Velu, Sadanandan E; Willey, Christopher D

    2013-09-01

    Kinase inhibitors are among the fastest growing class of anti-cancer therapies. One family of kinases that has recently gained attention as a target for treating malignant disorders is the Tec kinase family. Evidence has been published that one member of this family; the Bmx kinase, may play a role in the pathogenesis of glioblastoma, prostate, breast and lung cancer. Bmx has also shown potential as an anti-vascular therapy in combination with radiation or as a sensitizer to chemotherapeutic agents. Therefore, several companies such as Pharmacyclics, Avila Therapeutics, Merck and Co., Metaproteomics, IRM, and Moerae Matrix have developed compounds or peptides that function as Bmx kinase inhibitors. These companies have subsequently been issued patents for these inhibitors. Additionally, it has been shown that current clinical stage EGFR inhibitors can irreversibly inhibit Bmx, suggesting these compounds might be rapidly moved to clinical trials for other malignancies. This review will discuss current patents issued since 2009 that contain data specifically on inhibition of the Bmx kinase, and will also discuss the scientific literature that suggests their potential application as therapeutics in the treatment of the aforementioned malignancies. PMID:23198769

  8. 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 ...

  9. Obscure bleeding colonic duplication responds to proton pump inhibitor therapy

    OpenAIRE

    2013-01-01

    We report the case of a 17-year-old male admitted to our academic hospital with massive rectal bleeding. Since childhood he had reported recurrent gastrointestinal bleeding and had two exploratory laparotomies 5 and 2 years previously. An emergency abdominal computed tomography scan, gastroscopy and colonoscopy, performed after hemodynamic stabilization, were considered normal. High-dose intravenous proton pump inhibitor (PPI) therapy was initiated and bleeding stopped spontaneously. Two othe...

  10. 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

  11. 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 ...

  12. 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

  13. 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.

  14. 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

  15. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy

    DEFF Research Database (Denmark)

    Bruyand, Mathias; Ryom, Lene; Shepherd, Leah;

    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...

  16. 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...

  17. Aromatase inhibitors in stimulated IVF cycles

    DEFF Research Database (Denmark)

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

    2011-01-01

    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....... 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...

  18. Obscure bleeding colonic duplication responds to proton pump inhibitor therapy.

    Science.gov (United States)

    Jacques, Jérémie; Projetti, Fabrice; Legros, Romain; Valgueblasse, Virginie; Sarabi, Matthieu; Carrier, Paul; Fredon, Fabien; Bouvier, Stéphane; Loustaud-Ratti, Véronique; Sautereau, Denis

    2013-09-21

    We report the case of a 17-year-old male admitted to our academic hospital with massive rectal bleeding. Since childhood he had reported recurrent gastrointestinal bleeding and had two exploratory laparotomies 5 and 2 years previously. An emergency abdominal computed tomography scan, gastroscopy and colonoscopy, performed after hemodynamic stabilization, were considered normal. High-dose intravenous proton pump inhibitor (PPI) therapy was initiated and bleeding stopped spontaneously. Two other massive rectal bleeds occurred 8 h after each cessation of PPI which led to a hemostatic laparotomy after negative gastroscopy and small bowel capsule endoscopy. This showed long tubular duplication of the right colon, with fresh blood in the duplicated colon. Obscure lower gastrointestinal bleeding is a difficult medical situation and potentially life-threatening. The presence of ulcerated ectopic gastric mucosa in the colonic duplication explains the partial efficacy of PPI therapy. Obscure gastrointestinal bleeding responding to empiric anti-acid therapy should probably evoke the diagnosis of bleeding ectopic gastric mucosa such as Meckel's diverticulum or gastrointestinal duplication, and gastroenterologists should be aware of this potential medical situation. PMID:24124344

  19. Aromatase in human liver and its diseases

    International Nuclear Information System (INIS)

    Estrogens play important roles in the cell proliferation and invasion of estrogen-dependent human neoplasms. Aromatase overexpression has been also reported in hepatitis and hepatocellular carcinoma (HCC) compared with normal liver but its details in these hepatic disorders have remained unclear. Therefore, in this study, we first immunolocalized aromatase using immunohistochemistry in patients with liver cirrhosis, steatosis, hepatitis, HCC, and metastasis liver carcinoma (MLC) in order to study the detailed status of intrahepatic aromatase. Aromatase immunoreactivity was predominantly detected in nonneoplastic hepatocytes around tumor cells. We then evaluated the effects of an interaction between hepatocytes and carcinoma cells upon aromatase mRNA expression, using HepG2 as a substitute model of hepatocytes by coculture systems. Aromatase mRNA levels in HepG2 were significantly increased by coculture with all carcinoma cell lines examined. We also evaluated alternative splicing of aromatase exon 1 but the same splicing variant was used in HepG2 cells regardless of carcinoma cell lines employed in the coculture system. These findings obtained in HepG2 indicated that carcinoma cells, whether metastatic or primary, induced aromatase expression in adjacent normal hepatocytes possibly through the soluble aromatase inducible factors in human hepatic microenvironments

  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

    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 [H-3](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon tall fungicides), and dicofol tan...... 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 vitro, indicating the relevance of elucidating the endocrine effects in vivo of these compounds....

  1. 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

  2. Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia.

    Science.gov (United States)

    Bajpai, Anurag; Simm, Peter J; McPherson, Stephen J; Russo, Vincenzo C; Azar, Walid J; Wark, John D; Risbridger, Gail P; Werther, George A

    2010-10-01

    Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved. PMID:20675302

  3. Patient costs of breast cancer endocrine therapy agents under Medicare Part D vs with generic formulations

    OpenAIRE

    Nattinger, Ann Butler; Pezzin, Liliana E.; McGinley, Emily L; Charlson, John A; Yen, Tina W.F.; Neuner, Joan M

    2015-01-01

    Purpose The high expense of newer, more effective adjuvant endocrine therapy agents (aromatase inhibitors [AIs]) for postmenopausal breast cancer contributes to socioeconomic disparities in breast cancer outcomes. This study compares endocrine therapy costs for breast cancer patients during the first five years of Medicare Part D implementation, and when generic alternatives became available. Methods The out of pocket patient costs for AIs and tamoxifen under Medicare Part D drug plans were d...

  4. 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)....

  5. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    OpenAIRE

    Wong, Tsz Yan; Li, Fengjuan; Lin, Shu-mei; Franky L Chan; Chen, Shiuan; Leung, Lai K.

    2014-01-01

    Background Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. Methods In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-express...

  6. 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

  7. 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

  8. Ginkgo biloba extract EGb 761-mediated inhibition of aromatase for the treatment of hormone-dependent breast cancer.

    Science.gov (United States)

    Park, Yong Joo; Ahn, Hui Yeon; Kim, Ha Ryong; Chung, Kyu Hyuck; Oh, Seung Min

    2016-01-01

    Ginkgo biloba has been used in herbal medicines for thousands of years. Although a standard G. biloba extract, EGb 761 has been used to improve cognition in breast cancer patients, its effects on breast cancer are unknown. Therefore, we investigated the antitumorigenic effects of EGb 761 using an in vitro cell model and an in vivo xenograft model. EGb 761 significantly inhibited aromatase activity in aromatase over-expressing MCF-7 cells (MCF-7 AROM). In addition, EGb 761 exposure reduced cytochrome p450 aromatase (CYP19) mRNA and protein expression; CYP19 promoter I.3 and PII expression particularly decreased. These inhibitory effects on aromatase were accompanied by reduced 17β-estradiol levels in MCF-7 AROM cells. For elucidating antitumorigenic effects, MCF-7 AROM cells were implanted in BALB/c nude mice prior to oral EGb 761 treatment for 3 weeks. EGb 761 reduced the tumor size and significantly reduced tumor CYP19 mRNA expression. Taken together, our results indicated that EGb 761 inhibited aromatase and exerted antitumor effects on breast cancer cells both in vitro and in vivo. These findings suggest that EGb761 may be a useful aromatase inhibitor for the treatment for estrogen-sensitive breast cancer. PMID:26706698

  9. 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

  10. 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

  11. 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.

  12. 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 ...

  13. 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...

  14. 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

  15. 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...

  16. 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.

  17. 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.

  18. Search for Inhibitors of the Ubiquitin-Proteasome System from Natural Sources for Cancer Therapy.

    Science.gov (United States)

    Tsukamoto, Sachiko

    2016-01-01

    Since the approval of the proteasome inhibitor, Velcade(®), by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, inhibitors of the ubiquitin-proteasome system have been attracting increasing attention as promising drug leads for cancer therapy. While the development of drugs for diseases related to this proteolytic system has mainly been achieved by searching libraries of synthetic small molecules or chemical modifications to drug leads, limited searches have been conducted on natural sources. We have been searching natural sources for inhibitors that target this proteolytic system through in-house screening. Our recent studies on the search for natural inhibitors of the ubiquitin-proteasome system, particularly, inhibitors against the proteasome, E1 enzyme (Uba1), E2 enzyme (Ubc13-Uev1A heterodimer), and E3 enzyme (Hdm2), and also those against deubiquitinating enzyme (USP7), are reviewed here. PMID:26833439

  19. 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...

  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. Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders

    OpenAIRE

    Smith, Rosamund C.; Lin, Boris K.

    2013-01-01

    Purpose of review This review summarizes recent progress in the development of myostatin inhibitors for the treatment of muscle wasting disorders. It also focuses on findings in myostatin biology that may have implications for the development of antimyostatin therapies. Recent findings There has been progress in evaluating antimyostatin therapies in animal models of muscle wasting disorders. Some programs have progressed into clinical development with initial results showing positive impact o...

  2. Aromatase imaging with [N-methyl-C-11]vorozole PET in healthy men and women

    International Nuclear Information System (INIS)

    Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aims to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathological situations can be studied. Methods: (11)C-vorozole (111-296 MBq/subject) was injected I.V in 13 men and 20 women (age range 23 to 67). PET data were acquired over a 90 minute period. Each subject had 4 scans, 2/day separated by 2-6 weeks, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned following pretreatment with a clinical dose of the aromatase inhibitor letrozole.Time activity curves were obtained and standard uptake values (SUV) calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole body radiation exposures were calculated using Olinda software. Results: Liver uptake was higher than all other organs, but was not blocked by pretreatment with letrozole. Mean SUVs in men were higher than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than all other organs (ranging from 0.48±0.05 in lungs to 1.5±0.13 in kidneys). Mean ovarian SUVs (3.08±0.7) were comparable to brain levels and higher than all other organs. Furthermore, ovarian SUVs In young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, while aging and cigarette smoking reduced (11)C-vorozole uptake. Conclusions: PET with (11)C-vorozole is useful for assessing physiological changes in estrogen synthesis capacity in the human body. Baseline levels in

  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. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy.

    Science.gov (United States)

    Jenner, Zachary B; Sood, Anil K; Coleman, Robert L

    2016-06-01

    Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy. Comparable to rucaparib development, other PARP inhibitors, such as olaparib, niraparib, veliparib and talazoparib, are developing CDx tests for targeted therapy. PARP inhibitor clinical trials and CDx assays are discussed in this review, as are potential PARP inhibitor combination therapies and likely resistance mechanisms. PMID:27087632

  6. 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.

  7. THE PROBLEMS OF THE SAFETY OF THERAPY WITH TUMOR NECROSIS FACTOR-а INHIBITORS

    Directory of Open Access Journals (Sweden)

    Dmitry Evgenyevich Karateyev

    2009-09-01

    Full Text Available Due to the fact that tumor necrosis factor-а (TNF-а inhibitors are in wide use, the problem of the safety of therapy with drugs of this group is pressing. The review discusses the data of randomized and observational clinical trials of three drugs of this group (adalimumab, infliximab, and etanercept whether they can cause serious adverse reactions (SAR. The analysis leads to the conclusion that 10 years' experience in using TNF-а inhibitors generally suggests their satisfactory safety profile. Anti-TNF-а therapy is unassociated with the increased risk of fatal outcomes, at the same time one should be alert to tuberculosis, serious bacterial infections, and lymphoma although the frequency of SAR is generally low; the risk for the development of SAR becomes higher as the dose of TNF-а inhibitors is increased and it does not with longer survival. The currently available preventive methods and physicians' alertness to SAR help prevent their development.

  8. 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

  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. 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 ...

  11. 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.

  12. 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

  13. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

    Science.gov (United States)

    Whittle, Nigel; Singewald, Nicolas

    2014-04-01

    A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy

  14. PI3K isoform-selective inhibitors: next-generation targeted cancer therapies.

    Science.gov (United States)

    Wang, Xiang; Ding, Jian; Meng, Ling-hua

    2015-10-01

    The pivotal roles of phosphatidylinositol 3-kinases (PI3Ks) in human cancers have inspired active development of small molecules to inhibit these lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K isoforms play non-redundant roles in particular tumor types, which has prompted the development of isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K isoform-selective inhibitors is represented by CAL101 (Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin's lymphoma and relapsed small lymphocytic lymphoma. Inhibitors targeting other PI3K isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K isoform-selective inhibitors for cancer therapy. A deeper understanding of the action modes of novel PI3K isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K isoforms, while the identification of biomarkers to stratify patients who are likely to benefit from the therapy will be essential for the success of these agents. PMID:26364801

  15. Developmental regulation of aromatase activity in the rat hypothalamus

    International Nuclear Information System (INIS)

    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 3H2O 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

  16. 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

  17. 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

  18. Therapy of experimental NASH and fibrosis with galectin inhibitors.

    Directory of Open Access Journals (Sweden)

    Peter G Traber

    Full Text Available Non-alcoholic steatohepatitis (NASH and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than

  19. Possibility of Acetylcholinesterase Overexpression in Alzheimer Disease Patients after Therapy with Acetylcholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Alžběta Kračmarová

    2015-08-01

    Full Text Available Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing cholinergic function using inhibitors of acetylcholinesterase like rivastigmine, donepezil or galantamine. These drugs can influence not only the acetylcholinesterase activity but also other processes in treated organism. The paper is aimed mainly on possibility of increased expression and protein level of acetylcholinesterase caused by the therapy with acetylcholinesterase inhibitors.

  20. 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.

  1. Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the litterature and personal experience

    OpenAIRE

    F. Fantini; Gattinara, M; Pontikaki, I; Gerloni, V

    2011-01-01

    The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical...

  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. 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)

  4. [PARP1 inhibitors: contemporary attempts at their use in anticancer therapy and future perspective].

    Science.gov (United States)

    Wiśnik, Ewelina; Ryksa, Marcin; Koter-Michalak, Maria

    2016-01-01

    Current cancer therapies are based mainly on the use of compounds that cause DNA damage. Unfortunately, even the combination therapies do not give rewarding effects, due to the high efficiency of DNA damage repair mechanisms in tumor cells. Therefore, the present studies should be focused on proteins that are involved in DNA repair systems. Poly(ADP-ribose) polymerase-1 is an example of a protein commonly known as an enzyme that plays a role in the detection of DNA damage and repair. Activation of PARP1 in response to DNA damage leads to poly-ADP-ribosylation of proteins contributing to DNA repair systems, therefore facilitating the maintenance of genome stability. On the other hand, inhibition of PARP1 enzyme results in the accumulation of DNA damage, which in turn contributes to cell death. Studies on inhibitors of PARP1 are still ongoing, and some of them are currently in the third phase of clinical trials. To date, only one representative of the PARP1 inhibitors, called olaparib, has been approved for anti-cancer therapy in the EU and the USA. Moreover, a growing body of evidence indicates a role of this protein in various intracellular processes such as bioenergetics, proliferation, regulation of gene expression, cell death as well as immunoregulation. A number of different intracellular processes regulated by PARP1 give rise to potential wider use of PARP1 inhibitors in treatment of other diseases, including immune or autoimmune disorders. PMID:27117104

  5. Preventative therapies for healthy women at high risk of breast cancer

    Directory of Open Access Journals (Sweden)

    Sestak I

    2014-10-01

    Full Text Available Ivana Sestak Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London, UKAbstract: Tamoxifen has been shown to reduce the risk of developing estrogen receptor (ER-positive breast cancer by at least 50%, in both pre- and postmenopausal women. The current challenge is to find new agents with fewer side effects and to find agents that are specifically suitable for premenopausal women with ER-negative breast cancer. Other selective estrogen receptor modulators (SERMs, such as raloxifene, arzoxifene, and lasofoxifene, have been shown to reduce the incidence of breast cancer by 50%–80%. SERMs are interesting agents for the prevention of breast cancer, but longer follow-up is needed for some of them for a complete risk–benefit profile of these drugs. Aromatase inhibitors have emerged as new drugs in the prevention setting for postmenopausal women. In the Mammary Prevention 3 (MAP3 trial, a 65% reduction in invasive breast cancer with exemestane was observed, and the Breast Cancer Intervention Study-II trial, which compared anastrozole with placebo, reported a 60% reduction in those cancers. Although SERMs and aromatase inhibitors have been proven to be excellent agents in the preventive setting specifically for postmenopausal women and ER-positive breast cancer, newer agents have to be found specifically for ER-negative breast cancers, which mostly occur in premenopausal women. Keywords: breast cancer, preventive therapy, selective estrogen receptor modulators, aromatase inhibitors, high-risk women

  6. 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.

  7. 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

    BACKGROUND & AIMS: Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI). If RAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications. METHODS: A randomized, double-blind, placebo...... 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 for...

  8. Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction.

    Science.gov (United States)

    Okumura, Naoki; Sakamoto, Yuji; Fujii, Keita; Kitano, Junji; Nakano, Shinichiro; Tsujimoto, Yuki; Nakamura, Shin-Ichiro; Ueno, Morio; Hagiya, Michio; Hamuro, Junji; Matsuyama, Akifumi; Suzuki, Shingo; Shiina, Takashi; Kinoshita, Shigeru; Koizumi, Noriko

    2016-01-01

    The corneal endothelium maintains corneal transparency; consequently, its dysfunction causes severe vision loss. Tissue engineering-based therapy, as an alternative to conventional donor corneal transplantation, is anticipated to provide a less invasive and more effective therapeutic modality. We conducted a preclinical study for cell-based therapy in a primate model and demonstrated regeneration of the corneal endothelium following injection of cultured monkey corneal endothelial cells (MCECs) or human CECs (HCECs), in combination with a Rho kinase (ROCK) inhibitor, Y-27632, into the anterior chamber. We also evaluated the safety and efficacy of Good Manufacturing Practice (GMP)-grade HCECs, similar to those planned for use as transplant material for human patients in a clinical trial, and we showed that the corneal endothelium was regenerated without adverse effect. We also showed that CEC engraftment is impaired by limited substrate adhesion, which is due to actomyosin contraction induced by dissociation-induced activation of ROCK/MLC signaling. Inclusion of a ROCK inhibitor improves efficiency of engraftment of CECs and enables cell-based therapy for treating corneal endothelial dysfunction as a clinically relevant therapy. PMID:27189516

  9. 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...... in MBC. Trastuzumab is an important component of first-line treatment of HER2-positive MBC. New anti-HER2 drugs have the potential to change clinical practice. The potential role of the different drugs and regimens is yet to be determined. The response rate for trastuzumab-DM1 of 26-64% is comparable...... 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...

  10. 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

  11. 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

  12. Neoadjuvant endocrine therapy for breast cancer: medical perspectives.

    Science.gov (United States)

    Ellis, M J

    2001-12-01

    The indolent nature of estrogen-dependent breast cancer is the most important obstacle for development of new adjuvant endocrine treatments. Clinical trials require thousands of study participants and at least a decade of clinical investigation. How can we be sure that a new endocrine agent warrants this extraordinary level of investment? Traditionally, we have relied on advanced breast cancer trials to determine which drugs are suitable for adjuvant studies. However, with endocrine agents the high incidence of resistance in metastatic breast cancer may mask important advances in efficacy. Recent clinical results with the aromatase inhibitor letrozole suggest that neoadjuvant endocrine therapy is a highly informative additional approach to consider when planning adjuvant studies. In this report, new neoadjuvant endocrine therapy study designs are discussed that address the following issues: (a) the scientific opportunities afforded by gene microarray studies and other genetic technologies to investigate the molecular basis of estrogen-dependent breast cancer; (b) studies that address critical drug development questions as a prelude to adjuvant studies; and (c) the conduct of randomized trials that compare neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to establish a place for neoadjuvant endocrine therapy in routine clinical practice. PMID:11916229

  13.  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.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. Combination Therapy with Cholinesterase Inhibitors and Memantine for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

    OpenAIRE

    Matsunaga, Shinji; Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer’s disease. Methods: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Results: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean...

  19. 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)

  20. Escalating therapy of cutaneous side effects of EGFR inhibitors: experience of German reference centers.

    Science.gov (United States)

    Homey, Bernhard; Gerber, Peter Arne; Wollenberg, Andreas; Dirschka, Thomas; Hassel, Jessica C; Bölke, Edwin; Hauschild, Axel; Gutzmer, Ralf

    2012-08-01

    Recommendations for the management of cutaneous adverse effects of inhibitors of the epidermal growth factor receptor (EGFR) are urgently needed. In this context an expert panel of German dermatologists recently proposed a 3-step management concept based on personal experience and a current literature consensus. While steps 1 and 2 addressed general and preventive measures, as well as the therapy that can be performed by the primary treating physician, here we address the management of challenging cases (step 3) that do not respond well to basic measures and should be referred to an experienced dermatologist. PMID:22672156

  1. 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

  2. Intermittent targeting as a tool to minimize toxicity of tyrosine kinase inhibitor therapy.

    Science.gov (United States)

    Martinelli, Giovanni; Soverini, Simona; Iacobucci, Ilaria; Baccarani, Michele

    2009-02-01

    Tyrosine kinase inhibitor therapy has revolutionized the outcome of chronic myeloid leukemia (CML), and has transformed a fatal disease into a chronic condition for most patients. At present, the therapeutic armamentarium against CML includes imatinib for newly diagnosed patients, and dasatinib and nilotinib, which have both received marketing approval, for imatinib-resistant and imatinib-intolerant disease. Research efforts are now focused on how to optimize therapeutic strategies in an attempt to improve clinical results further, counteract the development of drug resistance and reduce adverse effects. A randomized, international, phase III study of dasatinib dose and schedule optimization in imatinib-resistant and imatinib-intolerant patients with CML has demonstrated that intermittent target inhibition can preserve therapeutic efficacy and reduce toxicity. This finding has important implications, not only for patients with CML, but also for the development of targeted therapies for human malignancies in general. PMID:19092801

  3. [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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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 ...

  10. 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.

  11. 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...

  12. 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

  13. 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 ...

  14. Sphingosine Kinase Inhibitors as Maintenance Therapy of Glioblastoma After Ceramide-Induced Response.

    Science.gov (United States)

    Sordillo, Laura A; Sordillo, Peter P; Helson, Lawrence

    2016-05-01

    Ceramide and sphingosine 1-phosphate (S1P) are sphingolipid metabolites with important signaling functions. Ceramides promote apoptosis, whereas S1P favors proliferation, angiogenesis and cell survival. The balance between these opposing signaling functions is referred to as the sphingolipid rheostat. A shift in this balance toward S1P is seen in glioblastoma (GBM) and other cancers, and results in tumor cell survival and resistance to chemotherapy. Sphingosine kinase (SK), the enzyme responsible for transforming sphingosine into S1P, plays the critical role in modulating the balance between S1P and ceramides. Chemotherapeutic agents or radiation therapy may induce short-term responses in GBM patients by increasing ceramide levels. However, we believe that the enzyme SK may cause the increased ceramide to be metabolized to S1P, restoring the abnormally high S1P to ceramide balance, and that this may be part of the reason for the near-100% recurrence rate of GBM. The use of maintenance therapy with an SK inhibitor, in patients with GBM who have tumor reduction or stable disease after therapy, should be investigated. PMID:27127108

  15. 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

  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. Aromatase expression is increased in BRCA1 mutation carriers

    International Nuclear Information System (INIS)

    Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls. We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women. We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts. Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers

  18. 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...

  19. 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...

  20. 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

    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...... first year 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....... about the true long run cost. Taking the actual medication practice into account is important for the evaluation of the costs and optimal sequencing of new and existing biological treatments. Objectives: To investigate the drug cost of TNF-inhibitors in the treatment of RA using real-life data from a...

  1. 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.

  2. 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

  3. The relationship of bone-tumor-induced spinal cord astrocyte activation and aromatase expression to mechanical hyperalgesia and cold hypersensitivity in intact female and ovariectomized mice.

    Science.gov (United States)

    Smeester, B A; O'Brien, E E; Michlitsch, K S; Lee, J-H; Beitz, A J

    2016-06-01

    Recently, our group established a relationship between tumor-induced spinal cord astrocyte activation and aromatase expression and the development of bone tumor nociception in male mice. As an extension of this work, we now report on the association of tumor-induced mechanical hyperalgesia and cold hypersensitivity to changes in spinal cord dorsal horn GFAP and aromatase expression in intact (INT) female mice and the effect of ovariectomy on these parameters. Implantation of fibrosarcoma cells produced robust mechanical hyperalgesia in INT animals, while ovariectomized (OVX) females had significantly less mechanical hyperalgesia. Cold hypersensitivity was apparent by post-implantation day 7 in INT and OVX females compared to their saline-injected controls and increased throughout the experiment. The decrease in mechanical hyperalgesia in OVX females was mirrored by significant decreases in spinal astrocyte activity in laminae I-II, III-IV, V-VI and X and aromatase expression in laminae V-VI and X in the dorsal horn of tumor-bearing animals. Administration of the aromatase inhibitor letrozole reduced tumor-induced hyperalgesia in INT females only suggesting that the tumor-induced increase in aromatase expression and its associated increase in spinal estrogen play a role in the development of bone tumor-induced hyperalgesia. Finally, intrathecal (i.t.) administration of 17β-estradiol caused a significant increase in tumor-induced hyperalgesia in INT tumor-bearing females. Since i.t. 17β-estradiol increases tumor pain and ovariectomy significantly decreases tumor pain, as well as spinal aromatase, estrogen may play a critical role in the spinal cord response to the changing tumor environment and the development of tumor-induced nociception. PMID:26995084

  4. 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.

  5. Switching from nitrate therapy to ranolazine in patients with coronary artery disease receiving phosphodiesterase type-5 inhibitors for erectile dysfunction.

    Science.gov (United States)

    Udeoji, Dioma U; Schwarz, Ernst R

    2014-01-01

    Coronary artery disease (CAD) and erectile dysfunction (ED) frequently coexist. The introduction of phosphodiesterase type-5 (PDE-5) inhibitors has revolutionized medical management of organic ED; however, in patients with angina pectoris, a common symptom of CAD, coadministration of PDE-5 inhibitors and nitrates has been implicated in CAD-related deaths following sexual activity. The mechanism of action of PDE-5 inhibitors results in a potential cumulative drop in blood pressure (BP); thus, these agents are contraindicated in patients receiving nitrates. Beta-blockers and calcium channel antagonists are considered the mainstays of antianginal therapy, but may not be tolerated by all patients. Ranolazine is an antianginal agent that produces minimal reductions in heart rate and BP. Here we report three cases of men with CAD, chronic angina, and concomitant ED. We describe our treatment approach in these patients, using ranolazine as a potential substitute to nitrate therapy. PMID:25452706

  6. 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

  7. Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy-A Hypothesis-Driven Review.

    Science.gov (United States)

    Laube, Markus; Kniess, Torsten; Pietzsch, Jens

    2016-01-01

    Radiation therapy (RT) evolved to be a primary treatment modality for cancer patients. Unfortunately, the cure or relief of symptoms is still accompanied by radiation-induced side effects with severe acute and late pathophysiological consequences. Inhibitors of cyclooxygenase-2 (COX-2) are potentially useful in this regard because radioprotection of normal tissue and/or radiosensitizing effects on tumor tissue have been described for several compounds of this structurally diverse class. This review aims to substantiate the hypothesis that antioxidant COX-2 inhibitors are promising radioprotectants because of intercepting radiation-induced oxidative stress and inflammation in normal tissue, especially the vascular system. For this, literature reporting on COX inhibitors exerting radioprotective and/or radiosensitizing action as well as on antioxidant COX inhibitors will be reviewed comprehensively with the aim to find cross-points of both and, by that, stimulate further research in the field of radioprotective agents. PMID:27104573

  8. Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

    Science.gov (United States)

    Subbian, Selvakumar; Tsenova, Liana; Holloway, Jennifer; Peixoto, Blas; O'Brien, Paul; Dartois, Véronique; Khetani, Vikram; Zeldis, Jerome B.; Kaplan, Gilla

    2016-01-01

    Objectives Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. Conclusions Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment. PMID:26981575

  9. 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.

  10. Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Meijer Danielle

    2011-07-01

    Full Text Available Abstract Background Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our experiments focus on unraveling the role of estrogen signaling in the regulation of neoplastic cartilage growth and on interference with estrogen signaling in chondrosarcomas in vitro and in vivo. Methods We investigated the protein expression of estrogen receptor alpha (ESR1, androgen receptor (AR, and aromatase in tumor specimens of various chondrosarcoma subtypes, and (primary chondrosarcoma cultures. Dose-response curves were generated of conventional central chondrosarcoma cell lines cultured in the presence of 17β-estradiol, dihydrotestosterone, 4-androstene-3,17 dione, 4-hydroxytamoxifen, fulvestrant and aromatase inhibitors. In a pilot series, the effect of anastrozole (n = 4 or exemestane (n = 2 treatment in 6 chondrosarcoma patients with progressive disease was explored. Results We showed protein expression of ESR1 and aromatase in a large majority of all subtypes. Only a minority of the tumors showed few AR positive cells. The dose-response assays showed no effect of any of the compounds on proliferation of conventional chondrosarcoma in vitro. The median progression-free survival of the patients treated with aromatase inhibitors did not significantly deviate from untreated patients. Conclusions The presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a possible role of estrogen signaling in chondrosarcoma proliferation. However, our in vitro and pilot in vivo studies have shown no effect of estrogen-signaling inhibition on tumor growth.

  11. 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, H;

    2011-01-01

    Objective 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). Methods Sixty-three HAART......, 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 with...... -6.1% (95% CI -8.2 to -4.0) and -5.0% (95% CI -6.8 to -3.1) in the protease inhibitor-sparing arm. There were no significant differences between arms. Low baseline CD4 cell count was independently associated with spine (P=0.007) and hip (P=0.04) BMD loss and low body mass index with hip BMD loss (P=0...

  12. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy.

    Science.gov (United States)

    Kaplan, Allen P

    2010-11-01

    A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein-high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH. PMID:20889195

  13. 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

  14. 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.

  15. Endocrinology and hormone therapy in breast cancer: Endocrine therapy in premenopausal women

    International Nuclear Information System (INIS)

    Endocrine therapy remains important in premenopausal women with hormone receptor positive breast cancer. Ovarian ablation, used alone, is effective in delaying recurrence and increasing survival in such women. When added to chemotherapy, it is less clear that it is effective perhaps because of the endocrine ablative effect of chemotherapy. Trials comparing ovarian ablation with or without tamoxifen to CMF-type chemotherapy suggest that the endocrine therapy is equivalent to or better than this chemotherapy in women whose tumors have estrogen and/or progesterone receptor. Tamoxifen is also effective in preventing recurrence and prolonging survival in the adjuvant setting in premenopausal women. While most of the available data deals with tamoxifen given alone, it appears to have a similar beneficial effect when added to chemotherapy in the premenopausal adjuvant setting. Adjuvant aromatase inhibitors should not be used in premenopausal women

  16. 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

  17. The effects of diabetes on placental aromatase activity.

    Science.gov (United States)

    McRobie, D J; Korzekwa, K R; Glover, D D; Tracy, T S

    1997-01-01

    Diabetes complicates 2-3% of all pregnancies and is associated with an increase in both perinatal morbidity and mortality, though reasons for these adverse outcomes are unknown. Estrogen biosynthesis is a critical factor during pregnancy and is carried out in the placenta via aromatase (cytochrome P450 19A1), which catalyzes the conversion of C-19 androgens to C-18 estrogens. Previous studies have shown that hormones such as insulin-like growth factors and insulin regulate aromatase activity when studied in vitro. Interestingly, levels of these hormones are altered in patients with diabetes. Thus, we hypothesized that the presence of maternal diabetes may alter placental aromatase activity and thus estrogen biosynthesis, possibly serving as one factor in the adverse outcomes of babies born to mothers with diabetes. To this end, we measured the production of 19-hydroxyandrostenedione, 19-oxoadrostenedione and estrone in 30 placental tissues from diabetic patients, using [7-3H]androst-4-ene-3,17-dione as a model substrate for aromatase (P450 19A1). A statistical difference was detected in the percentage of 19-oxoandrostenedione formed between the overt and control groups (P < 0.05). Additionally, NADPH P450-reductase levels were measured in these same tissues to determine whether alterations in this enzyme necessary for aromatase activity could be affected by diabetes. No differences in reductase levels were detected among the patient groups. However, a statistical correlation was found between NADPH P450-reductase activity and the formation velocities of all three estrogen products (P < 0.05). Thus, it appears that the presence of diabetes does not affect placental aromatase activity. PMID:9449216

  18. 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.

  19. 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.

  20. Hereditary Angioedema due to C1 Inhibitor Deficiency: C1-INH Replacement Therapy

    Directory of Open Access Journals (Sweden)

    Mauro Cancian

    2014-04-01

    Full Text Available Hereditary angioedema (HAE is a rare condition affecting about 1 in 50.000 individuals and caused by a mutation in the gene encoding the C1-esterase inhibitor (C1-INH, which is involved in the control of complement, clotting, fibrinolytic and kinin pathways. HAE is characterized by plasma outflow from blood vessels, leading to fluid collecting (edema in the deep tissue layers of the face, larynx, abdomen, and extremities. Three different types of HAE have been identified: in type I the mutation leads to the lack of production of C1-INH, in type II the mutation leads to the production of dysfunctional C1-INH, while type III is extremely rare and still not fully understood. Therapeutic approaches for HAE include on-demand treatments to stop angioedema attacks and prophylactic treatment to prevent attacks both by pre-procedural (short-term and routine (long-term prophylaxis. Aim of the present review is to present an overview of C1-INH replacement therapy with the plasma-derived concentrate of C1-INH Berinert® (CSL Behring GmbH in the treatment of type I and II HAE.http://dx.doi.org/10.7175/rhc.v5i2.913

  1. 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

  2. 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.

  3. 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

  4. Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists.

    Science.gov (United States)

    Kakavand, Hojabr; Wilmott, James S; Long, Georgina V; Scolyer, Richard A

    2016-02-01

    The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the

  5. PDE-5 inhibitors in monotherapy versus combination therapy in a sample of 1200 patients with erectile dysfunction

    OpenAIRE

    Luis Labairu-Huerta; Bárbara Padilla-Fernández; José Luis Arrondo-Arrondo; Lauro Sebastián Valverde-Martínez; Agustín Martín-Rodríguez; Juan Miguel Silva-Abuín; María Begoña García-Cenador; José Antonio Mirón-Canelo; María Fernanda Lorenzo-Gómez

    2015-01-01

    Objectives: To compare the effectiveness in the treatment of erectile dysfunction when using PDE-5 inhibitors (PDE5i), alprostadil (PG-E1) and testosterone (TES) in monotherapy or combination therapy. Material and Methods: Observational multicentre retrospective study of men diagnosed and treated for ED between January 2008 and January 2014. Age, social and employment situation, pathological medical history, risk factors, usual treatments, IIEF-5 at the first consultation and at first and eac...

  6. 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...

  7. 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.

  8. 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 is...

  9. Novel approaches to short stature therapy.

    Science.gov (United States)

    Wit, Jan M; Oostdijk, Wilma

    2015-06-01

    Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia. PMID:26051296

  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. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    International Nuclear Information System (INIS)

    Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. The animals were given celecoxib at 1500 ppm or aspirin at 200 ppm by oral administration with androstenedione injection. Our results showed that both COX inhibitors could suppress the cancer xenograft growth without changing the plasma estrogen level. Protein expression of ERα, COX-2, Cyclin A, and Bcl-xL were reduced in celecoxib-treated tumor samples, whereas only Bcl-xL expression was suppressed in those treated with aspirin. Among the breast cancer-related miRNAs, miR-222 expression was elevated in samples treated with celecoxib. Further studies in culture cells verified that the increase in miR-222 expression might contribute to ERα downregulation but not the growth deterrence of cells. Overall, this study suggested that both celecoxib and aspirin could prevent breast cancer growth by regulating proteins in the cell cycle and apoptosis without blocking estrogen synthesis. Besides, celecoxib might affect miR expression in an undesirable fashion

  12. 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.

  13. 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

  14. 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.

  15. Tumor reoxygenation following administration of Mitogen-Activated Protein Kinase inhibitors: A rationale for combination with radiation therapy

    International Nuclear Information System (INIS)

    Background and purpose: The relevance of Mitogen Activated Protein Kinase (MAPK) inhibitors as co-treatments for radiation therapy is investigated, with special focus on a potential link between the MAPK pathway and tumor hypoxia, which is a critical determinant for response to therapy. Materials and methods: The effects of two MAPK inhibitors, Sorafenib and PD0325901, were monitored daily using in vivo EPR (Electron Paramagnetic Resonance) oximetry in FSaII and TLT tumor models in order to identify a window of reoxygenation, during which tumor blood flow, oxygen consumption and radiation sensitivity were assessed. Results: Reoxygenation was shown after two days of treatments with Sorafenib or PD0325901 in two tumor models, which was further successfully exploited with Sorafenib for improving the radiation response of FSaII tumors by a factor of 1.5. The increase in tumor oxygenation was shown to be the result of two major factors: (i) an increase in blood flow for Sorafenib, that might be linked to its anti-angiogenic effect (vascular normalization), and (ii) a decrease in oxygen consumption for Sorafenib and PD0325901, due to an alteration of the mitochondrial activity. Conclusion: We evidenced tumor reoxygenation in vivo following MAPK inhibition and suggest a rationale for the combination of radiation therapy with Sorafenib.

  16. In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer

    International Nuclear Information System (INIS)

    Radiation therapy triggers blood monocytes to an increased secretion of immunosuppressive prostaglandins (PGs), which in part can explain the post-irradiation impairment of lymphocyte blastogenesis. Since low mitogen responses of lymphocytes in irradiated breast cancer patients is linked to a poor prognosis a clinical trial is planned to examine if treatment with inhibitors of PG-synthesis during irradiation can counteract immunosuppression and increase survival. In the present investigation the authors have compared 9 different inhibitors of PG-synthesis for capacity to enhance phytohemagglutinin responses of blood lymphocytes before and after irradiation for breast cancer. 5 of the drugs (aspisol, indomethacin, meclofenamic acid, ketoprofen and diclofenac) enhanced the reactivity to more than 150 percent. In general, the strongest enhancements were observed in lymphocyte preparations obtained at completion of irradiation when reactivity was most depressed followed by those obtained at one month and before irradiation. (author). 28 refs.; 5 figs.; 1 tab

  17. In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Blomgren, H.; Rotstein, S. (Karolinska Sjukhuset, Stockholm (Sweden)); Wasserman, J.; Petrini, B. (Stockholm County Council (Sweden). Central Microbiological Laboratory); Hammarstroem, S. (Linkoeping University Faculty of Health Sciences (Sweden). Department of Cell Biology, Division of Medical and Physical Chemistry)

    1990-12-01

    Radiation therapy triggers blood monocytes to an increased secretion of immunosuppressive prostaglandins (PGs), which in part can explain the post-irradiation impairment of lymphocyte blastogenesis. Since low mitogen responses of lymphocytes in irradiated breast cancer patients is linked to a poor prognosis a clinical trial is planned to examine if treatment with inhibitors of PG-synthesis during irradiation can counteract immunosuppression and increase survival. In the present investigation the authors have compared 9 different inhibitors of PG-synthesis for capacity to enhance phytohemagglutinin responses of blood lymphocytes before and after irradiation for breast cancer. 5 of the drugs (aspisol, indomethacin, meclofenamic acid, ketoprofen and diclofenac) enhanced the reactivity to more than 150 percent. In general, the strongest enhancements were observed in lymphocyte preparations obtained at completion of irradiation when reactivity was most depressed followed by those obtained at one month and before irradiation. (author). 28 refs.; 5 figs.; 1 tab.

  18. 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〉

  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. 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

  1. Significance of Ovarian Function Suppression in Endocrine Therapy for Breast Cancer in Pre-Menopausal Women

    Science.gov (United States)

    Scharl, A.; Salterberg, A.

    2016-01-01

    Ovarian function suppression (OFS) for treating breast cancer in pre-menopausal women was introduced for the first time in the late 19th century as bilateral oophorectomy. It was not until the 1960s that the oestrogen receptor was identified and a test for detecting endocrine sensitivity of the breast cancer was developed. A weakness of early trials on OFS for breast cancer treatment is therefore their failure to take receptor sensitivity into account when selecting participants. A meta-analysis performed in the early 1990s first proved that adjuvant OFS significantly improved the cure rate of oestrogen receptor-positive breast cancer in pre-menopausal women regardless of whether it was carried out through oophorectomy, radiation-induced ablation or drug therapy. In the 1970s, tamoxifen was synthesized. It became one of the most important cancer drugs and today constitutes the gold standard for endocrine adjuvant therapy. Taking tamoxifen for a five-year period lowers mortality by 30 % over 15 years. Ten years of tamoxifen therapy reduces mortality even further, with increased side effects, however. Research over the past ten years has proven that for post-menopausal women, aromatase inhibitors have benefits over tamoxifen. Current trial results have rekindled the debate about the combination of OFS with tamoxifen or with aromatase inhibitors for adjuvant breast cancer treatment of pre-menopausal women. These trials have reported an improvement in disease-free survival in patients with a high risk of recurrence when they are treated with a combination of OFS plus tamoxifen or aromatase inhibitors, especially in women younger than 35. However, combination therapy causes significantly more side effects, which could negatively impact compliance. Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years. Inadequate compliance compromises efficacy and increases the risk of mortality. For

  2. 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

  3. 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

  4. 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

  5. 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...

  6. 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...

  7. The ferrous-oxy complex of human aromatase

    International Nuclear Information System (INIS)

    In this communication, we document the self-assembly of heterologously expressed truncated human aromatase (CYP19) into nanometer scale phospholipids bilayers (Nanodiscs). The resulting P450 CYP19 preparation is stable and can tightly associate with the substrate androstenedione to form a nearly complete high-spin ferric protein. Ferrous CYP19 in Nanodiscs was mixed anaerobically in a rapid-scan stopped-flow with atmospheric dioxygen and the formation of the ferrous-oxy complex observed. First order decay of the oxy-complex to release superoxide and regenerate the ferric enzyme was monitored kinetically. Surprisingly, the ferrous-oxy complex of aromatase is more stable than that of hepatic CYP3A4, opening the path to precisely determine the biochemical and biophysical properties of the reaction cycle intermediates in this important human drug target

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

    International Nuclear Information System (INIS)

    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

  10. Cytochrome P450 aromatase expression in human seminoma

    Directory of Open Access Journals (Sweden)

    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.

  11. The role of intracavernosal injection therapy and the reasons of withdrawal from therapy in patients with erectile dysfunction in the era of PDE5 inhibitors.

    Science.gov (United States)

    Sung, H H; Ahn, J S; Kim, J J; Choo, S H; Han, D H; Lee, S W

    2014-01-01

    There has been little data regarding the role of intracavernosal injection (ICI) treatment, its discontinuation rate and the reasons of withdrawal in patients with erectile dysfunction (ED) in the era of phosphodiesterase type 5 (PDE5) inhibitors. The aim of this study was to investigate the rate of withdrawal and its associated reasons in patients undergoing ICI therapy. Patients who were prescribed with ICI treatment two times or more were included since the introduction of sildenafil in Korea in 1999. Telephone surveys were performed to evaluate intercourse rates, withdrawal rates and their associated reasons, adverse events and the patients' satisfaction with their sex lives after the ICI treatments. Two hundred and ninety-four men were contacted by telephone. The mean age was 61.8 ± 7.9 years with a follow-up duration of 25.6 ± 32.1 months. At the last follow-up, 79.9% had discontinued the treatment. Most patients had previously failed PDE5 inhibitor treatment prior to the ICI therapy, and more than half had two or more risk factors of ED. Adequate penile rigidity after ICI therapy was restored in 60.2% of patients. The reasons for discontinuation of ICI were poor response (43.1%), inconvenience of use (18.3%), switch to other treatments (10.7%), loss of libido (6.7%), adverse events (5.5%) and return of spontaneous erection (2.8%). Pain was the most common adverse event in the withdrawal group, whereas prolonged erection was most common in the continuing group. Following ICI treatment, PDE5 inhibitors were the most common therapeutic option (63.1%). The overall satisfaction rate regarding sex life was significantly high in the treatment-continuing group. In conclusion, patients on ICI treatment had severe ED and high withdrawal rates in the era of PDE5 inhibitors. The most common reason for treatment discontinuation was poor response. Before initiating ICI treatments, sufficient counselling is necessary. PMID:24194017

  12. 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

  13. 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

  14. Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy.

    Science.gov (United States)

    Clement, Omoshile O; Freeman, Clive M; Hartmann, Rolf W; Handratta, Venkatesh D; Vasaitis, Tadas S; Brodie, Angela M H; Njar, Vincent C O

    2003-06-01

    We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors of human cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature pharmacophore model(s) to explain the putative binding requirements for two classes of human CYP17 inhibitors. Common chemical features in the steroid and nonsteroid human CYP17 enzyme inhibitors, as deduced by the Catalyst/HipHop program, are one to two hydrogen bond acceptors (HBAs) and three hydrophobic groups. For azole-steroidal ligands, the 3beta-OH group of ring A and the N-3 of the azole ring attached to ring D at C-17 act as hydrogen bond acceptors. A model that permits hydrogen bond interaction between the azole functionality on ring D and the enzyme is consistent with experimental deductions for type II CYP17 inhibitors where a sixth ligating atom interacts with Fe(II) of heme. In general, pharmacophore models derived for steroid and nonsteroidal compounds bear striking similarities to all azole sites mapping the HBA functionality and to three hydrophobic features describing the hydrophobic interactions between the ligands and the enzyme. Using the pharmacophore model derived for azole-steroidal inhibitors as a 3D search query against several 3D multiconformational Catalyst formatted databases, we identified several steroidal compounds with potential inhibition of this enzyme. Biological testing of some of these compounds show low to high inhibitory potency against the human CYP17 enzyme. This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identifying and optimizing new leads. PMID:12773039

  15. 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. PMID:26941261

  16. 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.

  17. 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

  18. Safety of C1-Esterase Inhibitor in Acute and Prophylactic Therapy of Hereditary Angioedema

    DEFF Research Database (Denmark)

    Busse, Paula; Bygum, Anette; Edelman, Jonathan; Lumry, William; Machnig, Thomas; Martinez-Saguer, Inmaculada; Rojavin, Mikhail

    2014-01-01

    BACKGROUND: The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products...

  19. Cancer Cell Resistance to Aurora Kinase Inhibitors: Identification of Novel Targets for Cancer Therapy

    Czech Academy of Sciences Publication Activity Database

    Hrabáková, Rita; Kollaredy, M.; Tylečková, Jiřina; Halada, Petr; Hajdúch, M.; Gadher, S. J.; Kovářová, Hana

    2013-01-01

    Roč. 12, č. 1 (2013), s. 455-469. ISSN 1535-3893 R&D Projects: GA MŠk LC07017 Institutional support: RVO:67985904 ; RVO:61388971 Keywords : Aurora kinase inhibitors * resistance * p53 * apoptosis Subject RIV: CE - Biochemistry Impact factor: 5.001, year: 2013

  20. Long-Term Cholinesterase Inhibitor Therapy for Alzheimer's Disease: Practical Considerations for the Primary Care Physician

    OpenAIRE

    Geldmacher, David S

    2003-01-01

    Background: With the aging of the population, primary care physicians are increasingly expected to manage patients with Alzheimer's disease. For patients with this disease to obtain the best outcomes over the long term, early diagnosis and effective treatment are critical. Currently, cholinesterase inhibitors are the only drugs approved in the United States for the treatment of mild-to-moderate Alzheimer's disease.

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. New and emerging biologic therapies for moderate-to-severe plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors

    OpenAIRE

    Gaspari, Anthony A.; Tyring, Stephen

    2015-01-01

    The development of effective and well-tolerated biologic therapies has advanced the management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological basis of psoriasis has led to the development of biologic agents targeting specific downstream mediators in the psori...

  6. 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

  7. 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

  8. Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

    Science.gov (United States)

    Prange-Kiel, Janine; Dudzinski, Danuta A.; Pröls, Felicitas; Glatzel, Markus; Matschke, Jakob; Rune, Gabriele M.

    2016-01-01

    Numerous studies show that 17β-estradiol (E2) protects against Alzheimer's disease (AD) induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice). In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry) than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases. PMID:27298742

  9. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

    OpenAIRE

    Whittle, Nigel; Singewald, Nicolas

    2014-01-01

    A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevent...

  10. 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

  11. 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

  12. 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- ...

  13. 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...

  14. 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.

  15. 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.

  16. 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

  17. 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...

  18. 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...

  19. [REVIEW OF CLINICAL STUDIES ON COMBINATION THERAPY OF 5α-REDUCTASE INHIBITORS AND α1-BLOCKERS IN PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA].

    Science.gov (United States)

    Spivak, L G; Lokshin, K L; Vinarov, A Z

    2015-01-01

    The review presents the results of studies on combination therapy of 5α-reductase inhibitors and α-blockers in patients with benign prostatic hyperplasia (BPH). These data demonstrate a significant advantage of the combination therapy versus monotherapy in terms of quality of life and subjective symptoms as well as the safety, better results in the prevention of BPH progression and acute urinary retention, and reduced need for surgery. PMID:26665780

  20. Increased Bowel Toxicity in Patients Treated With a Vascular Endothelial Growth Factor Inhibitor (VEGFI) After Stereotactic Body Radiation Therapy (SBRT)

    Energy Technology Data Exchange (ETDEWEB)

    Barney, Brandon M., E-mail: barney.brandon@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Markovic, Svetomir N. [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Laack, Nadia N.; Miller, Robert C.; Sarkaria, Jann N. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Macdonald, O. Kenneth [Therapeutic Radiologists Incorporated, Kansas City, Kansas (United States); Bauer, Heather J.; Olivier, Kenneth R. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2013-09-01

    Purpose: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. Methods and Materials: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. Results: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log–rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). Conclusions: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future.

  1. Increased Bowel Toxicity in Patients Treated With a Vascular Endothelial Growth Factor Inhibitor (VEGFI) After Stereotactic Body Radiation Therapy (SBRT)

    International Nuclear Information System (INIS)

    Purpose: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. Methods and Materials: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. Results: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log–rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). Conclusions: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future

  2. PDE-5 inhibitors in monotherapy versus combination therapy in a sample of 1200 patients with erectile dysfunction

    Directory of Open Access Journals (Sweden)

    Luis Labairu-Huerta

    2015-09-01

    Full Text Available Objectives: To compare the effectiveness in the treatment of erectile dysfunction when using PDE-5 inhibitors (PDE5i, alprostadil (PG-E1 and testosterone (TES in monotherapy or combination therapy. Material and Methods: Observational multicentre retrospective study of men diagnosed and treated for ED between January 2008 and January 2014. Age, social and employment situation, pathological medical history, risk factors, usual treatments, IIEF-5 at the first consultation and at first and each 6 months follow-ups, physical examination, calculated total and free testosterone and received treatment were analysed. Descriptive statistics, one-way ANOVA analysis, Chi2 for qualitative data, t-test, Fisher's exact test and Pearson's correlation coefficient were used; p < 0.05 is considered significant. Results: Average age was 58.61 years, SD5.02, average follow- up time 48.21 months, SD 6.21, range 6-174 months. Out of the patients 76.12% were married, 9.81% divorced/separated, 10.04% single, 4.03% widowed; 85.14% of the total in stable partnership but 66.16% were not accompanied by their partners. In total 844 patients received monotherapy (597 PDE5i; 62 PG-E1; 36 TES; 27 penile prosthesis; 121 psychotherapy/alternative therapies and 357 combination therapy (167 PDE5i+TES; 124 PDE5i+PGE1; 66 PG-E1+TES. There was a homogeneous distribution between risk factors and medical history groups. Satisfactory response according to IIEF-5 was achieved for 72.33% of patients on PDE5i monotherapy, 46.65% of patients on PDE5i+PG-E1 combination therapy and 83.41% of patients on PDE5i+TES. Conclusions: The best therapeutic success for ED in this series was achieved through a combination of testosterone+PDE-5 inhibitors without increasing morbidity and maintaining the response over time. Larger studies with longer follow-up will corroborate these findings.

  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. PMID:27145599

  4. 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...

  5. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma.

    Science.gov (United States)

    Spain, L; Higgins, R; Gopalakrishnan, K; Turajlic, S; Gore, M; Larkin, J

    2016-06-01

    Immune checkpoint inhibitors such as ipilimumab and nivolumab improve survival in patients with advanced melanoma and are increasingly available to clinicians for use in the clinic. Their safety in organ transplant recipients is not well defined but published case reports describing treatment with ipilimumab have not been complicated by graft rejection. No cases of anti-programmed cell death protein 1 administration are reported in this group. We describe a case of acute graft rejection in a kidney transplant recipient after treatment with nivolumab, after progression on ipilimumab. Potential factors increasing the risk of graft rejection in this case are discussed, in particular the contribution of nivolumab. PMID:26951628

  6. 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-...

  7. 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...

  8. 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.

  9. Target Therapy Using a Small Molecule Inhibitor against Angiogenic Receptors in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Peter Büchler

    2007-02-01

    Full Text Available PURPOSE: PD173074, a small molecule inhibitor of VEGF-RII and FGF-RI, targets neoangiogenesis and mitogenesis. This study aimed to analyze a singlecompound-driven inhibition of FGF and VEGF receptors in pancreatic cancer. EXPERIMENTAL DESIGN: RT-PCR and Western blots were performed to quantify protein expression and phosphorylation. Anchorage dependent and independent growth assays were used to study cell growth. With flow cytometry, cell cycle analysis and apoptosis were studied. In vivo HPAF-II and MIA PaCa-2 cells were xenografted. Animals were treated daily for 10 weeks. Immunohistochemistry was used to quantify microvessel density and apoptosis. RESULTS: Highest levels of FGF-RI were detectable in MIA PaCa-2 cells, lowest in HPAF-II cells. PD173074 inhibited cell growth most prominently in cells expressing high levels of FGF-RI. Cell cycle progression was inhibited by blocking transition in the G0/G1 phase, and consequently, apoptosis was increased. In vivo significant inhibition of orthotopic tumor growth was achieved by a combination effect of inhibition of mitogenesis, induction of apoptosis, and reduction of angiogenesis in PD173074-treated animals. CONCLUSIONS: These data highlight VEGF-RII and FGF-RI as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable pancreatic cancer patients.

  10. 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

  11. Modulation of hypericin photodynamic therapy by pretreatment with 12 various inhibitors of arachidonic acid metabolism in colon adenocarcinoma HT-29 cells

    Czech Academy of Sciences Publication Activity Database

    Kleban, J.; Mikeš, J.; Szilárdiová, B.; Koval, J.; Sačková, V.; Solár, P.; Horváth, Viktor; Hofmanová, Jiřina; Kozubík, Alois; Fedoročko, P.

    2007-01-01

    Roč. 83, č. 5 (2007), s. 1174-1185. ISSN 0031-8655 R&D Projects: GA AV ČR(CZ) 1QS500040507 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : hypericin * photodynamic therapy * arachidonic acid inhibitors Subject RIV: BO - Biophysics Impact factor: 2.172, year: 2007

  12. Possibility of Acetylcholinesterase Overexpression in Alzheimer Disease Patients after Therapy with Acetylcholinesterase Inhibitors

    OpenAIRE

    Alžběta Kračmarová; Lucie Drtinová; Miroslav Pohanka

    2015-01-01

    Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing choli...

  13. The role of TNF inhibitors in psoriasis therapy: new implications for associated comorbidities

    OpenAIRE

    Yost, John; Gudjonsson, Johann E.

    2009-01-01

    Over the past several years, tumor necrosis factor (TNF) antagonists have become first-line agents in the treatment of moderate-to-severe psoriasis. These medications are highly effective in treating both psoriasis and psoriatic arthritis and may also reduce the risk of cardiovascular events in patients with chronic inflammatory disorders. In this article we review the use of anti-TNF therapy in psoriasis and its implications in regards to the co-morbid conditions associated with psoriasis.

  14. Impact of gastro-oesophageal reflux disease on work productivity despite therapy with proton pump inhibitors in Germany

    Directory of Open Access Journals (Sweden)

    Gross M

    2010-03-01

    Full Text Available Abstract Background Gastro-oesophageal reflux disease (GERD is a common disorder with consequences for the patient's health-related quality of life (HRQoL. In Germany, few data are available on the impact of GERD on work-related productivity. Aim To study the impact of GERD on work productivity despite proton pump inhibitor (PPI therapy and the association between productivity and symptom duration, severity, and HRQoL. Methods Retrospective data from randomly selected patients with chronic GERD symptoms, treated by office-based general practitioners or general internists with routine clinical care, were analyzed together with information from self-administered instruments assessing work productivity (WPAI-GERD, symptoms (RDQ, and HRQoL (QOLRAD. Results Reduced productivity was reported by 152 of 249 patients (61.0%, although 89.5% of them were treated with PPI. The reduction in work productivity was 18.5% in all patients and 30.3% in those with reduced productivity. Patients with impaired productivity showed a significantly lower HRQoL and more-severe symptoms of reflux disease. In all patients, the mean sick leave attributable to reflux symptoms was 0.6 hours in the previous seven days and 1.4 work days in the previous three months. Conclusion GERD has a substantial impact on work productivity in Germany, even in patients receiving routine clinical care and PPI therapy.

  15. 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

  16. 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.

  17. Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2003-01-01

    occur. Therefore, it is as yet uncertain wether DDP-IV inhibitors will affect gastrointestinal motility, appetite and food intake. Even the effects of GLP-1 effects on the pancreatic islets may be partly neurally mediated and therefore uninfluenced by DPP-IV inhibition....... and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic effects...... include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. However, continuous...

  18. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies.

    Science.gov (United States)

    Bauer, Renato A

    2015-09-01

    Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease. PMID:26002380

  19. 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

  20. 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

  1. Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.

    Science.gov (United States)

    Muth-Köhne, Elke; Westphal-Settele, Kathi; Brückner, Jasmin; Konradi, Sabine; Schiller, Viktoria; Schäfers, Christoph; Teigeler, Matthias; Fenske, Martina

    2016-07-01

    The Fish Sexual Development Test (FSDT) is a non-reproductive test to assess adverse effects of endocrine disrupting chemicals. With the present study it was intended to evaluate whether gene expression endpoints would serve as predictive markers of endocrine disruption in a FSDT. For proof-of-concept, a FSDT according to the OECD TG 234 was conducted with the non-steroidal aromatase inhibitor fadrozole (test concentrations: 10μg/L, 32μg/L, 100μg/L) using zebrafish (Danio rerio). Gene expression analyses using quantitative RT-PCR were included at 48h, 96h, 28days and 63days post fertilization (hpf, dpf). The selection of genes aimed at finding molecular endpoints which could be directly linked to the adverse apical effects of aromatase inhibition. The most prominent effects of fadrozole exposure on the sexual development of zebrafish were a complete sex ratio shift towards males and an acceleration of gonad maturation already at low fadrozole concentrations (10μg/L). Due to the specific inhibition of the aromatase enzyme (Cyp19) by fadrozole and thus, the conversion of C19-androgens to C18-estrogens, the steroid hormone balance controlling the sex ratio of zebrafish was altered. The resulting key event is the regulation of directly estrogen-responsive genes. Subsequently, gene expression of vitellogenin 1 (vtg1) and of the aromatase cyp19a1b isoform (cyp19a1b), were down-regulated upon fadrozole treatment compared to controls. For example, mRNA levels of vtg1 were down-regulated compared to the controls as early as 48 hpf and 96 hpf. Further regulated genes cumulated in pathways suggested to be controlled by endocrine mechanisms, like the steroid and terpenoid synthesis pathway (e.g. mevalonate (diphospho) decarboxylase (mvd), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase; lss), methylsterol monooxygenase 1 (sc4mol)) and in lipid transport/metabolic processes (steroidogenic acute regulatory protein (star), apolipoprotein Eb (apoEb)). Taken together

  2. 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...

  3. 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

  4. 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.

  5. C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study.

    Science.gov (United States)

    Viglietti, D; Gosset, C; Loupy, A; Deville, L; Verine, J; Zeevi, A; Glotz, D; Lefaucheur, C

    2016-05-01

    Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody-mediated rejection (ABMR). We performed a prospective, single-arm pilot study to investigate the potential effects and safety of C1 inhibitor (C1-INH) Berinert added to high-dose intravenous immunoglobulin (IVIG) for the treatment of acute ABMR that is nonresponsive to conventional therapy. Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1-INH and IVIG for 6 months (six patients). The primary end point was the change in eGFR at 6 months after inclusion (M+6). Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6. All patients showed an improvement in eGFR between inclusion and M+6: from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m(2) (p = 0.0277). There was no change in histological features, except a decrease in the C4d deposition rate from 5/6 to 1/6 (p = 0.0455). There was a change in DSA C1q status from 6/6 to 1/6 positive (p = 0.0253). One deep venous thrombosis was observed. In a secondary analysis, C1-INH patients were compared with a similar historical control group (21 patients). C1-INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR. PMID:26693703

  6. 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.

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

    International Nuclear Information System (INIS)

    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

  8. 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.

  9. 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

  10. Proton pump inhibitor-amoxicillin-clarithromycin versus proton pump inhibitor-amoxicillin-metronidazole as first-line Helicobacter pylori eradication therapy

    OpenAIRE

    Nishizawa, Toshihiro; Suzuki, Hidekazu; Suzuki, Masayuki; Takahashi, Masahiko; Hibi, Toshifumi

    2012-01-01

    The aim of this study was to compare the efficacy and tolerability of the first-line Helicobacter pylori (H. pylori) eradication regimen composed of proton pump inhibitor, clarithromycin, and amoxicillin, with those of a regimen composed of proton pump inhibitor, metronidazole, and amoxicillin. Data of patients, who were administered the first-line H. pylori eradication regimen at Tokyo Medical Center between 2008 and 2011, were reviewed. All patients had H. pylori gastritis without peptic ul...

  11. 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

  12. 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

  13. 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

  14. Sex Differences in Brain Aromatase Activity: Genomic and Non-Genomic Controls

    OpenAIRE

    JacquesBalthazart; NobuhiroHarada; AnneT.M.Konkle; CornelliaVoigt; GregoryFBall

    2011-01-01

    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 se...

  15. 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

  16. Acute Stress Differentially Affects Aromatase Activity in Specific Brain Nuclei of Adult Male and Female Quail

    OpenAIRE

    Dickens, Molly J; Cornil, Charlotte; Balthazart, Jacques

    2011-01-01

    The rapid and temporary suppression of reproductive behavior is often assumed to be an important feature of the adaptive acute stress response. However, how this suppression operates at the mechanistic level is poorly understood. The enzyme aromatase converts testosterone to estradiol in the brain to activate reproductive behavior in male Japanese quail (Coturnix japonica). The discovery of rapid and reversible modification of aromatase activity (AA) provides a potential mechanism for fast, s...

  17. 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...

  18. 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 ...

  19. 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.

  20. Potential usefulness of glycolytic inhibitors as adjuvants in temozolomide-radiation therapy of malignant gliomas: in vitro studies

    International Nuclear Information System (INIS)

    Malignant gliomas remain virtually incurable, in spite of increase in median survival with Temozolomide (TMZ)-Radiation therapy after surgical resection. Following a span of initial remission-depending on the degree of malignancy-there is tumour recurrence and impairment of vital body functions, leading ultimately to death. Therefore, it is important to carry out further preclinical studies to improve treatment of these tumours. Inhibitors of glycolytic energy metabolism, such as 2-deoxy-D-glucose (2-DG) and Lonidamine (LND) have been shown earlier to differentially inhibit growth and survival of tumour cells invitro. They also increase tumour regression and animal survival in preclinical studies; and have been used as radio/chemosensitizers in a several clinical trials. In our present studies, TMZ ± LND or 2-DG were added to exponentially growing cultures. The drugs were continuously present for 2-6 days in the initial experiments. Subsequently, cells were exposed to 60Co-Gamma-rays (1-2 Gy) and drugs were removed 4 hours later. Effects on proliferation response, viability and cell death were studied after post-treatment growth. Ultra-structural damage was studied immediately after cytotoxic treatments

  1. 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.

  2. 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...... was not significantly improved with either sequential treatment as compared with letrozole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women...... who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment...

  3. 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

  4. Regulation of serum matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 following rituximab therapy in patients with rheumatoid arthritis refractory to anti-tumor necrosis factor blockers

    OpenAIRE

    Klimiuk, Piotr Adrian; Domysławska, Izabela; Sierakowski, Stanisław; Chwiećko, Justyna

    2014-01-01

    In our article, we evaluated the regulatory effects of the infusions of rituximab, a monoclonal antibody directed against CD20+ B cells, on the serum matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in patients with active rheumatoid arthritis (RA) not responding to anti-tumor necrosis factor (anti-TNF) therapy. Twelve RA patients were planned to receive four infusions of 1,000 mg of rituximab at weeks 0, 2, 24 and 26. The therapy was combined with...

  5. 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

  6. 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

  7. Protease inhibitor-based triple therapy in chronic hepatitis C: guidelines by the French Association for the Study of the Liver.

    Science.gov (United States)

    Leroy, Vincent; Serfaty, Lawrence; Bourlière, Marc; Bronowicki, Jean-Pierre; Delasalle, Patrick; Pariente, Alexandre; Pol, Stanislas; Zoulim, Fabien; Pageaux, Georges-Philippe

    2012-11-01

    The recent marketing authorizations and hence availability of the new protease inhibitors, telaprevir and boceprevir, have profoundly changed the management of chronic hepatitis C patients. Guidelines for the use of these new drugs as part of a triple therapy, in combination with the standard therapy of peginterferon plus ribavirin, are proposed. The guidelines have been drawn up and evaluated by a meeting of the French Association for the Study of the Liver, posted online for comments, and extensively reviewed by international experts. The current published data on the various treatment strategies are reviewed. The guidelines address the majority of patient profiles including treatment-naïve patients and patients with failure of previous treatment. They recommend which patients should be treated with triple therapy and consider the results of triple therapy including the factors that are predictive of response. They consider the circumstances in which the length of triple therapy can be shortened and the advantages of a peginterferon plus ribavirin lead-in phase. Virological monitoring, stopping criteria, the evaluation of resistance to protease inhibitors, practical treatment management, treatment adherence and the management of side effects are discussed and simple guidelines proposed. PMID:22891751

  8. 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.

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

    OpenAIRE

    Schwartz, Stanley

    2016-01-01

    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...

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

    OpenAIRE

    Schwartz SS; Katz A

    2016-01-01

    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 opt...

  11. 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 ...

  12. 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 ...

  13. 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...

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. Contribution of Gag and Protease to HIV-1 Phenotypic Drug Resistance in Pediatric Patients Failing Protease Inhibitor-Based Therapy.

    Science.gov (United States)

    Giandhari, Jennifer; Basson, Adriaan E; Sutherland, Katherine; Parry, Chris M; Cane, Patricia A; Coovadia, Ashraf; Kuhn, Louise; Hunt, Gillian; Morris, Lynn

    2016-04-01

    Protease inhibitors (PIs) are used as a first-line regimen in HIV-1-infected children. Here we investigated the phenotypic consequences of amino acid changes in Gag and protease on lopinavir (LPV) and ritonavir (RTV) susceptibility among pediatric patients failing PI therapy. The Gag-protease from isolates from 20 HIV-1 subtype C-infected pediatric patients failing an LPV and/or RTV-based regimen was phenotyped using a nonreplicativein vitroassay. Changes in sensitivity to LPV and RTV relative to that of the matched baseline (pretherapy) sample were calculated. Gag and protease amino acid substitutions associated with PI failure were created in a reference clone by site-directed mutagenesis and assessed. Predicted phenotypes were determined using the Stanford drug resistance algorithm. Phenotypic resistance or reduced susceptibility to RTV and/or LPV was observed in isolates from 10 (50%) patients, all of whom had been treated with RTV. In most cases, this was associated with protease resistance mutations, but substitutions at Gag cleavage and noncleavage sites were also detected. Gag amino acid substitutions were also found in isolates from three patients with reduced drug susceptibilities who had wild-type protease. Site-directed mutagenesis confirmed that some amino acid changes in Gag contributed to PI resistance but only in the presence of major protease resistance-associated substitutions. The isolates from all patients who received LPV exclusively were phenotypically susceptible. Baseline isolates from the 20 patients showed a large (47-fold) range in the 50% effective concentration of LPV, which accounted for most of the discordance seen between the experimentally determined and the predicted phenotypes. Overall, the inclusion of thegaggene and the use of matched baseline samples provided a more comprehensive assessment of the effect of PI-induced amino acid changes on PI resistance. The lack of phenotypic resistance to LPV supports the continued use of

  20. 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

  1. 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...

  2. 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...

  3. Switching from Nitrate Therapy to Ranolazine in Patients with Coronary Artery Disease Receiving Phosphodiesterase Type-5 Inhibitors for Erectile Dysfunction

    OpenAIRE

    Udeoji, Dioma U; Ernst R. Schwarz

    2014-01-01

    Coronary artery disease (CAD) and erectile dysfunction (ED) frequently coexist. The introduction of phosphodiesterase type-5 (PDE-5) inhibitors has revolutionized medical management of organic ED; however, in patients with angina pectoris, a common symptom of CAD, coadministration of PDE-5 inhibitors and nitrates has been implicated in CAD-related deaths following sexual activity. The mechanism of action of PDE-5 inhibitors results in a potential cumulative drop in blood pressure (BP); thus, ...

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. AB081. Effects of combination therapy of Tamoxifen, L-carnitine and daily PDE5 inhibitors in the Peyronie’s disease

    Science.gov (United States)

    Kang, Jae Il; Park, Tae Yong; Jeong, Hyeong Guk; Park, Jong Jin; Chae, Ji Yun; Kim, Jong Wook; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong; Moon, Du Geon

    2016-01-01

    Objective This study was designed to evaluate the efficacy of combination therapy of Tamoxifen, L-carnitine and daily PDE5 inhibitors and to compare with Potassium para-aminobenzoate (Potaba) monotherapy in the medical treatment of Peyronie’s disease. Methods From January 2011 to December 2014, a total of 104 patients with Peyronie’s disease enrolled in this study. Sixty-eight patients were treated with Tamoxifen 20 mg and Acetyl L-carnitine 330 mg twice a daily in addition to daily PDE5 inhibitors (Tadalafil 5 mg once daily) combination therapy (Group 1), while thirty-four patients were treated with Potassium para-aminobenzoate 12 g daily (Group 2), Pain on erection, impossibility of intercourse, plaque size, penile curvature and IIEF-5 were assessed. Plaque volume was assessed by penile ultrasonography. Results Both groups showed resolution of pain and intercourse satisfaction after treatment. The pre-treatment plaque sizes of both groups were 17.1±7.2, 17.0±5.0 mm, respectively. After treatment, those parameters significantly reduced to 13.2±5.6, 16.2±5.3 mm. In group 1, combination therapy significantly improved the angle of penile curvature, plaque size, and IIEF (P value <0.05). In group 2, the size of the plaque, penile curvature and IIEF were improved after Potassium para-aminobenzoate monotherapy. However, no significant differences were observed. Conclusion Statistically significant improvement in intercourse satisfaction, plaque size, degree of curvature and IIEF-5 was observed in combination therapy. Combination therapy may be the more effective than Potassium para-aminobenzoate monotherapy in medical treatment of Peyronie’s disease.

  13. AB093. The efficacy of medical treatment of Peyronie’s disease: Potaba monotherapy vs. combination therapy with Tamoxifen, L-carnitine, and PDE5 inhibitor

    Science.gov (United States)

    Park, Jong Jin; Kim, Jong Wook; Moon, Du Geon

    2016-01-01

    Objective This study was designed to evaluate the efficacy of combination therapy of Tamoxifen, L-carnitine and daily PDE5 inhibitors and to compare with Potassium para-aminobenzoate (Potaba) monotherapy in the medical treatment of Peyronie’s disease. Methods From January 2011 to December 2014, a total of 104 patients with Peyronie’s disease enrolled in this study. Sixty-eight patients were treated with Tamoxifen 20 mg and Acetyl L-carnitine 330 mg twice a daily in addition to daily PDE5 inhibitors (Tadalafil 5 mg once daily) combination therapy (Group 1), while thirty-four patients were treated with Potassium para-aminobenzoate 12 g daily (Group 2), Pain on erection, impossibility of intercourse, plaque size, penile curvature and IIEF-5 were assessed. Plaque volume was assessed by penile ultrasonography. Results Both groups showed resolution of pain and intercourse satisfaction after treatment. The pre-treatment plaque sizes of both groups were 17.1±7.2, 17.0±5.0 mm, respectively. After treatment, those parameters significantly reduced to 13.2±5.6, 16.2±5.3 mm. In group 1, combination therapy significantly improved the angle of penile curvature, plaque size, and IIEF (P<0.05). In group 2, the size of the plaque, penile curvature and IIEF were improved after Potassium para-aminobenzoate monotherapy. However, no significant differences were observed. Conclusions Statistically significant improvement in intercourse satisfaction, plaque size, degree of curvature and IIEF-5 was observed in combination therapy. Combination therapy may be the more effective than Potassium para-aminobenzoate monotherapy in medical treatment of Pyeronie’s disease.

  14. Are separable aromatase systems involved in hormonal regulation of the male brain

    International Nuclear Information System (INIS)

    In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells

  15. Are separable aromatase systems involved in hormonal regulation of the male brain

    Energy Technology Data Exchange (ETDEWEB)

    Hutchison, J.B.; Schumacher, M.; Steimer, T.; Gahr, M. (Institute of Animal Physiology, Babraham, Cambridge (England))

    1990-07-01

    In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells.

  16. 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

  17. 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)). ...

  18. 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, ...

  19. 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...

  20. Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy

    OpenAIRE

    de Jonge, Boudewijn L. M.; Walkup, Grant K.; Lahiri, Sushmita D.; Huynh, Hoan; Neckermann, Georg; Utley, Luke; Nash, Tory J.; Brock, Jesse; San Martin, Maryann; Kutschke, Amy; Johnstone, Michele; Laganas, Valerie; Hajec, Laurel; Gu, Rong-Fang; Ni, Haihong

    2013-01-01

    Inhibitors of 4′-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosph...

  1. 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

  2. Effective Concentration of a Multikinase Inhibitor within Bone Marrow Correlates with In Vitro Cell Killing in Therapy-Resistant Chronic Myeloid Leukemia.

    Science.gov (United States)

    Mu, Chaofeng; Wu, Xiaoyan; Ma, Helen; Tao, Wenjing; Zhang, Guodong; Xia, Xiaojun; Shen, Jianliang; Mai, Junhua; Sun, Tong; Sun, Xiaoping; Arlinghaus, Ralph B; Shen, Haifa

    2016-05-01

    Leukemia cells escape BCR-ABL-targeted therapy by developing mutations, such as T315I, in the p210(BCR-ABL) fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I-mutant CML cells to 10 μmol/L of the multikinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell-cycle arrest at G2-M. Further increase in drug concentration to 17.5 μmol/L blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μmol/L for effective killing of CML cells in vivo Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapy-resistant CML. Mol Cancer Ther; 15(5); 899-910. ©2016 AACR. PMID:26846820

  3. 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...

  4. 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

  5. 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

  6. Risk of Hormone Escape in a Human Prostate Cancer Model Depends on Therapy Modalities and Can Be Reduced by Tyrosine Kinase Inhibitors

    Science.gov (United States)

    Guyader, Charlotte; Céraline, Jocelyn; Gravier, Eléonore; Morin, Aurélie; Michel, Sandrine; Erdmann, Eva; de Pinieux, Gonzague; Cabon, Florence; Bergerat, Jean-Pierre; Poupon, Marie-France; Oudard, Stéphane

    2012-01-01

    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 (RRintermittent: 14.5, RRcomplete 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 tumors displayed

  7. Evaluation of costs accrued through inadvertent continuation of hospital-initiated proton pump inhibitor therapy for stress ulcer prophylaxis beyond hospital discharge: a retrospective chart review

    Directory of Open Access Journals (Sweden)

    Shin S

    2015-04-01

    Full Text Available Sooyoung Shin Ajou University College of Pharmacy, Yeongtong-gu, Suwon-si, Gyeonggi-do, South Korea Background: Stress ulcers and related upper gastrointestinal bleeding are well-known complications in intensive care unit (ICU patients. Proton pump inhibitor (PPI-based stress ulcer prophylaxis (SUP has been widely prescribed in noncritically ill patients who are at low risk for clinically significant bleeding, which is then injudiciously continued after hospital discharge. This study aimed to evaluate the incidence of inappropriate prescribing of PPI-based preventative therapy in ICU versus non-ICU patients that subsequently continued postdischarge, and to estimate the costs incurred by the unwarranted outpatient continuation of PPI therapy.Methods: A retrospective review of patient data at a major teaching hospital in Korea was performed. During the 4-year study period, adult patients who were newly initiated on PPI-based SUP during hospital admission and subsequently discharged on a PPI without a medical indication for such therapy were captured for data analysis. The incidence rates of inappropriate prescribing of PPIs were compared between ICU and non-ICU patients, and the costs associated with such therapy were also examined.Results: A total of 4,410 patients, more than half of the inpatient-initiated PPI users, were deemed to have been inadvertently prescribed a PPI at discharge in the absence of a medical need for acid suppression. The incidence of inappropriate outpatient continuation of the prophylaxis was higher among ICU patients compared with non-ICU patients (57.7% versus 52.2%, respectively; P=0.001. The total expenditure accrued through the continuation of nonindicated PPI therapy was approximately US$40,175.Conclusion: This study confirmed that excess usage of PPIs for SUP has spread to low-risk, non-ICU patients. The overuse of unwarranted PPI therapy can incur large health care expenditure, as well as clinical complications

  8. Sensitivity of New Zealand mudsnail Potamopyrgus antipodarum (Gray) to a specific aromatase inhibitor

    OpenAIRE

    M. Gust; Garric, J.; Giamberini, L.; Mons, R.; Abbaci, K.; Garnier, F; Buronfosse, T.

    2010-01-01

    The freshwater prosobranch Potamopyrgus antipodarum (Molluska, Hydrobiidea, Smith 1889) has been proposed as a suitable species to assess the impact of endocrine disrupting compounds (EDC) in aquatic ecosystems. Steroid hormone biosynthesis pathway is potentially an important target for EDC, and vertebrate-like sex steroids seem to play a functional role in the control of mollusk reproduction. To assess the response and the sensitivity of P. antipodarum to disrupters of the steroid hormone bi...

  9. Influence of different chromosomal abnormalities in Ph-positive bone marrow cells on the chronic myeloid leukemia course during tyrosine kinase inhibitors therapy

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    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. 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.

  11. 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.

  12. 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

  13. 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.

  14. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain

    Directory of Open Access Journals (Sweden)

    Anat Biegon

    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.

  15. 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

  16. 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; Tarp, Ulrik; Manilo, Natalia; Loft, Anne Gitte Rasmussen; Hansen, Annette; Schlemmer, Annette; Fana, Victoria; Lindegaard, Hanne M; Nordin, Henrik; Rasmussen, Claus; Ejstrup, Leif; Jensen, Dorte Vendelbo; Petersen, Peter Mosborg; Hetland, Merete Lund

    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...

  17. 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.

  18. Inhibition of Post-Transcriptional RNA Processing by CDK Inhibitors and Its Implication in Anti-Viral Therapy

    Czech Academy of Sciences Publication Activity Database

    Holčáková, J.; Müller, P.; Tomasec, P.; Hrstka, R.; Nekulová, M.; Kryštof, Vladimír; Strnad, Miroslav; Wilkinson, G. W. G.; Vojtěšek, B.

    2014-01-01

    Roč. 9, č. 2 (2014). E-ISSN 1932-6203 R&D Projects: GA ČR GBP206/12/G151 Institutional support: RVO:61389030 Keywords : IMMUNODEFICIENCY-VIRUS TYPE-1 * DEPENDENT KINASE INHIBITORS * LARGE T-ANTIGEN Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.234, year: 2014

  19. Contribution of HIV minority variants to drug resistance in an integrase strand transfer inhibitor-based therapy

    Czech Academy of Sciences Publication Activity Database

    Weber, Jan; Gibson, R. M.; Meyer, A. M.; Winner, D.; Robertson, D. L.; Miller, M. D.; Quinones-Mateu, M. E.

    2013-01-01

    Roč. 18, Suppl. 1 (2013), A66-A66. ISSN 1359-6535. [International Workshop on HIV & Hepatitis Virus Drug Resistance Curative Strategies. 04.06.2013-08.06.2013, Toronto] Institutional support: RVO:61388963 Keywords : HIV minority variants * integrase inhibitor * replicative fitness Subject RIV: CE - Biochemistry

  20. 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...

  1. 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

  2. Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

    International Nuclear Information System (INIS)

    Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

  3. Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy.

    Science.gov (United States)

    Reddy, Sangeetha M; Reuben, Alexandre; Wargo, Jennifer A

    2016-07-01

    The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses. PMID:27215436

  4. 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

  5. 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...

  6. 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 ...

  7. 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

  8. 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...

  9. 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...

  10. Post-proliferative immature radial glial cells female-specifically express aromatase in the medaka optic tectum.

    Directory of Open Access Journals (Sweden)

    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.

  11. Immunocytochemical and biochemical evidence for aromatase in neurons of the retina, optic tectum and retinotectal pathways in goldfish.

    Science.gov (United States)

    Gelinas, D; Callard, G V

    1993-12-01

    Using an animal model in which neural aromatase is apparently overexpressed (the goldfish, Carassius auratus) and an anti-human placental antibody which specifically crossreacts with goldfish brain aromatase, aromatase-immunoreactive neuronal cell bodies and fibers have been localized within the retina. These include a subset of horizontal cells, bipolar cells, and amacrine cells of the inner nuclear layer, some fibers of the outer and inner synaptic layers and certain cells of the ganglion cell layer; photoreceptors were never labeled. Some ganglion cell projections to the brain via the optic nerve and optic tract were aromatase-positive, as were small neurons of the stratum periventriculare (SPV) and fibers of two other strata of the optic tectum. Aromatase activity, as measured by [3H]androgen by tissue homogenates and cell cultures, confirmed the presence of aromatase in retina and in brain regions containing the optic tectum. This localization of the rate-limiting enzyme in estrogen biosynthesis suggests that neuroestrogen derived from circulating androgen m ay modulate transmission and integration of visual information important for reproduction in this species. PMID:8680435

  12. 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

  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. 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

  15. 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

  16. 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

  17. 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.

  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 pat...

  19. 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.

  20. 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

    Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides ...... to the natural ligands, the integrated response in the organism might be amplified by the ability of the pesticides to act via several mechanism and the frequent simultaneous exposure to several pesticides.......Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides...... to their frequent use in Danish greenhouses. In addition, the metabolite mercaptodimethur sulfoxide, the herbicide tribenuron-methyl, and the organochlorine dieldrin, were included. Several of the pesticides, dieldrin, endosulfan, methiocarb, and fenarimol, acted both as estrogen agonists and...

  1. 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

  2. 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...

  3. 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...

  4. 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

    International Nuclear Information System (INIS)

    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.)

  5. Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer′s Disease Therapy

    Directory of Open Access Journals (Sweden)

    Houssem Boulebd

    2016-03-01

    Full Text Available Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-ylethan-1-one (4 is non-hepatotoxic (cell viability assay on HepG2 cells, a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM, and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound.

  6. The Efficacy of Medical Treatment of Peyronie's Disease: Potassium Para-Aminobenzoate Monotherapy vs. Combination Therapy with Tamoxifen, L-Carnitine, and Phosphodiesterase Type 5 Inhibitor

    Science.gov (United States)

    Park, Tae Yong; Jeong, Hyeong Guk; Park, Jong Jin; Chae, Ji Yun; Kim, Jong Wook; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong

    2016-01-01

    Purpose This study was designed to evaluate the efficacy of medical treatment of Peyronie's disease. Materials and Methods A total of 109 patients with Peyronie's disease who had been treated from January 2011 to December 2014 were retrospectively reviewed in this study. Forty-four patients (Group 1) were treated with 12 mg of potassium para-aminobenzoate daily. Sixty-five patients (Group 2) were treated with combination therapy: tamoxifen (20 mg) and acetyl-L-carnitine (300 mg) twice daily in addition to a phosphodiesterase type 5 inhibitor. Ability to perform sexual intercourse, pain during erection, size of plaque, and penile curvature angle were assessed. Results In Group 1, 30 of 44 patients (68.2%) discontinued treatment within 12 weeks, while 5 patients (7.7%) in Group 2 discontinued treatment. Pain during erection and plaque size were improved in both groups but showed no statistical difference due to the high dropout rate in Group 1. In both groups, penile curvature was improved, but demonstrated no statistical difference between the treatment groups. However, combination therapy demonstrated a better response rate in patients whose penile curvature angle was less than 30° (44.4% vs. 79.1%, p=0.048). The rate of successful sexual intercourse was significantly higher in Group 2 (42.8% vs. 78.3%, p=0.034). The number of patients who underwent surgical correction despite medical treatment was significantly higher in Group 1 (35.7% vs. 13.3%, p=0.048). Conclusions Early medical combination therapy in Peyronie's disease may present better results in patients whose curvature angle is less than 30°. PMID:27169128

  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. 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

  10. Tumor necrosis factor inhibitor therapy but not standard therapy is associated with resolution of erosion in the sacroiliac joints of patients with axial spondyloarthritis

    DEFF Research Database (Denmark)

    Pedersen, Susanne J; Wichuk, Stephanie; Chiowchanwisawakit, Praveena; Lambert, Robert G; Maksymowych, Walter P

    2014-01-01

    INTRODUCTION: Radiography is an unreliable and insensitive tool for the assessment of structural lesions in the sacroiliac joints (SIJ). Magnetic resonance imaging (MRI) detects a wider spectrum of structural lesions but has undergone minimal validation in prospective studies. The Spondyloarthritis...... Research Consortium of Canada (SPARCC) MRI Sacroiliac Joint (SIJ) Structural Score (SSS) assesses a spectrum of structural lesions (erosion, fat metaplasia, backfill, ankylosis) and its potential to discriminate between therapies requires evaluation. METHODS: The SSS score assesses five consecutive coronal...... (ANOVA), discrimination was assessed using Guyatt's effect size, and treatment group differences were assessed using t-tests and the Mann-Whitney test. We identified baseline demographic and structural damage variables associated with change in SSS score by univariate analysis and analyzed the effect of...

  11. 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

  12. 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

  13. 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.

  14. Angiotensin system inhibitors and survival in patients with metastatic renal cell carcinoma treated with VEGF-targeted therapy: A pooled secondary analysis of clinical trials.

    Science.gov (United States)

    Sorich, Michael J; Kichenadasse, Ganessan; Rowland, Andrew; Woodman, Richard J; Mangoni, Arduino A

    2016-05-01

    Use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) has been reported to be associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with vascular endothelial growth factor-targeted therapies. This study was a secondary pooled analysis of two Phase III randomized controlled trials (RCTs) of patients with mRCC: NCT00334282 comparing pazopanib to placebo and NCT00720941 comparing pazopanib to sunitinib. ASI users were defined as patients using an ASI at baseline. Association with overall survival (OS; primary outcome) and progression-free survival (PFS) was evaluated using Cox proportional hazards regression. The association was adjusted in multivariable analysis for baseline systolic blood pressure (SBP), use of other antihypertensive drugs and prognostic factors comprising the Heng risk criteria for mRCC. Of 1,545 patients pooled from the two RCTs, 649 (42%) were using one or more antihypertensive drugs at baseline, 385 (59%) of which were using an ASI. In the multivariable analysis of patients using pazopanib or sunitinib, no significant association was observed between baseline ASI use and OS (hazard ratio [HR] 0.97 [95% confidence interval (CI) 0.80-1.18], p = 0.80) or PFS (HR 0.88 [95% CI 0.73-1.06], p = 0.17). Exploratory subgroup analysis of NCT00720941 highlighted that the effect of baseline ASI use on OS may differ between patients treated with sunitinib and pazopanib. In conclusion, use of ASIs at baseline was not a significant independent prognostic factor for improved survival in a pooled analysis of mRCC patients treated with pazopanib or sunitinib. PMID:26685869

  15. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice.

    Science.gov (United States)

    Thrailkill, Kathryn M; Clay Bunn, R; Nyman, Jeffry S; Rettiganti, Mallikarjuna R; Cockrell, Gael E; Wahl, Elizabeth C; Uppuganti, Sasidhar; Lumpkin, Charles K; Fowlkes, John L

    2016-01-01

    Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p<0.0001, for all) while cortical porosity was increased (p<0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p<0.001 for all). Significant increases in PTH (p<0.0001), RatLAPs (p=0.0002), and urine calcium concentration (p<0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: impact on cancer therapy.

    Science.gov (United States)

    Maier-Salamon, Alexandra; Thalhammer, Theresia; Reznicek, Gottfried; Böhmdorfer, Michaela; Zupkó, István; Hartl, Alexander; Jaeger, Walter

    2014-08-01

    The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 (V(max)/K(m)) were 1.7- and 2.7‑fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients. PMID:24889073

  2. Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain.

    Science.gov (United States)

    Cisternas, Carla D; Tome, Karina; Caeiro, Ximena E; Dadam, Florencia M; Garcia-Segura, Luis M; Cambiasso, María J

    2015-10-15

    Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the "four core genotypes" mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex. Furthermore, estradiol or dihydrotestosterone increased aromatase expression in cultures of anterior amygdala neurons derived from XX embryos, but not in those derived from XY embryos. This effect was also independent of gonadal sex. The expression of other steroidogenic molecules, estrogen receptor-α and androgen receptor was not influenced by sex chromosomes. In conclusion, sex chromosomes determine sex dimorphisms in aromatase expression and regulation in the developing mouse brain. PMID:26231585

  3. Pattern Alopecia during Hormonal Anticancer Therapy in Patients with Breast Cancer.

    Science.gov (United States)

    Park, Jin; Kim, Ju-Ik; Yun, Seok-Kweon; Kim, Han-Uk; Ihm, Chull-Wan

    2014-12-01

    We report five cases of pattern alopecia in female patients who are undergoing hormonal anticancer therapy for the prevention of recurrence of breast cancer after surgery. Three patients demonstrated male pattern alopecia with receding frontal hairlines, and two patients demonstrated female pattern alopecia without receding hairlines. The detailed clinical history showed that the pattern alopecia of the patients developed after the full recovery of global hair loss of the entire scalp due to previous cytotoxic chemotherapy. All of the adjuvant hormonal anticancer drugs that were used in the patients are antiestrogenic agents, either aromatase inhibitors or selective estrogen receptor modulators. Considering androgen effect on the hair follicles of the fronto-parietal scalp, the androgen-estrogen imbalance caused by the drugs was thought to be the reason for the onset of pattern alopecia in the patients. In general, alopecia that develops during cytotoxic chemotherapy is well known to both physicians and patients; however, the diagnosis of pattern alopecia during hormonal anticancer therapy in breast cancer patients seems to be overlooked. PMID:25473228

  4. Diagnostics and Therapy for Malignant (Degenerate) Colon Endometriosis – Three Case Reports

    Science.gov (United States)

    Schutz, R.; Woziwodzki, J.; Schweppe, K.-W.

    2016-01-01

    Malignant degeneration of colon endometriosis is a very rare event. We report here on three cases. A 48-year-old woman with a 10-year history of endometriosis was treated for a rectal adenocarcinoma, a 61-year-old G1P1, who was operated at the age of 40 years for ovarian endometriosis and again at the age of 53 years for an endometriosis-associated endometroid ovarian carcinoma, presented for therapy for a lymph node recurrence of the ovarian cancer and, secondly, due to a malignantly degenerated rectum-sigmoid colon endometriosis; furthermore a 54-year old woman with a 21-year history of endometriosis was operated for malignant colon endometriosis. The tumour occurred during an adjuvant anti-oestrogen treatment with an aromatase inhibitor following surgical and radiotherapy for breast cancer. In all cases a radical cancer operation was followed by adjuvant chemotherapy and in one case with an additional radiotherapy. In the follow-up periods of 18 months, 2 and 5 years, respectively, all women remained free of recurrences. Although this is not a randomised controlled study due to the rare occurrence of such cases, a radical operation followed by individualised adjuvant therapy appears to be the treatment of choice. PMID:27134299

  5. 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

  6. 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

  7. Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast

    International Nuclear Information System (INIS)

    Estrogen is a mitogenic factor that is implicated in the genesis and progression of breast cancer via its binding to estrogen receptor (ER)-α. Synthesis of estrogen in situ is believed to be catalyzed mainly by aromatase. Previous studies comparing the relative contributions from tumor cells and stromal cells to local estrogen synthesis, as assessed by immunohistochemical analysis, were quite controversial and no consistent relationship was found between the presence of aromatase and any clinicopathologic factor. In addition, previous studies into aromatase gene expression and clinicopathologic factors are limited. We assessed the level of expression of aromatase mRNA, using quantitative real-time RT-PCR, in 162 cases of invasive ductal carcinoma of the breast. Associations between aromatase expression and different clinicopathologic factors were sought. It was found that aromatase mRNA was expressed at significantly higher levels in patients older than 50 years, in those without axillary lymph node involvement, in those with tumor size less than 2 cm, and in ER-α positive tumors. However, no relationship was found between aromatase mRNA expression and any other clinicopathologic factor, including histologic grade and progesterone receptor status. Patients with high levels of expression of aromatase mRNA tended to have a better prognosis than did those patients with low expression. These findings imply that ER-α and aromatase may be coexpressed in endocrine responsive patients. They may also indicate that aromatase expression could be a marker of endocrine responsiveness, and it may have prognostic implications for breast cancer progression

  8. 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

  9. 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:

  10. Indirect treatment comparison of bevacizumab + interferon-α-2a vs tyrosine kinase inhibitors in first-line metastatic renal cell carcinoma therapy

    Directory of Open Access Journals (Sweden)

    Gerald HJ Mickisch

    2011-01-01

    Full Text Available Gerald HJ Mickisch1, Björn Schwander2, Bernard Escudier3, Joaquim Bellmunt4, José P Maroto5, Camillo Porta6, Stefan Walzer7, Uwe Siebert8,91Department of Urology, Center of Operative Urology Bremen, Bremen, Germany; 2Department of Outcomes Research, AiM GmbH Assessment-in-Medicine, Lörrach, Germany; 3Immunotherapy Unit, Institut Gustave Roussy, Villejuif, France; 4Department of Medical Oncology, University Hospital del Mar UPF, Barcelona, Spain; 5Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6Department of Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy; 7Global Health Economics, F Hoffmann-La Roche Pharmaceuticals AG, Basel, Switzerland; 8Department of Public Health, Medical Decision Making and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria; 9Department of Health Policy and Management, Harvard School of Public Health, Boston, MA, USABackground: The vascular endothelial growth factor inhibitor bevacizumab (BEV given in combination with interferon-α-2a (IFN, and the tyrosine kinase inhibitors (TKIs sunitinib (SUN and pazopanib (PAZ, have all shown significant increase in progression-free survival (PFS in first-line metastatic renal-cell carcinoma (mRCC therapy. These targeted therapies are currently competing to be primary choice; hence, in the absence of direct head-to-head comparison, there is a need for valid indirect comparison assessment.Methods: Standard indirect comparison methods were applied to independent review PFS data of the pivotal Phase III trials, to determine indirect treatment comparison hazard-ratios (HR with 95% confidence intervals (95% CI. As BEV+IFN and SUN have been compared to IFN, indirect comparison was enabled by the common IFN comparator arms. As PAZ was compared to placebo (PLA, a connector trial (IFN vs PLA was required for the indirect comparison to BEV

  11. Effect of Shifting from Combination Therapy to Monotherapy of α-Blockers or 5α-Reductase Inhibitors on Prostate Volume and Symptoms in Patients with Benign Prostatic Hyperplasia

    OpenAIRE

    Kim, Hyoung Woo; Moon, Dae Geun; Kim, Hyun Min; Hwang, Jong Ho; Kim, Soon Chan; Nam, Sam Geuk; Park, Jun Tag

    2011-01-01

    Purpose Combination therapy of α-blockers and 5α-reductase inhibitors (5-ARIs) is widely used for the treatment of benign prostatic hyperplasia (BPH). We aimed to study the effect on prostate volume and symptoms of shifting to monotherapy in patients who previously received a combination therapy. Materials and Methods A prospective study was conducted of 60 patients who were diagnosed with BPH. Patients were aged 45 years or older and had a prostate volume of 30 cc or more, International Pros...

  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

    Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects on...... steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced...

  13. 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

  14. 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

  15. Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naive to Antiretroviral Therapy: A Pilot Randomized Trial.

    Directory of Open Access Journals (Sweden)

    Sergio Serrano-Villar

    2016-01-01

    Full Text Available Whether initiation of antiretroviral therapy (ART regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6, lipoteichoic acid (LTA, soluble CD14 (sCD14 and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively, with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease

  16. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics

    International Nuclear Information System (INIS)

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E2) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden

  17. 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

  18. 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

  19. In vitro effects of heparin and tissue factor pathway inhibitor on factor VII assays. possible implications for measurements in vivo after heparin therapy.

    Science.gov (United States)

    Bladbjerg, E M; Larsen, L F; Ostergaard, P; Jespersen, J

    2000-12-01

    The coagulant activity of blood coagulation factor VII (FVII:C) can be lowered by changes in lifestyle and by therapeutic intervention, e.g. heparin infusion. The question is, however, whether FVII:C determined ex vivo is a valid measure of the FVII activity in vivo. We measured plasma FVII:C, activated FVII (FVIIa), FVII protein (FVII:Ag), tissue factor pathway inhibitor (TFPI), triglycerides, and free fatty acids (FFA) before and 15 min after infusion of a bolus of unfractionated heparin (50 IU/kg body weight) in 12 healthy subjects. Additionally, we conducted in vitro experiments to investigate the effect of unfractionated heparin and TFPI, which is released from the endothelium by heparin, on FVII:C, FVIIa, and FVII:Ag. Heparin infusion decreased triglycerides and increased FFA and TFPI. This was accompanied by significant reductions in FVIIa, FVII:C and FVII:Ag. In vitro, anti-TFPI antibodies increased FVIIa and FVII:C, and heparin reduced FVIIa. The heparinase Hepzyme was unable to abolish the effect of heparin. There were no in vitro effects on FVII:Ag. We conclude that, due to interference by TFPI and heparin in post-heparin plasma, it is impossible to measure the in vivo FVII activity by means of FVII clotting assays. These assays should therefore not be used to measure the coagulation status of patients in heparin therapy, unless extraordinary precautions are taken to eliminate TFPI and heparin effects ex vivo. The observed effect of heparin on FVII:Ag should be investigated further. PMID:11132652

  20. Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

    International Nuclear Information System (INIS)

    Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2nd EGFR-TKI administration. We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment. Three patients (27%) were treated with gefitinib as the 2nd EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2nd EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2nd EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2nd EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy. Our results indicate that a 2nd EGFR-TKI treatment can be an effective treatment option for gefitinib responders

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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

  7. 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.

  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. 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.

  10. 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

  11. 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.

  12. Sex Differences in Brain Aromatase Activity: Genomic and Non-Genomic Controls

    Science.gov (United States)

    Balthazart, Jacques; Charlier, Thierry D.; Cornil, Charlotte A.; Dickens, Molly J.; Harada, Nobuhiro; Konkle, Anne T. M.; Voigt, Cornelia; Ball, Gregory F.

    2011-01-01

    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 (AA), and transcription are markedly (four- to sixfold) increased by genomic actions of sex steroids. Initial work indicated that the preoptic AA 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 AA, 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. AA 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 AA 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 significance. PMID:22645508

  13. 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.

  14. 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...

  15. 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.

  16. The role of aromatase inhibitors in ameliorating deleterious effects of ovarian stimulation on outcome of infertility treatment

    OpenAIRE

    Diamond Michael P; Casper Robert F; Mitwally Mohamed FM

    2005-01-01

    Abstract Clinical utilization of ovulation stimulation to facilitate the ability of a couple to conceive has not only provided a valuable therapeutic approach, but has also yielded extensive information on the physiology of ovarian follicular recruitment, endometrial receptivity and early embryo competency. One of the consequences of the use of fertility enhancing agents for ovarian stimulation has been the creation of a hyperestrogenic state, which may influence each of these parameters. Use...

  17. 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...... was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite...

  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. Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells

    Science.gov (United States)

    Kim, Ji Eun; Rewcastle, Gordon W; Finlay, Graeme J; Baguley, Bruce C

    2011-01-01

    Background Treatment with anti-estrogens or aromatase inhibitors is commonly used for patients with estrogen receptor-positive (ER+) breast cancers; however resistant disease develops almost inevitably, requiring a choice of secondary therapy. One possibility is to use inhibitors of the PI3K/mTOR pathway and several candidate drugs are in development. We examined the in vitro effects of two inhibitors of the PI3K/mTOR pathway on resistant MCF-7 cells. Results The derived sub-lines showed increased resistance to tamoxifen but none exhibited concomitantly increased sensitivity to the PI3K inhibitors. NVP-BEZ235 and GSK2126458 acted mainly by induction of cell cycle arrest, particularly in G1-phase, rather than by induction of apoptosis. The lines varied considerably in their utilization of the AKT, p70S6K and ERK pathways. NVP-BEZ235 and GSK2126458 inhibited AKT signaling but NVP-BEZ235 showed greater effects than GSK2126458 on p70S6K and rpS6 signaling with effects resembling those of rapamycin. Methods We cultured MCF-7 cells for prolonged periods either in the presence of the anti-estrogen tamoxifen (three sub-lines) or in estrogen free medium (two sub-lines) to mimic the effects of clinical treatment. We then analyzed the effects of two dual PI3K/mTOR phosphoinositide-3-kinase inhibitors, NVP-BEZ235 and GSK2126458, on the growth and signaling pathways of these MCF-7 sub-lines. The functional status of the PI3K, mTOR and ERK pathways was analyzed by measuring phosphorylation of AKT, p70S6K, rpS6 and ERK. Conclusion Increased resistance to tamoxifen in these MCF-7 sub-lines is not associated with hypersensitivity to PI3K inhibitors. While both drugs inhibited AKT signaling, NVP-BEZ235 resembled rapamycin in inhibiting the mTOR pathway. PMID:21464613

  1. Phosphodiesterase-5 inhibitors.

    Science.gov (United States)

    Cockrill, Barbara A; Waxman, Aaron B

    2013-01-01

    Nitric oxide (NO) signaling plays a key role in modulating vascular tone and remodeling in the pulmonary circulation. The guanylate cyclase/cyclic guanylate monophosphate-signaling pathway primarily mediates nitric oxide signaling. This pathway is critical in normal regulation of the pulmonary vasculature, and is an important target for therapy in patients with pulmonary hypertension. In the pulmonary vasculature, degradation of cGMP is primarily regulated by PDE-5, and inhibition of this enzyme has important effects on pulmonary vasculature smooth muscle tone. Large randomized placebo-controlled trials of PDE-5 inhibitors demonstrated improved exercise capacity, hemodynamics and quality of life in adult patients with PAH. This chapter will discuss the mechanisms of NO signaling in the vasculature, characteristics of the PDE5-inhibitors approved for treatment of PH, and review available data on the use of phosphodiesterase inhibitors in PH. PMID:24092343

  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. 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...

  4. 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...

  5. Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.

    OpenAIRE

    Goodall, RL; Dunn, DT; T Pattery; van Cauwenberge, A.; Nkurunziza, P.; Awio, P.; Ndembi, N.; Munderi, P; Kityo, C.; Gilks, CF; Kaleebu, P.; Pillay, D.; DART Virology Group and Trial Teams, (incd. Grosskurth, H; )

    2014-01-01

    OBJECTIVES We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count

  6. The effect of oral contraceptives on aromatase and Cox-2 expression in the endometrium of patients with idiopathic menorrhagia or adenomyosis

    Directory of Open Access Journals (Sweden)

    Maia H Jr

    2013-06-01

    Full Text Available Hugo Maia Jr,1–3 Clarice Haddad,3 Nathaniel Pinheiro,4 Julio Casoy31School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil; 2Itaigara Memorial Day Hospital, Salvador, Bahia, Brazil; 3CEPARH (Centro de Pesquisas e Assistência em Reprodução Humana, Salvador, Bahia, Brazil; 4Imagepat Pathology Laboratory, Federal University of Bahia, Salvador, Bahia, BrazilBackground: The presence of aromatase and cyclooxygenase-2 (Cox-2 expression was investigated in the endometrium of patients with idiopathic menorrhagia or adenomyosis. The effect of oral contraceptives administered in extended regimens on the endometrial expression of these enzymes was also investigated.Methods and results: Aromatase expression was detected by immunohistochemistry in the endometrial glands and stroma of patients with idiopathic menorrhagia or adenomyosis. There was no difference in the percentage of aromatase expression in the endometria between the two groups. The mean intensity of Cox-2 expression in the glandular epithelium also did not differ significantly between the groups. Among the patients using oral contraceptives in extended regimens, the relative decrease in both aromatase and Cox-2 expression was significantly greater in amenorrheic patients compared with those who were experiencing breakthrough bleeding.Conclusion: The presence of aromatase expression in the endometrium is associated with the occurrence of menorrhagia, irrespective of the presence of adenomyosis. Continuous expression of these enzymes in the endometrium of users of oral contraceptives in extended regimens is positively associated with the presence of breakthrough bleeding. This suggests a role for both aromatase and Cox-2 in the etiology of abnormal uterine bleeding.Keywords: menorrhagia, aromatase, endometrium, Cox-2, adenomyosis

  7. Drug-resistance development differs between HIV-1-infected patients failing first-line antiretroviral therapy containing nonnucleoside reverse transcriptase inhibitors with and without thymidine analogues

    OpenAIRE

    Santoro, MM; Sabin, C.; Forbici, F; Bansi, L.; Dunn, D; Fearnhill, E.; Boumis, E; Nicastri, E.; Antinori, A; Palamara, G.; Callegaro, A.; Francisci, D; Zoncada, A.; Maggiolo, F; Zazzi, M.

    2013-01-01

    We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group).

  8. Drug-Related Pneumonitis During Mammalian Target of Rapamycin Inhibitor Therapy: Radiographic Pattern-Based Approach in Waldenström Macroglobulinemia as a Paradigm

    OpenAIRE

    Nishino, Mizuki; Boswell, Erica N.; Hatabu, Hiroto; Ghobrial, Irene M.; Ramaiya, Nikhil H.

    2015-01-01

    A retrospective study of 40 patients with Waldenström macroglobulinemia treated with the mammalian target of rapamycin inhibitor everolimus was performed to investigate the imaging characteristics and radiographic patterns of pneumonitis. Drug-related pneumonitis was noted in 23 patients (58%). The most common findings were bilateral ground glass and reticular opacities, demonstrating cryptogenic organizing pneumonia and nonspecific interstitial pneumonia patterns.

  9. 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

  10. 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

  11. Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema.

    Science.gov (United States)

    Chen, Xinde; Wang, Kai; Xu, Wenwei; Ma, Quanxin; Chen, Minli; Du, Lili; Mo, Mingguang; Wang, Yiping; Shen, Jianhua

    2016-03-24

    Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME. PMID:26927682

  12. 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...

  13. Improvement in duration of erection following phosphodiesterase type 5 inhibitor therapy with vardenafil in men with erectile dysfunction: the ENDURANCE study

    OpenAIRE

    Rosenberg, M. T.; Adams, P L; McBride, T A; Roberts, J N; McCallum, S W

    2009-01-01

    Objective: The ENDURANCE study evaluated the efficacy of vardenafil, a phosphodiesterase type 5 (PDE5) inhibitor, in men with erectile dysfunction (ED), by measuring the duration of erection leading to successful intercourse using a stopwatch as the assessment instrument. Methods: This was a randomised, multicentre, double-blind, placebo-controlled, crossover study consisting of a 4-week treatment-free run-in phase after which patients were randomised to either fixed-dose vardenafil 10 mg or ...

  14. 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

  15. Effect of a randomized controlled exercise trial on bone outcomes: influence of adjuvant endocrine therapy.

    Science.gov (United States)

    Knobf, M Tish; Jeon, Sangchoon; Smith, Barbara; Harris, Lyndsay; Kerstetter, Jane; Thompson, A Siobhan; Insogna, Karl

    2016-02-01

    Bone loss is a significant clinical problem for female cancer survivors (FCS) and increases fracture risk. The aim of the Yale Fitness Intervention Trial (Yale FIT) was to determine the effects of a 12-month aerobic-resistance exercise intervention compared to a home-based physical activity group on bone outcomes [bone mineral density (BMD)] and biomarkers bone turnover). Early postmenopausal FCS (N = 154) were randomized to the exercise intervention (3 times/week) or to a home-based physical activity group. Calcium (1200 mg) and Vitamin D (400 IU) supplements were provided to both groups. BMD was measured at baseline and 12 months. No significant difference in BMD was observed for the exercise vs home-based group. However, subjects on Tamoxifen or no endocrine therapy did not significantly lose BMD, with the exception of the femoral neck (FN). In contrast subjects on aromatase inhibitors (AIs) had significant BMD loss at all sites. The majority of subjects had sufficient serum levels of Vitamin D (>20 ng/mL) but there was significantly less bone loss in subjects in the 20-29 ng/mL range at the LS (p = 0.01), hip (p = 0.03), and GT (p = 0.008) compared to lower or higher levels. Exercise stimulates bone remodeling but the intervention was not superior for BMD outcomes at one year. The dose of the osteogenic stimulus in the intervention has been effective in preserving BMD in healthy postmenopausal women but it may be inadequate for survivors with chemotherapy-induced menopause and for those on adjuvant AI therapy. PMID:26850265

  16. 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.

  17. 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

  18. PARP-1 expression in breast cancer including BRCA1-associated, triple negative and basal-like tumors: possible implications for PARP-1 inhibitor therapy

    OpenAIRE

    Domagala, Pawel; Huzarski, Tomasz; Lubinski, Jan; Gugala, Karol; Domagala, Wenancjusz

    2011-01-01

    Abstract Despite ongoing trials of PARP inhibitors in the treatment of breast cancer (BC), the extent of poly(ADP-ribose)polymerase-1 (PARP-1) protein expression in BCs, which may influence treatment results, is not known. The purpose of this report is to assess expression of PARP-1 in BC including BRCA1-associated, triple negative (TN), and basal-like tumors. Immunohistochemistry with a PARP-1 antibody on tissue microarrays from 130 BRCA1-associated and 594 BRCA1-non-related BCs w...

  19. 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.

  20. 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.

  1. Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

    Science.gov (United States)

    Tang, Michele W.; Rhee, Soo-Yon; Bertagnolio, Silvia; Ford, Nathan; Holmes, Susan; Sigaloff, Kim C.; Hamers, Raph L.; de Wit, Tobias F. Rinke; Fleury, Herve J.; Kanki, Phyllis J.; Ruxrungtham, Kiat; Hawkins, Claudia A.; Wallis, Carole L.; Stevens, Wendy; van Zyl, Gert U.; Manosuthi, Weerawat; Hosseinipour, Mina C.; Ngo-Giang-Huong, Nicole; Belec, Laurent; Peeters, Martine; Aghokeng, Avelin; Bunupuradah, Torsak; Burda, Sherri; Cane, Patricia; Cappelli, Giulia; Charpentier, Charlotte; Dagnra, Anoumou Y.; Deshpande, Alaka K.; El-Katib, Ziad; Eshleman, Susan H.; Fokam, Joseph; Gody, Jean-Chrysostome; Katzenstein, David; Koyalta, Donato D.; Kumwenda, Johnstone J.; Lallemant, Marc; Lynen, Lutgarde; Marconi, Vincent C.; Margot, Nicolas A.; Moussa, Sandrine; Ndung'u, Thumbi; Nyambi, Phillipe N.; Orrell, Catherine; Schapiro, Jonathan M.; Schuurman, Rob; Sirivichayakul, Sunee; Smith, Davey; Zolfo, Maria; Jordan, Michael R.; Shafer, Robert W.

    2013-01-01

    Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy. PMID:23687292

  2. 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.

  3. [NF-κB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-κB].

    Science.gov (United States)

    Jimi, Eijiro; Fukushima, Hidefumi

    2016-02-01

    The transcriptional factor nuclear factor κB(NF-κB)regulates the expression of a wide variety of genes that are involved in immune and inflammatory responses, proliferation, and tumorigenesis. NF-κB consists of five members, such as p65(RelA), RelB, c-Rel, p50/p105(NF-κB1), and p52/p100(NF-κB2). There are two distinct NF-κB activation pathways, termed the classical and alternative NF-κB signaling pathways. Since mice lacking both p50 and p52 subunits developed typical osteopetrosis, due to total lack of osteoclasts, NF-κB is also important osteoclast differentiation. A selective NF-κB inhibitor blocked receptor activator of NF-κB ligand(RANKL)-induced osteoclastogenesis both in vitro and in vivo. Recent findings have shown that inactivation of NF-κB enhances osteoblast differentiation in vitro and bone formation in vivo. NF-κB is constitutively activated in many cancers including oral squamous cell carcinoma(OSCC), and is involved in the invasive characteristics of OSCC. A selective NF-κB inhibitor also prevented jaw bone destruction by OSCC by reduced osteoclast numbers in animal model. Thus the inhibition of NF-κB might useful for the treatment of bone diseases, such as arthritis, osteoporosis, periodontitis, and bone invasion by OSCC by inhibiting bone resorption and by stimulating bone formation. PMID:26813510

  4. Rapid increase in aggressive behavior precedes the decrease in brain aromatase activity during socially mediated sex change in Lythrypnus dalli

    OpenAIRE

    Black, Michael P; Balthazart, Jacques; Baillien, Michelle; Grober, Matthew S.

    2010-01-01

    In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study, within hours of male removal, aromatase activity in the brain (bAA) of dominant females was almost 50% lower than that of control females from a group in which the male had not been removed. For those females that displayed increased aggressive behavior after the male was removed, the larger the...

  5. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Michelle L Van Sinderen

    Full Text Available The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2 treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα and interleukin 6 (IL6. Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.

  6. Corrosion inhibitors

    International Nuclear Information System (INIS)

    In this paper, we briefly describe the characteristics, cost and electrochemical nature of the corrosion phenomena as well as some of the technologies that are currently employed to minimize its effect. The main subject of the paper however, deals with the description, classification and mechanism of protection of the so-called corrosion inhibitors. Examples of the use of these substances in different aggressive environments are also presented as means to show that these compounds, or their combination, can in fact be used as excellent and relatively cheap technologies to control the corrosion of some metals. In the last part of the paper, the most commonly used techniques to evaluate the efficiency and performance of corrosion inhibitors are presented as well as some criteria to make a careful and proper selection of a corrosion inhibitor technology in a given situation. (Author) 151 refs

  7. 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

  8. A Real World Report on Intravenous High-Dose and Non-High-Dose Proton-Pump Inhibitors Therapy in Patients with Endoscopically Treated High-Risk Peptic Ulcer Bleeding

    Directory of Open Access Journals (Sweden)

    Lung-Sheng Lu

    2012-01-01

    Full Text Available Background and Study Aims. The optimal dose of intravenous proton-pump inhibitor (PPI therapy for the prevention of peptic ulcer (PU rebleeding remains controversial. This study aimed to understand the real world experiences in prescribing high-dose PPI and non-high-dose PPI for preventing rebleeding after endoscopic treatment of high-risk PU. Patients and Methods. A total of 220 subjects who received high-dose and non-high-dose pantoprazole for confirmed acute PU bleeding that were successfully treated endoscopically were enrolled. They were divided into rebleeding (n=177 and non-rebleeding groups (n=43. Randomized matching of the treatment-control group was performed. Patients were randomly selected for non-high-dose and high-dose PPI groups (n=44 in each group. Results. Univariate analysis showed, significant variables related to rebleeding were female, higher creatinine levels, and higher Rockall scores (≧6. Before case-control matching, the high-dose PPI group had higher creatinine level, higher percentage of shock at presentation, and higher Rockall scores. After randomized treatment-control matching, no statistical differences were observed for rebleeding rates between the high-dose and non-high-dose groups after case-control matching. Conclusion. This study suggests that intravenous high-dose pantoprazole may not be superior to non-high-dose regimen in reducing rebleeding in high-risk peptic ulcer bleeding after successful endoscopic therapy.

  9. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    Directory of Open Access Journals (Sweden)

    Nicolas Defarge

    2016-02-01

    Full Text Available Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH, the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations, and not the declared active ingredient glyphosate (G alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone.

  10. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    Science.gov (United States)

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-01-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  11. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels.

    Science.gov (United States)

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-01-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co-formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  12. Weight gain and inflammation regulate aromatase expression in male adipose tissue, as evidenced by reporter gene activity.

    Science.gov (United States)

    Polari, L; Yatkin, E; Martínez Chacón, M G; Ahotupa, M; Smeds, A; Strauss, L; Zhang, F; Poutanen, M; Saarinen, N; Mäkelä, S I

    2015-09-01

    Obesity and white adipose tissue (WAT) inflammation are associated with enhanced aromatization in women, but little is known about the regulation of aromatase (CYP19A1) gene expression in male WAT. We investigated the impact of weight gain and WAT inflammation on the regulation of CYP19A1 in males, by utilizing the hARO-Luc aromatase reporter mouse model containing a >100-kb 5'-region of the human CYP19A1 gene. We show that hARO-Luc reporter activity is enhanced in WAT of mice with increased adiposity and inflammation. Dexamethasone and TNFα, as well as forskolin and phorbol 12-myristate 13-acetate, upregulate hARO-Luc activity, suggesting the involvement of promoters I.4 and I.3/II. Furthermore, we show that diet enriched with antioxidative plant polyphenols attenuates WAT inflammation and hARO-Luc activity in obese males. In conclusion, our data suggest that obesity-associated WAT inflammation leads to increased peripheral CYP19A1 expression in males, and that polyphenol-enriched diet may have the potential to attenuate excessive aromatization in WAT of obese men. PMID:26054748

  13. Brain cytochrome P450 aromatase activity in roach (Rutilus rutilus): seasonal variations and impact of environmental contaminants.

    Science.gov (United States)

    Geraudie, Perrine; Hinfray, Nathalie; Gerbron, Marie; Porcher, Jean-Marc; Brion, François; Minier, Christophe

    2011-10-01

    P450 aromatase catalyses the conversion of C19 androgens to C18 estrogens which is thought to be essential for the regulation of the reproductive function. In this study, brain aromatase activity (AA) was measured monthly over a reproductive cycle in wild roach (Rutilus rutilus) sampled in a reference site in Normandy. AA peaked during the breeding season, reaching 35 fmol mg(-1)min(-1) in both male and female fish, and was low during the rest of the year except for a significant rise in October. AA was correlated with ovary maturation (measured either as gonado-somatic index or by histological analysis of the gonads) and plasma sex-steroid levels (11-ketotestosterone in males and 17-β-estradiol in females). Measurements of AA in polluted sites showed that activity was significantly upregulated in sites with fish showing high levels of plasma vitellogenin and large proportion of intersexuality (20-50%) thus suggesting the occurrence of estrogenic compounds and their involvement in AA modulation. PMID:21820384

  14. Differential responsiveness of luteinized human granulosa cells to gonadotropins and insulin-like growth factor I for induction of aromatase activity

    International Nuclear Information System (INIS)

    The objective of this study was to examine the in vitro responsiveness of cultured luteinized human granulosa cells over time to insulin-like growth factor 1 (IGF-1), human follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) for the induction of aromatase activity. Granulosa cells were retrieved from preovulatory follicles in patients undergoing in vitro fertilization. Cells were cultured for a period of 72 hours or 10 days. The ability of hCG, human FSH, and/or IGF-I to induce aromatase activity was assayed by the stereospecific release of tritium from [1B-3H]androstenedione. Short-term cultures (72 hours) demonstrated a marked rise in aromatase activity in response to human FSH and IGF-I, whereas a smaller response to hCG was observed. In contrast, 10-day cultures demonstrated responsiveness predominantly to hCG rather than human FSH for the induction of aromatase activity with no remarkable effect of IGF-I. Luteinized human granulosa cells undergo a transformation from an initial human FSH and IGF-I responsive state to an hCG responsive state in long-term cultures

  15. Age-related decrease in aromatase and estrogen receptor(ERαand ERβ) expression in rat testes: protective effect of low caloric diets

    Institute of Scientific and Technical Information of China (English)

    Khaled Hamden; Dorothee Silandre; Christelle Delalande; Abdefattah El Feki; Serge Carreau

    2008-01-01

    Aim: To examine the effects on rat aging of caloric restriction (CR1) and undernutrition (CR2) on the body and on testicular weights, on two enzymatic antioxidants (superoxide dismutase and catalase), on lipid peroxidation and on the expression of testicular aromatase and estrogen receptors (ER). Methods: CR was initiated in 1-month-old rats and carried on until the age of 18 months. Results: In control and CR2 rats an age-related decrease of the aromatase and of ER (α and β) gene expression was observed; in parallel a diminution of testicular weights, and of the total number and motility of epididymal spermatozo was recorded. In addition, aging in control and CR2 rats was accom-panied by a significant decrease in testicular superoxide dismutase, catalase activities, and an increase in lipid peroxidation level (thiobarbituric acid reactive substance), associated with alterations of spermatogenesis. Conversely, caloric restriction-treatment exerted a protective effect and all the parameters were less affected by aging. Conclusion:These results indicate that during aging, a low caloric diet (not undernutrition) is beneficial for spermatogenesis and likely improves the protection of the cells via an increase of the cellular antioxidant defense system in which aromatase/ER could play a role.

  16. The effects of COX-Inhibitors (Diclofenac and Ibuprofen on growth rate, mortality and sex reversal in Nile Tilapia (Oreochromis niloticus

    Directory of Open Access Journals (Sweden)

    Mutaz A. Al-Qutob

    2009-10-01

    Full Text Available Several studies have been conducted to detect the direct effect of inhibiting the aromatase activity, the rate limiting enzyme that converts androgens to estrogens needed for ovarian differentiation in fish to overcome the immediate need for a more environmentally friendly substitute of methyl testosterone. Cyclooxygenase (COX-inhibitors are potent and irreversible inhibitors of the COX pathway and since studies on human breast cancer cells shows that they decrease aromatase messenger ribonucleic acid (mRNA expression at the transcriptional level we tested the hypothesis of possible aromatase inhibition by the non-selective COX-inhibitors in fry fish tilapia. The effects of supplementation of COX-inhibitors (diclofenac and ibuprofen in the diets of tilapia on growth rate, mortality and sexual differentiation have been studied. 20 Genetically females (XX (O. niloticus larvae were stocked in triplicates in a closed system and each were given control diet (C group and control diet supplemented with (10 mgKg-1 diclofenac (1% diclofenac group, (5 mgKg-1 ibuprofen (0.5% ibuprofen group, and (5 mgKg-1 (0.5% diclofenac group respectively for 4 weeks. After the 4th week all diets were changed to control diet. At the end of 12-weeks, no significant differences were found in growth rate (GR between diets (p>0.05. Mortality ranged from 1.67% +- 2.89 (SD, n=3 in control group to 58.3% +- 14.4 (SD, n=3 in the 1% diclofenac group during the experimental feeding and from 6.67+-2.89 (SD, n=3 to 63.3%+-10.4 (SD, n=3 at the end of 12-weeks period. 7% In the control group, 36% in the 1% diclofenac group, 17% in the 0.5% ibuprofen group, and 22.2% in the 0.5% diclofenac group respectively never produced egg during the entire experimental period. Macroscopically all the nonspawning fish in the experimental groups were females with apparently larger ovaries and full of eggs compared to control. Microscopically they were full of apparently normal eggs with morphology

  17. The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination

    International Nuclear Information System (INIS)

    Background and purpose: RAD51 is a key protein involved in homologous recombination (HR) and a potential target for radiation- and chemotherapies. Amuvatinib (formerly known as MP470) is a novel receptor tyrosine kinase inhibitor that targets c-KIT and PDGFRα and can sensitize tumor cells to ionizing radiation (IR). Here, we studied amuvatinib mechanism on RAD51 and functional HR. Materials and methods: Protein and RNA analyses, direct repeat green fluorescent protein (DR-GFP) assay and polysomal fractioning were used to measure HR efficiency and global translation in amuvatinib-treated H1299 lung carcinoma cells. Synergy of amuvatinib with IR or mitomycin c (MMC) was assessed by clonogenic survival assay. Results: Amuvaninib inhibited RAD51 protein expression and HR. This was associated with reduced ribosomal protein S6 phosphorylation and inhibition of global translation. Amuvatinib sensitized cells to IR and MMC, agents that are selectively toxic to HR-deficient cells. Conclusions: Amuvatinib is a promising agent that may be used to decrease tumor cell resistance. Our work suggests that this is associated with decreased RAD51 expression and function and supports the further study of amuvatinib in combination with chemotherapy and radiotherapy.

  18. Glycemic Effectiveness of Metformin-Based Dual-Combination Therapies with Sulphonylurea, Pioglitazone, or DPP4-Inhibitor in Drug-Naïve Korean Type 2 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Young Ki Lee

    2013-12-01

    Full Text Available BackgroundThis study compared the glycemic effectiveness of three metformin-based dual therapies according to baseline hemoglobin A1c (HbA1c to evaluate the appropriateness of the guideline enforced by the National Health Insurance Corporation of Korea for