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Sample records for inhibitor rad001 everolimus

  1. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001).

    Druce, M R; Kaltsas, G A; Fraenkel, M; Gross, D J; Grossman, A B

    2009-09-01

    Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.

  2. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A; Goff, D J; Kiyoi, H; Naoe, T

    2011-01-01

    In Ph-positive (Ph + ) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph + acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ null (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G 0 cells in the CD34 + CD38 − population compared with the CD34 + CD38 + and CD34 − populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34 + CD38 − population than in the other populations. Although slow-cycling G 0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34 + CD38 − population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34 + cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph + leukemia due to quiescence

  3. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Goff, D J [Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA (United States); Kiyoi, H [Department of Infectious Diseases, Nagoya University Hospital, Nagoya (Japan); Naoe, T [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2011-05-01

    In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +} leukemia due to quiescence.

  4. RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

    Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org [Department of Radiation Oncology, Experimental Therapeutics and Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida (United States); Won, Minhee [Radiation Therapy Oncology Group, Philadelphia, Pennsylvania (United States); Wen, Patrick Y. [Center for Neuro-Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, Massachusetts (United States); Rojiani, Amyn M. [Department of Pathology, Medical College of Georgia, Augusta, Georgia (United States); Wendland, Merideth [Radiation Oncology, US Oncology-Willamette Valley Cancer Institute, Eugene, Oregon (United States); Dipetrillo, Thomas A. [Department of Radiation Oncology, Rhode Island Hospital, Providence, Rhode Island (United States); Corn, Benjamin W. [Department of Radiation Oncology, Tel Aviv Medical Center, Tel Aviv (Israel); Mehta, Minesh P. [Department of Radiation Oncology, University of Maryland, Baltimore, Maryland (United States)

    2013-08-01

    Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.

  5. A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL.

    Decker, Thomas; Sandherr, Michael; Goetze, Katharina; Oelsner, Madlen; Ringshausen, Ingo; Peschel, Christian

    2009-03-01

    Although B-cell chronic lymphocytic leukemia (CLL) is treatable, it remains an incurable disease and most patients inevitably suffer relapse. Many therapeutic options exist for those requiring therapy, including monoclonal antibodies and stem cell transplantation, but remissions tend to last shorter in the course of the disease. Targeting the cell cycle has recently been realized to be an attractive therapeutic approach in solid and hematological malignancies, and the proliferative nature of B-CLL is increasingly accepted. Here, we report data on a phase II pilot trial with the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 5 mg/daily in patients with advanced B-CLL who had progressive disease after at least two lines of treatment. After treatment of seven patients, this trial was stopped because of toxicity concerns, although some degree of activity was observed (one partial remission, three patients with stable disease). Interestingly, cyclin E expression decreased in responding patients. Further strategies of mTOR inhibition by RAD001 in B-CLL should focus on different treatment schedules, adequate anti-infectious prophylaxis, or combinations with cytotoxic drugs.

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

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

    2016-01-01

    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. In this study we utilized two AI-resistant breast cancer cell lines, MCF-7:5C and MCF-7:2A, which were clonally derived from estrogen receptor positive (ER+) MCF-7 breast cancer cells following long-term estrogen deprivation. Cell viability assay, colony formation assay, cell cycle analysis and soft agar anchorage-independent growth assay were used to determine the efficacy of everolimus in inhibiting the proliferation and tumor forming potential of MCF-7, MCF-7:5C, MCF-7:2A and MCF10A cells. Confocal microscopy and transmission electron microscopy were used to evaluate LC3-II production and autophagosome formation, while ERE-luciferase reporter, Western blot, and RT-PCR analyses were used to assess ER expression and transcriptional activity. Everolimus inhibited the proliferation of MCF-7:5C and MCF-7:2A cells with relatively equal efficiency to parental MCF-7 breast cancer cells. The inhibitory effect of everolimus was due to G1 arrest as a result of downregulation of cyclin D1 and p21. Everolimus also dramatically reduced estrogen receptor (ER) expression (mRNA and protein) and transcriptional activity in addition to the ER chaperone, heat shock protein 90 protein (HSP90). Everolimus restored 4-hydroxy-tamoxifen (4OHT) sensitivity in MCF-7:5C cells and enhanced 4OHT sensitivity in MCF-7 and MCF-7:2A cells. Notably, we found that autophagy is one method of everolimus insensitivity in MCF-7 breast cancer cell lines. This study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as

  7. Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

    Zeng, Yizhou; Tian, Xiaofang; Wang, Quan; He, Weiyang; Fan, Jing; Gou, Xin

    2018-01-01

    Aim The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway. Methods and results: RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis. Conclusion These results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001. PMID:29719377

  8. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial

    Gullestad, Lars; Iversen, Martin; Mortensen, Svend-Aage

    2010-01-01

    The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking.......The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking....

  9. The Role of Everolimus in Renal Cell Carcinoma

    Malek Meskawi

    2015-12-01

    Full Text Available Everolimus (RAD001 is an orally administered agent that inhibits the mammalian target of rapamycin serine-threonine kinase. A phase III pivotal trial on everolimus, published in 2008, provided the first evidence for the efficacy of sequential therapy for patients with metastatic clear cell renal cell carcinoma (RCC. In this study, everolimus was used after failure of one or several previous lines of therapy, and it demonstrated a 3-month survival benefit relative to placebo. Currently, based on the level 1 evidence, everolimus represents the molecule of choice for third-line therapy after failure of previous two tyrosine kinase inhibitors (TKIs. However, second-line use after failure of one TKI is challenged by two new molecules (nivolumab and cabozantinib, which proved to have better efficacy with similar toxicity profile. In non-clear cell metastatic RCC, the current evidence recommends everolimus as a second-line therapy after failure of previous first-line sunitinib.

  10. Everolimus

    ... that last several days; headaches; seizures; confusion; or personality changes.Everolimus may cause a blood clot in ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

  11. Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients

    Andreassen, A K; Andersson, B; Gustafsson, F

    2016-01-01

    In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal...... events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow...

  12. Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation

    T. van Gelder (Teun); L. Fischer (Lutz); Shihab, F. (Fuad); M. Shipkova (Maria)

    2017-01-01

    textabstractThe mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for

  13. Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology.

    Gabardi, Steven; Baroletti, Steven A

    2010-10-01

    Everolimus, a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) drug class, has many clinical applications, including in organ transplantation, oncology, and cardiology. It currently has United States Food and Drug Administration (FDA) approval for prophylaxis against rejection in de novo renal transplant recipients, treatment of renal cell carcinoma, and use as a drug-eluting stent. To review the pharmacology, pharmacokinetics, efficacy, and safety of everolimus, we performed a search of the MEDLINE database (January 1997-April 2010) for all English-language articles of in vitro and in vivo studies that evaluated everolimus, as well as abstracts from recent scientific meetings and the manufacturer. In transplantation, everolimus demonstrates immunosuppressive properties and has been used to prevent acute rejection in cardiac, liver, lung, and renal transplant recipients. It appears that this agent may be potent enough to allow for the minimization or removal of calcineurin inhibitors in the long-term management of renal transplant recipients. In oncology, everolimus has been proven effective for the management of treatment-resistant renal cell carcinoma. In cardiology, everolimus is available as a drug-coated stent and is used in percutaneous coronary interventions for prevention of restenosis. In transplant recipients and patients with renal cell carcinoma, everolimus appears to have an extensive adverse-event profile. The pharmacologic properties of everolimus differentiate this agent from other drugs used in these clinical areas, and its pharmacokinetic properties differentiate it from sirolimus.

  14. Two-year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open-label, randomized trial

    Gullestad, Lars; Mortensen, Svend-Aage; Eiskjær, Hans

    2010-01-01

    Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required....

  15. Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial lv

    Gullestad, Lars; Eiskjaer, Hans; Gustafsson, Finn

    2016-01-01

    The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus...

  16. Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation : Results of the randomized ELEVATE trial

    de Fijter, Johan W; Holdaas, Hallvard; Øyen, Ole; Sanders, Jan Stephan; Sundar, Sankaran; Bemelman, Frederike J; Sommerer, Claudia; Pascual, Julio; Avihingsanon, Yingyos; Pongskul, Cholatip; Oppenheimer, Frederic; Toselli, Lorenzo; Russ, Graeme; Wang, Zailong; Lopez, Patricia; Kochuparampil, Jossy; Cruzado, Josep M; van der Giet, Markus

    In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n=359) or remain on standard calcineurin inhibitor (CNI) therapy (n=356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and

  17. Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients

    Arora, Satish; Gude, Einar; Sigurdardottir, Vilborg

    2012-01-01

    The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated...... NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure....

  18. Renal function three years after early conversion from a calcineurin inhibitor to everolimus

    Mjörnstedt, Lars; Schwartz Sørensen, Søren; von Zur Mühlen, Bengt

    2015-01-01

    In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to mo......, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post-transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued....

  19. Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib

    Chris Coppin

    2010-04-01

    Full Text Available Chris CoppinMedical Oncology, BC Cancer Agency and University of British Columbia, Vancouver, CanadaAbstract: Everolimus (RAD001, Afinitor® Novartis is the first oral inhibitor of mTOR (mammalian target of rapamycin to reach the oncology clinic. Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients. A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib. The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001 and 25% were still progression-free after 10 months of everolimus therapy. There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo. In 2009, everolimus was approved in the US and Europe as the only validated option for this indication. Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary. Opportunistic infections and non-infectious pneumonitis are seen as a class effect. Management of common practical management issues are discussed. Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.Keywords: everolimus, drug therapy, advanced renal cancer

  20. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients

    Andreassen, A K; Andersson, B; Gustafsson, F

    2014-01-01

    In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3–6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59...... infection was less common with everolimus (5.4% vs. 30.5%, p heart transplantation. Since postoperative safety...

  1. Role of everolimus in the treatment of renal cell carcinoma

    Saby George

    2009-08-01

    Full Text Available Saby George1, Ronald M Bukowski21University of Texas Health Sciences Center, MC-8221, Division of Hematology and Oncology, San Antonio, Texas, USA; 2CCF Lerner College of Medicine Division of Hematology and Oncology, Cleveland, Ohio, USAAbstract: The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC. Everolimus (RAD 001 is an oral inhibitor of the mammalian target of rapamycin (mTOR pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1 conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P ≤ 0 0.001. Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.Keywords: mTOR inhibitor, mammalian target of rapamycin inhibitor, signal transduction inhibitor, renal cell carcinoma, targeted therapy

  2. A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor.

    Gurk-Turner, Cheryle; Manitpisitkul, Wana; Cooper, Matthew

    2012-10-15

    As new immunosuppressive agents are introduced to the market, clinicians are faced with the daunting task of sifting through the published literature to decide the value that the agent will add to their own practice. We often must extrapolate information provided through study in other solid-organ transplantation populations than our specific area of interest as we interpret the results and outcomes. With these challenges in mind, this compilation of published work for the newest mammalian target of rapamycin inhibitor everolimus (Certican; Novartis Pharmaceuticals, Hanover, NJ) (Zortress; Novartis Pharmaceuticals, Basel, Switzerland) is intended to provide a concise but thorough presentation of available literature so that the reader who may be unfamiliar with the agent can make their own judgment. Both Ovid and PubMed search engines were queried with a particular focus on high-impact articles noted in the Web of Science or Citation Index. Work described solely in abstract or case report form was excluded, as well as meta-analyses or those that were editorial or commentary in nature. Included were publications presented using the English language that described adult human subjects who received a heart, lung, kidney, or liver allograft. The goal of this strategy was to allow for the inclusion of pertinent literature in an unbiased fashion. Tables are provided that outline trial specific information, leaving a discussion of major outcomes to the text of the review.

  3. Improved renal function after early conversion from a calcineurin inhibitor to everolimus

    Mjörnstedt, L; Sørensen, S S; von Zur Mühlen, B

    2012-01-01

    .2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All......In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids...... controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent....

  4. Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials.

    Bono, Petri; Oudard, Stephane; Bodrogi, Istvan; Hutson, Thomas E; Escudier, Bernard; Machiels, Jean-Pascal; Thompson, John A; Figlin, Robert A; Ravaud, Alain; Basaran, Mert; Porta, Camillo; Bracarda, Sergio; Brechenmacher, Thomas; Lin, Chinjune; Voi, Maurizio; Grunwald, Viktor; Motzer, Robert J

    2016-10-01

    Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies. Copyright

  5. Effect of everolimus initiation and early calcineurin inhibitor withdrawal on myocardial FOXP3+ regulatory T cells in heart transplantation

    Mirza, Kiran; Gustafsson, Finn; Gullestad, Lars

    2016-01-01

    BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We hypothes......BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We...... hypothesized treatment with everolimus reduced the risk of CAV by modulating myocardial FoxP3 levels. METHODS: 15 patients from the Schedule trial comparing everolimus, MMF, steroid and early CNI (Everolimus, n=8) withdrawal to conventional CNI based immunosuppression (Controls, n=7) after de novo HTx were...

  6. The role of mTOR inhibitors in the prevention of organ rejection in adult liver transplant patients: a focus on everolimus

    Casanovas T

    2014-06-01

    Full Text Available Teresa Casanovas Liver Transplant Unit, Bellvitge University Hospital, Barcelona, Spain Abstract: Liver transplantation remains the therapy of choice for patients with end-stage liver disease and in selected cases of hepatocellular carcinoma. While short-term allograft survival has improved significantly in recent years, there has been little improvement in long-term survival after liver transplantation. A growing body of evidence on factors influencing the long-term outcomes and the safety profiles of existing immunosuppressive agents after liver transplant points to a need to continue searching for alternative strategies. The calcineurin inhibitors (CNIs (cyclosporine and tacrolimus currently represent the backbone of most immunosuppressor regimens. They have had a revolutionary effect on the overall success of transplantation, as is reflected in greatly reduced rates of acute rejection. However, the CNIs have significant toxicities that produce renal dysfunction, cardiovascular disease, and other unwanted effects, such as malignancies. The recognition of these risk factors has sparked interest in regimens that limit exposure to CNIs. Nowadays, the use of immunosuppressive drugs with different mechanisms of action, which allow for a reduction or avoidance of CNIs, is common. Everolimus, which belongs to the mammalian target-of-rapamycin inhibitor family and is best known for its use in kidney and heart transplantation, has recently been approved for liver transplantation. This overview discusses the emerging evidence on the role of everolimus in the prevention of rejection after liver transplantation, in de novo transplants, conversion regimens, or as a rescue therapy. In addition, some of the most relevant and current clinical problems related to everolimus in this field are discussed. Keywords: everolimus, mTOR inhibitors, tacrolimus, liver transplant, cyclosporine, renal impairment

  7. Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature

    Patricia Lopez

    2014-01-01

    Full Text Available Interstitial lung disease (ILD has been reported with the use of mammalian target of rapamycin inhibitors (mTORi. The clinical and safety databases of three Phase III trials of everolimus in de novo kidney (A2309, heart (A2310, and liver (H2304 transplant recipients (TxR were searched using a standardized MedDRA query (SMQ search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

  8. The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease

    Frentzel Stefan

    2010-06-01

    Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD. In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD. Results Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels. Conclusions Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.

  9. Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients.

    Pacheco, Larissa Sgaria; Garcia, Valter Duro; Prá, Ronivan Luis Dal; Cardoso, Bruna Doleys; Rodrigues, Mariana Ferras; Zanetti, Helen Kris; Meinerz, Gisele; Neumann, Jorge; Gnatta, Diego; Keitel, Elizete

    2018-05-14

    Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 =15 and control group, Group 2 =13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M= 0.852), overtime intra-groups (p-value M=0.889) and between group (p-value G=0.286). Group 1 showed a higher incidence of dyslipidemia (p=0.03) and proteinuria events (p=0.01), while no difference was observed in the incidence of anemia (p=0.17), new onset of post-transplant diabetes mellitus (p=1.00) or urinary tract infection (p=0.60). The mean eGFR was similar in both groups. Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy.

  10. Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis.

    Wei-Xiang Qi

    Full Text Available BACKGROUND: Two novel mammalian targets of rapamycin (mTOR inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs with these drugs is not well defined. METHODS: We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs by using either random effects or fixed effect models according to the heterogeneity of the included studies. RESULTS: A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%, and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%. Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p = 0.019. On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed. CONCLUSION: With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

  11. Everolimus in Heart Transplantation: An Update

    Stephan W. Hirt

    2013-01-01

    Full Text Available The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

  12. A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.

    Werner, Theresa L; Wade, Mark L; Agarwal, Neeraj; Boucher, Kenneth; Patel, Jesal; Luebke, Aaron; Sharma, Sunil

    2015-12-01

    JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22%, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.

  13. Regression of Cardiac Rhabdomyomas in a Neonate after Everolimus Treatment

    Helen Bornaun

    2016-01-01

    Full Text Available Cardiac rhabdomyoma often shows spontaneous regression and usually requires only close follow-up. However, patients with symptomatic inoperable rhabdomyomas may be candidates for everolimus treatment. Our patient had multiple inoperable cardiac rhabdomyomas causing serious left ventricle outflow-tract obstruction that showed a dramatic reduction in the size after everolimus therapy, a mammalian target of rapamycin (mTOR inhibitor. After discontinuation of therapy, an increase in the diameter of masses occurred and everolimus was restarted. After 6 months of treatment, rhabdomyomas decreased in size and therapy was stopped. In conclusion, everolimus could be a possible novel therapy for neonates with clinically significant rhabdomyomas.

  14. Fatal acute pulmonary injury associated with everolimus.

    Depuydt, Pieter; Nollet, Joke; Benoit, Dominique; Praet, Marleen; Caes, Frank

    2012-03-01

    To report a case of fatal alveolar hemorrhage associated with the use of everolimus in a patient who underwent a solid organ transplant. In a 71-year-old cardiac transplant patient, cyclosporine was replaced with everolimus because of worsening renal function. Over the following weeks, the patient developed nonproductive cough and increasing dyspnea. His condition deteriorated to acute respiratory failure with hemoptysis, requiring hospital admission. Bilateral patchy alveolar infiltrates were apparent on chest X-ray and computed tomography. Cardiac failure was ruled out and empiric antimicrobial therapy was initiated. Additional extensive workup could not document opportunistic infection. Everolimus was discontinued and high-dose corticosteroid therapy was initiated. Despite this, the patient required invasive mechanical ventilation and died because of refractory massive hemoptysis. Autopsy revealed diffuse alveolar hemorrhage. Everolimus is a mammalian target of rapamycin inhibitor approved for use as an immunosuppressant and antineoplastic agent. Its main advantage over calcineurin inhibitors (tacrolimus and cyclosporine) is a distinct safety profile. Although it has become clear that everolimus induces pulmonary toxicity more frequently than initially thought, most published cases thus far represented mild and reversible disease, and none was fatal. Here, we report a case of pulmonary toxicity developing over weeks following the introduction of everolimus, in which a fatal outcome could not be prevented by drug withdrawal and corticosteroid treatment. The association of everolimus and this syndrome was probable according to the Naranjo probability scale. This case indicates that with the increasing use of everolimus, clinicians should be aware of the rare, but life-threatening manifestation of pulmonary toxicity.

  15. Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma

    Li, Siming; Kong, Yan; Si, Lu; Chi, Zhihong; Cui, Chuanliang; Sheng, Xinan; Guo, Jun

    2014-01-01

    The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment. Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules. In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of

  16. ELEVATE: an innovative study design to assess the efficacy, safety, and evolution of cardiovascular parameters in de novo kidney transplant recipients after early conversion from a calcineurin inhibitor to everolimus

    van der Giet M

    2014-03-01

    Full Text Available Markus van der Giet,1 Josep M Cruzado,2 Johan W de Fijter,3 Hallvard Holdaas,4 Zailong Wang,5 Antonio Speziale,6 Guido Junge61Department of Nephrology, Campus Benjamin Franklin, Charite'-Universitätsmedizin, Berlin, Germany; 2Department of Nephrology, University Hospital of Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain; 3Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; 4Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 5Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, NJ, USA; 6Research and Development, Novartis Pharma AG, Basel, SwitzerlandAbstract: Progressive decline in allograft function and cardiovascular mortality after kidney transplantation remain major clinical challenges that can potentially be addressed by the mammalian target of rapamycin (mTOR inhibitors, everolimus and sirolimus. mTOR inhibitors maintain immunosuppressive efficacy after minimization of calcineurin inhibitor (CNI therapy and can achieve significant long-term improvements in renal function. Recently, data have accumulated that suggest mTOR inhibitors may offer cardioprotective effects. In animal models, inhibition of mTOR leads to regression of cardiac hypertrophy, and the limited data consistently point to a remodeling benefit following heart transplantation. Experimentally, mTOR inhibitors restrict atherogenesis, confirmed clinically by intravascular ultrasound data demonstrating lower rates of transplant vasculopathy in heart transplant recipients on everolimus. Lastly, mTOR inhibitors appear to ameliorate arterial stiffness, a known risk factor for post-transplant cardiovascular events, but data remain sparse. The ELEVATE study will examine the renal effect of early conversion from CNI therapy to everolimus after kidney transplantation. Key secondary endpoints include the change in left ventricular mass index, the first time

  17. A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients

    Erp, N.P. van; Herpen, C.M. van; Wit, D. de; Willemsen, A.; Burger, D.M.; Huitema, A.D.; Kapiteijn, E.; Heine, R. ter

    2016-01-01

    INTRODUCTION AND OBJECTIVE: Everolimus (a drug from the class of mammalian target of rapamycin [mTOR] inhibitors) is associated with frequent toxicity-related dose reductions. Everolimus accumulates in erythrocytes, but the extent to which hematocrit affects everolimus plasma pharmacokinetics and

  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

    Guo, Jun; Straub, Patrick; Pirotta, Nicoletta; Gogov, Sven; Huang, Yiran; Zhang, Xu; Zhou, Fangjian; Sun, Yinghao; Qin, Shukui; Ye, Zhangqun; Wang, Hui; Jappe, Annette

    2013-01-01

    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. Everolimus for Advanced Pancreatic Neuroendocrine Tumors.

    Yao, James C.; Shah, Manisha H.; Ito, Tetsuhide; Bohas, Catherine Lombard; Wolin, Edward M.; Van Cutsem, Eric; Hobday, Timothy J.; Okusaka, Takuji; Capdevila, Jaume; de Vries, Elisabeth G. E.; Tomassetti, Paola; Pavel, Marianne E.; Hoosen, Sakina; Haas, Tomas; Lincy, Jeremie; Lebwohl, David; Oberg, Kjell

    2011-01-01

    Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. Methods: We randomly assigned 410

  20. Everolimus: a review of its pharmacologic properties and use in solid organ transplantation

    Paul Huiras

    2011-10-01

    Full Text Available The aim of this review article is to review the pharmacology, pharmacokinetics, efficacy and safety of everolimus. Primary literature was obtained via MEDLINE. Studies and abstracts evaluating everolimus in solid organ transplantation were considered for evaluation. English-language studies and abstracts only were selected for inclusion. Everolimus, a proliferation signal inhibitor that prevents growth factor-induced cell proliferation, is effective in reducing the incidence of acute rejection in solid organ transplantation. This agent is also useful in reducing cyclosporine-related nephrotoxicity. Everolimus directly inhibits vascular remodelling and intimal thickening, which are often associated with chronic rejection. Clinical trials have shown that everolimus is generally safe. The most commonly reported adverse events were haematologic effects and hyperlipidaemia. Everolimus is the second proliferation signal inhibitor to be proven effective in preventing acute rejection in solid organ transplant recipients. However, its exact role in the transplant immunosuppressive armamentarium is still unknown.

  1. Everolimus: a review of its pharmacologic properties and use in solid organ transplantation

    Huiras, Paul; Gabardi, Steven

    2011-01-01

    The aim of this review article is to review the pharmacology, pharmacokinetics, efficacy and safety of everolimus. Primary literature was obtained via MEDLINE. Studies and abstracts evaluating everolimus in solid organ transplantation were considered for evaluation. English-language studies and abstracts only were selected for inclusion. Everolimus, a proliferation signal inhibitor that prevents growth factor-induced cell proliferation, is effective in reducing the incidence of acute rejectio...

  2. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

    Motzer, Robert J; Escudier, Bernard; McDermott, David F

    2015-01-01

    BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus...... of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. RESULTS: The median overall survival was 25.0 months (95% confidence...... interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate...

  3. Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

    Penttilä, P; Donskov, F; Rautiola, J

    2017-01-01

    BACKGROUND: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: Eighty-five mRCC patients received everolimus at Helsinki University...

  4. Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells

    Ariaans, Gerke; Jalving, Mathilde; de Vries, Emma Geertruida Elisabeth; de Jong, Steven

    2017-01-01

    Background: Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We

  5. Research and innovation in the development of everolimus for oncology.

    Lebwohl, David; Thomas, George; Lane, Heidi A; O'Reilly, Terence; Escudier, Bernard; Yao, James C; Pavel, Marianne; Franz, David; Berg, William; Baladi, Jean-Francois; Stewart, Jubilee; Motzer, Robert J

    2011-03-01

    The critical role of increased activity of mammalian target of rapamycin (mTOR) in the pathophysiology of multiple diseases is well established. Inhibition of the mTOR pathway may block disease progression and improve patient outcomes. Everolimus, an mTOR inhibitor, began in clinical development as part of a regimen (Certican, Zortress) for prevention of organ transplant rejection and is now an approved oncology agent. The objective of this review is to discuss the history of key findings and innovative cancer research undertaken to successfully develop everolimus as an oncology therapy (Afinitor) now approved for patients with advanced renal cell carcinoma (RCC) and for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis. In addition, data for the use of everolimus in the treatment of other cancers and rare diseases are also discussed. A PubMed search of English articles without time restrictions was conducted using the search terms 'everolimus or rapamycin' and 'cancer'. Bibliographies of retrieved articles were manually searched for additional relevant articles. Major cancer congresses were also searched. The clinical efficacy of everolimus alone and in combination with other agents has been observed in recently completed Phase II-III studies in a wide spectrum of tumors, including RCC, neuroendocrine tumors, tuberous sclerosis complex, SEGAs and angiomyolipomas, lymphoma and gastric, breast and hepatocellular cancers. These findings emphasize the importance of mTOR in diverse cancers and rare diseases and underscore the potential role for everolimus as an effective agent in multiple indications.

  6. A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

    Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

    2018-02-01

    Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

  7. Everolimus Implicated in Case of Severe Gastrointestinal Hemorrhage

    Paul Gonzales

    2017-01-01

    Full Text Available Breast cancer remains the leading cause of cancer and the third leading cause of cancer related deaths among our population with an estimated number of 246,660 new cases and 40,450 deaths in 2016. With treatment advancements, including targeted agents such as Everolimus, a mammalian target of rapamycin (mTOR inhibitor, survivability and quality of life continue to improve. However, with the use of these agents come adverse effects, some of which are still being characterized. Our case demonstrates recurrent episodes of gastrointestinal bleeding in a 60-year-old woman being treated with Everolimus for progressive metastatic breast cancer. On endoscopy, bleeding was secondary to erosive gastritis. Previous case reports have described bleeding due to gastric antral vascular ectasia (GAVE, which was described in two prior reported cases. In our case, bleeding also occurred on a reduced dose of Everolimus compared to what is previously reported (5 mg versus 10 mg. As a result of her gastrointestinal bleeding, she required multiple endoscopic interventions including argon plasma coagulation and multipolar heater probe to achieve hemostasis. This is the first case reported of gastrointestinal bleeding not consistent with GAVE and occurring while being on a reduced dose of Everolimus. It is important to document our case so that the Gastroenterology and Hematology communities can be educated and made aware for their patient populations on Everolimus.

  8. Recommendations for use of everolimus after heart transplantation: results from a Latin-American Consensus Meeting.

    Bocchi, E A; Ahualli, L; Amuchastegui, M; Boullon, F; Cerutti, B; Colque, R; Fernandez, D; Fiorelli, A; Olaya, P; Vulcado, N; Perrone, S V

    2006-04-01

    Despite improvements during the last decades, heart transplantation remains associated with several medical complications, which limit clinical outcomes: acute rejection with hemodynamic compromise, cytomegalovirus (CMV) infections, allograft vasculopathy, chronic renal failure, and neoplasias. Everolimus, a proliferation signal inhibitor, represents a new option for adjunctive immunosuppressive therapy. Everolimus displays better efficacy in de novo heart transplant patients than azathioprine for prophylaxis of biopsy-proven acute rejection episodes of at least ISHLT grade 3A (P Latin America produced recommendations for everolimus use in daily practice based on available data and their own experience.

  9. Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas.

    Moavero, Romina; Carai, Andrea; Mastronuzzi, Angela; Marciano, Sara; Graziola, Federica; Vigevano, Federico; Curatolo, Paolo

    2017-03-01

    Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Glycolysis in Panc-1 human pancreatic cancer cells is inhibited by everolimus.

    Liu, Ling; Gong, Liansheng; Zhang, Yangde; Li, Nianfeng

    2013-01-01

    The aim of this study was to evaluate the effects and molecular mechanisms of everolimus on Panc-1 human pancreatic cancer cells. Panc-1 human pancreatic cancer cells were treated with everolimus (10 μg/ml) at selected time points (6, 12 and 24 h). Cell proliferation and apoptosis were evaluated by MTT and flow cytometric analyses. The glycolytic activity was determined by measuring the activity of the key enzyme lactate dehydrogenase (LDH) and lactate production. The activity of mammalian target of rapamycin (mTOR) signaling was measured by western blotting. The expression of genes, including hexokinase 2 (HK2) and microRNA-143 (miR-143), was evaluated by real-time polymerase chain reaction (PCR). The administration of everolimus time-dependently inhibited proliferation and glycolysis and induced apoptosis in the Panc-1 human pancreatic cancer cells. As the time of treatment with everolimus increased, the mTOR signaling activity decreased, indicated by lower phosphorylation levels of S6 kinase; however, the phosphorylation levels of mTOR barely changed. Moreover, our data showed an everolimus-induced increase in miR-143 and decrease in HK2 in Panc-1 cells in a time-dependent manner. In conclusion, the current study indicates a novel role of everolimus in its antitumor effect as an inhibitor of glycolysis in Panc-1 human pancreatic cancer cells. Furthermore, our data highlights the significance of exploring the mechanisms of everolimus and miR-143 in malignant tumors.

  11. 18F-FDG and 18F-FLT-PET Imaging for Monitoring Everolimus Effect on Tumor-Growth in Neuroendocrine Tumors

    Johnbeck, Camilla Bardram; Munk Jensen, Mette; Nielsen, Carsten Haagen

    2014-01-01

    INTRODUCTION: The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors...

  12. Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer.

    Tomas Pascual

    Full Text Available Metastatic breast cancer (MBC progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs on outcomes from this treatment through a pharmacogenetic analysis.Blood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities, dose reductions or treatment suspensions due to toxicity, progression free survival (PFS and overall survival.We found that CYP3A4 rs35599367 variant (CYP3A4*22 allele carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019. ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031, while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively. Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006.CYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

  13. [The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer].

    Jerusalem, G; Rorive, A; Collignon, J

    2014-09-01

    Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

  14. Clinical evidence of the efficacy of everolimus and its potential in the treatment of breast cancer

    Saksena R

    2013-05-01

    Full Text Available Rujuta Saksena, Serena T WongThe Cancer Institute of New Jersey, New Brunswick, NJ, USAAbstract: The PI3K/Akt/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway regulates several key cellular functions and its dysregulation creates an environment that promotes tumorigenesis as well as resistance to therapy. The mTOR inhibitor everolimus has emerged as a promising agent in the treatment of breast cancer and was recently approved in combination with exemestane for advanced hormone receptor–positive disease after progression on a nonsteroidal aromatase inhibitor. Everolimus may also be effective in combination with cytotoxic and human epidermal growth factor receptor-2-directed therapies for the treatment of other subtypes of breast cancer. This paper highlights preclinical and clinical data that have emerged on the role of mTOR inhibition in breast cancer. Although generally well tolerated, everolimus carries a unique side effect profile of which both patients and providers should be made aware. Recommendations related to the administration of everolimus in the clinical setting are also discussed.Keywords: everolimus, breast cancer, mTOR inhibition

  15. Recommendations of everolimus use in liver transplant.

    Rubín Suárez, Angel; Bilbao Aguirre, Itxarone; Fernández-Castroagudin, Javier; Pons Miñano, José Antonio; Salcedo Plaza, Magdalena; Varo Pérez, Evaristo; Prieto Castillo, Martín

    2017-11-01

    Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice. Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.

  16. Everolimus for Advanced Pancreatic Neuroendocrine Tumours: A Subgroup Analysis Evaluating Japanese Patients in the RADIANT-3 Trial

    Ito, Tetsuhide; Okusaka, Takuji; Ikeda, Masafumi; Igarashi, Hisato; Morizane, Chigusa; Nakachi, Kohei; Tajima, Takeshi; Kasuga, Akio; Fujita, Yoshie; Furuse, Junji

    2012-01-01

    Objective Everolimus, an inhibitor of the mammalian target of rapamycin, has recently demonstrated efficacy and safety in a Phase III, double-blind, randomized trial (RADIANT-3) in 410 patients with low- or intermediate-grade advanced pancreatic neuroendocrine tumours. Everolimus 10 mg/day provided a 2.4-fold improvement compared with placebo in progression-free survival, representing a 65% risk reduction for progression. The purpose of this analysis was to investigate the efficacy and safety of everolimus in the Japanese subgroup enrolled in the RADIANT-3 study. Methods Subgroup analysis of the Japanese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17). The primary endpoint was progression-free survival. Safety was evaluated on the basis of the incidence of adverse drug reactions. Results Progression-free survival was significantly prolonged with everolimus compared with placebo. The median progression-free survival was 19.45 months (95% confidence interval, 8.31–not available) with everolimus vs 2.83 months (95% confidence interval, 2.46–8.34) with placebo, resulting in an 81% risk reduction in progression (hazard ratio, 0.19; 95% confidence interval, 0.08–0.48; P< 0.001). Adverse drug reactions occurred in all 23 (100%) Japanese patients receiving everolimus and in 13 (77%) patients receiving placebo; most were grade 1/2 in severity. The most common adverse drug reactions in the everolimus group were rash (n = 20; 87%), stomatitis (n = 17; 74%), infections (n = 15; 65%), nail disorders (n = 12; 52%), epistaxis (n = 10; 44%) and pneumonitis (n = 10; 44%). Conclusions These results support the use of everolimus as a valuable treatment option for Japanese patients with advanced pancreatic neuroendocrine tumours. PMID:22859827

  17. Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

    Helio Tedesco-Silva Jr

    2011-01-01

    , mainly to preserve renal function and to manage patients with malignancy. There is no definition of the ideal strategy for conversion, ie, abrupt or sequential, initial dose of everolimus, or target therapeutic trough blood concentrations. Intensive monitoring is recommended after conversion, especially for acute rejection and proteinuria. Because mTOR is ubiquitous and central to many intracellular processes, an array of adverse reactions may occur, including delayed tissue regeneration, proteinuria, dyslipidemia, diabetes, myelosuppression, infertility, ovarian cysts, and mouth ulcers. Because long-term benefits are the goal of any immunosuppressive strategy, further investigations aiming to understand, prevent, and manage everolimus-related adverse reactions are necessary to mitigate the risks and improve tolerability, allowing maximization of all the benefits of this drug.Keywords: everolimus, immunosuppression, mTOR inhibitors, calcineurin inhibitors, kidney transplantation

  18. Patient-reported outcomes in a phase iii study of everolimus versus placebo in patients with metastatic carcinoma of the kidney that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.

    Beaumont, Jennifer L; Butt, Zeeshan; Baladi, Jeanfrancois; Motzer, Robert J; Haas, Tomas; Hollaender, Norbert; Kay, Andrea; Cella, David

    2011-01-01

    A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes. Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo. The Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) and European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 were administered before randomization and on day 1 of each cycle. The FKSI-DRS and the EORTC QLQ-C30 Physical Functioning and Global Quality of Life scores were the primary endpoints examined. Longitudinal models were used to compare treatment arms. Sensitivity analyses were conducted to explore the impact of missing data assumptions. Longitudinal trends for FKSI-DRS scores did not differ by treatment arm. Taking nonignorable missing data into account, there were significant differences between treatment arms in the trend over time for physical functioning and global quality of life, with the everolimus arm exhibiting greater decreases. All three of these measures of health-related quality of life were significantly related to progression-free survival. There was no evidence of a difference between everolimus and placebo in longitudinal patterns of disease-related symptoms, and little difference between the arms in physical functioning or global quality of life trends. This supports the conclusion that delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning, or quality of life, as reported by patients.

  19. Wound complications and surgical events in de novo heart transplant patients treated with everolimus

    Rashidi, Mitra; Esmaily, Sorosh; Fiane, Arnt E

    2016-01-01

    OBJECTIVES: The use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin...

  20. The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation.

    Deuse, Tobias; Bara, Christoph; Barten, Markus J; Hirt, Stephan W; Doesch, Andreas O; Knosalla, Christoph; Grinninger, Carola; Stypmann, Jörg; Garbade, Jens; Wimmer, Peter; May, Christoph; Porstner, Martina; Schulz, Uwe

    2015-11-01

    In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

    Huijts, Charlotte M; Santegoets, Saskia J; Eertwegh, Alfons J van den; Pijpers, Laura S; Haanen, John B; Gruijl, Tanja D de; Verheul, Henk M; Vliet, Hans J van der

    2011-01-01

    For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell

  2. Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

    Huijts Charlotte M

    2011-11-01

    Full Text Available Abstract Background For patients with metastatic renal cell cancer (mRCC who progressed on vascular endothelial growth factor (VEGF receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. Methods/design This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part. In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. Discussion This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus

  3. Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study

    Ohtsu, Atsushi; Ajani, Jaffer A.; Bai, Yu-Xian; Bang, Yung-Jue; Chung, Hyun-Cheol; Pan, Hong-Ming; Sahmoud, Tarek; Shen, Lin; Yeh, Kun-Huei; Chin, Keisho; Muro, Kei; Kim, Yeul Hong; Ferry, David; Tebbutt, Niall C.; Al-Batran, Salah-Eddin; Smith, Heind; Costantini, Chiara; Rizvi, Syed; Lebwohl, David; Van Cutsem, Eric

    2013-01-01

    Purpose The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients and Methods Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Results Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Conclusion Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers. PMID:24043745

  4. Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma – systematic review and meta-analysis

    Yamanaka, Kenya; Petrulionis, Marius; Lin, Shibo; Gao, Chao; Galli, Uwe; Richter, Susanne; Winkler, Susanne; Houben, Philipp; Schultze, Daniel; Hatano, Etsuro; Schemmer, Peter

    2013-01-01

    Everolimus is an orally administrated mammalian target of rapamycin (mTOR) inhibitor. Several large-scale randomized controlled trials (RCTs) have demonstrated the survival benefits of everolimus at the dose of 10 mg/day for solid cancers. Furthermore, mTOR-inhibitor-based immunosuppression is associated with survival benefits for patients with hepatocellular carcinoma (HCC) who have received liver transplantation. However, a low rate of tumor reduction and some adverse events have been pointed out. This review summarizes the antitumor effects and adverse events of everolimus and evaluates its possible application in advanced HCC. For the meta-analysis of adverse events, we used the RCTs for solid cancers. The odds ratios of adverse events were calculated using the Peto method. Manypreclinical studies demonstrated that everolimus had antitumor effects such as antiproliferation and antiangiogenesis. However, some differences in the effects were observed among in vivo animal studies for HCC treatment. Meanwhile, clinical studies demonstrated that the response rate of single-agent everolimus was low, though survival benefits could be expected. The meta-analysis revealed the odds ratios (95% confidence interval [CI]) of stomatitis: 5.42 [4.31–6.73], hyperglycemia: 3.22 [2.37–4.39], anemia: 3.34 [2.37–4.67], pneumonitis: 6.02 [3.95–9.16], aspartate aminotransferase levels: 2.22 [1.37–3.62], and serum alanine aminotransferase levels: 2.94 [1.72–5.02], respectively. Everolimus at the dose of 10 mg/day significantly increased the risk of the adverse events. In order to enable its application to the standard conventional therapies of HCC, further studies are required to enhance the antitumor effects and manage the adverse events of everolimus

  5. Adjuvant Everolimus for Resected Kidney Cancer

    In this clinical trial, patients with renal cell cancer who have undergone partial or complete nephrectomy will be randomly assigned to take everolimus tablets or matching placebo tablets daily for 54 weeks.

  6. Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

    Jappe Annette

    2011-01-01

    Full Text Available Abstract Background This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors. Methods A total of 24 patients with advanced breast cancer (n = 6, gastric cancer (n = 6, non-small cell lung cancer (n = 6, or renal cell carcinoma (n = 6 who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued. Results Everolimus was absorbed rapidly; median Tmax was 3 h (range, 1-4 and 2 h (range, 0.9-6 in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7% and fatigue (16.7% and 33.3% in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83% and 6 (50% patients in the 5 and 10 mg/day groups, respectively. Conclusions Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies. Trial registration Chinese Health Authorities 2008L09346

  7. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.

    Yardley, Denise A; Noguchi, Shinzaburo; Pritchard, Kathleen I; Burris, Howard A; Baselga, José; Gnant, Michael; Hortobagyi, Gabriel N; Campone, Mario; Pistilli, Barbara; Piccart, Martine; Melichar, Bohuslav; Petrakova, Katarina; Arena, Francis P; Erdkamp, Frans; Harb, Wael A; Feng, Wentao; Cahana, Ayelet; Taran, Tetiana; Lebwohl, David; Rugo, Hope S

    2013-10-01

    Effective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.

  8. Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study.

    David N Franz

    Full Text Available Everolimus, a mammalian target of rapamycin (mTOR inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs and other manifestations of tuberous sclerosis complex (TSC. However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828.EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years who received ≥1 dose of everolimus (median duration, 47.1 months, 57.7% (95% confidence interval [CI], 47.9-67.0 achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2% achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence suspected to be treatment-related were stomatitis (43.2% and mouth ulceration (32.4%.Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a

  9. Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer.

    Lousberg, Laurence; Jerusalem, Guy

    2016-01-01

    Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus-exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile.

  10. Efficacy and Safety of Everolimus for Maintenance Immunosuppression of Kidney Transplantation: A Meta-Analysis of Randomized Controlled Trials.

    Jinyu Liu

    Full Text Available Conversion to everolimus is often used in kidney transplantation to overcome calcineurin inhibitor (CNI nephrotoxicity but there is conflicting evidence for this approach.To investigate the benefits and harm from randomized clinical trials (RCTs involving the conversion from CNI to everolimus after kidney transplantation.Databases were searched up to March 2016. Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as risk ratio (RR or mean difference (MD with 95% confidence intervals (CI.Eleven RCTs, with a total of 1,633 patients, met the final inclusion criteria. Patients converted to everolimus had improved renal function at 1 year posttransplant with an estimated glomerular filtration rate (eGFR of 5.36 mL/min per 1.73 m2 greater than patients remaining on CNI (p = 0.0005 and the longer-term results (> 1 year of renal function was identical to that of 1 year. There was not a substantial difference in graft loss, mortality, and the occurrence of adverse events (AEs or serious AEs. However, the risks of acute rejection and trial termination due to AEs with everolimus are respectively 1.82 and 2.63 times greater than patients staying on CNI at 1 year posttransplant (p = 0.02, p = 0.03, respectively. Further, those patients who converted to everolimus had a substantially greater risk of anemia, hyperlipidemia, hypercholesterolemia, hypokalemia, proteinuria, stomatitis, mouth ulceration, and acne.Conversion from CNI to everolimus after kidney transplantation is associated with improved renal function in the first 5 years posttransplant but increases the risk of acute rejection at 1 year posttransplant and may not be well endured.

  11. An acute episode of rhabdomyolysis associated with everolimus and cabergoline intake in a postpartum kidney recipient

    B. I. Yaremin

    2017-01-01

    Full Text Available Kidney transplantation is one of the most promising ways to ensure the onset and successful maintenance of pregnancy in patients with end-stage chronic renal disease. A multicomponent drug therapy in such patients creates risks for fetal development, primarily due to the teratogenicity of mTOR receptor inhibitors and mycophenolate. Moreover, the inhibitors of the proliferative signal may have potential drug interactions, which can result in additional complications.Rhabdomyolysis is one of them. The paper describes the clinical case of an acute episode of reversible rhabdomyolysis in a patient on everolimus therapy.

  12. Supplementary Administration of Everolimus Reduces Cardiac Systolic Function in Kidney Transplant Recipients.

    Tsujimura, Kazuma; Ota, Morihito; Chinen, Kiyoshi; Nagayama, Kiyomitsu; Oroku, Masato; Nishihira, Morikuni; Shiohira, Yoshiki; Abe, Masami; Iseki, Kunitoshi; Ishida, Hideki; Tanabe, Kazunari

    2017-05-26

    BACKGROUND The effect of everolimus, one of the mammalian targets of rapamycin inhibitors, on cardiac function was evaluated in kidney transplant recipients. MATERIAL AND METHODS Seventy-six participants who underwent kidney transplant between March 2009 and May 2016 were retrospectively reviewed. To standardize everolimus administration, the following criteria were used: (1) the recipient did not have a donor-specific antigen before kidney transplantation; (2) the recipient did not have proteinuria and uncontrollable hyperlipidemia after kidney transplantation; and (3) acute rejection was not observed on protocol biopsy 3 months after kidney transplantation. According to these criteria, everolimus administration for maintenance immunosuppression after kidney transplantation was included. Cardiac function was compared between the treatment group (n=30) and non-treatment group (n=46). RESULTS The mean observation periods of the treatment and non-treatment groups were 41.3±12.6 and 43.9±19.8 months, respectively (p=0.573). The mean ejection fraction and fractional shortening of the treatment and non-treatment groups after kidney transplant were 66.5±7.9% vs. 69.6±5.5% (p=0.024) and 37.1±6.2% vs. 39.3±4.7% (p=0.045), respectively. In the treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation did not differ significantly (p=0.604 and 0.606, respectively). In the non-treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation differed significantly (p=0.004 and 0.006, respectively). CONCLUSIONS Supplementary administration of everolimus after kidney transplantation can reduce cardiac systolic function.

  13. Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE: study protocol for a randomized controlled trial

    Chrispijn Melissa

    2011-11-01

    Full Text Available Abstract Background Polycystic liver disease (PLD is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. Methods/design This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. Discussion This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. Trial registration number ClinicalTrials.gov: NCT01157858

  14. Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas

    Karajannis, Matthias A.; Legault, Geneviève; Hagiwara, Mari; Giancotti, Filippo G.; Filatov, Alexander; Derman, Anna; Hochman, Tsivia; Goldberg, Judith D.; Vega, Emilio; Wisoff, Jeffrey H.; Golfinos, John G.; Merkelson, Amanda; Roland, J. Thomas; Allen, Jeffrey C.

    2014-01-01

    Background Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m2/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic (“phase 0”) study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors. PMID:24311643

  15. Everolimus-associated acute kidney injury in patients with metastatic breast cancer

    A Chandra

    2017-01-01

    Full Text Available Recently, everolimus (Evl has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up.

  16. FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

    Chen, James L; Appelbaum, Daniel E; Kocherginsky, Masha; Cowey, Charles L; Kimryn Rathmell, Wendy; McDermott, David F; Stadler, Walter M

    2013-01-01

    The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([ 18 F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre- and 2-week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability. In this phase II trial, FDG-PET was explored as a predictive biomarker

  17. Inhibitors

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  18. The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

    Pignochino, Ymera; Dell’Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

    2015-01-01

    Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

  19. [Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer - Japanese subgroup analysis of BOLERO -2].

    Ito, Yoshinori; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Tokuda, Yutaka; Kuroi, Katsumasa; Mori, Asuka; Ohno, Nobutsugu; Noguchi, Shinzaburo

    2015-01-01

    In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

  20. A prospective, randomized evaluation of a novel everolimus-eluting coronary stent

    Stone, Gregg W; Teirstein, Paul S; Meredith, Ian T

    2011-01-01

    We sought to evaluate the clinical outcomes with a novel platinum chromium everolimus-eluting stent (PtCr-EES) compared with a predicate cobalt chromium everolimus-eluting stent (CoCr-EES) in patients undergoing percutaneous coronary intervention (PCI).......We sought to evaluate the clinical outcomes with a novel platinum chromium everolimus-eluting stent (PtCr-EES) compared with a predicate cobalt chromium everolimus-eluting stent (CoCr-EES) in patients undergoing percutaneous coronary intervention (PCI)....

  1. Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients.

    Fernández-Yunquera, Ainhoa; Ripoll, Cristina; Bañares, Rafael; Puerto, Marta; Rincón, Diego; Yepes, Ismael; Catalina, Vega; Salcedo, Magdalena

    2014-06-24

    To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen. This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-β (TGF-β), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon-inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages. A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-α, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-β [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-β1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-β1

  2. Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

    du Rusquec, Pauline; Palpacuer, Clément; Campion, Loic; Patsouris, Anne; Augereau, Paule; Gourmelon, Carole; Robert, Marie; Dumas, Laurence; Caroline, Folliard; Campone, Mario; Frenel, Jean-Sébastien

    2018-04-01

    Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

  3. Addition of Everolimus Post VEGFR Inhibition Treatment Failure in Advanced Sarcoma Patients Who Previously Benefited from VEGFR Inhibition: A Case Series

    ElNaggar, Adam C.; Hays, John L.; Chen, James L.

    2016-01-01

    Background Patients with metastatic sarcoma who progress on vascular endothelial growth factor receptor inhibitors (VEGFRi) have limited treatment options. Upregulation of the mTOR pathway has been demonstrated to be a means of resistance to targeted VEGFRi in metastatic sarcoma. Patients and methods Retrospective cohort study to evaluate the clinical benefit at four months of combining mTOR inhibition (mTORi) via everolimus with VEGFRi in patients who have derived benefit from single-agent V...

  4. Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

    Narayan, Vivek; Vapiwala, Neha; Mick, Rosemarie; Subramanian, Pearl; Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji; Haas, Naomi B.

    2017-01-01

    Purpose: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. Methods and Materials: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Results: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Conclusions: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

  5. Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy.

    Narayan, Vivek; Vapiwala, Neha; Mick, Rosemarie; Subramanian, Pearl; Christodouleas, John P; Bekelman, Justin E; Deville, Curtiland; Rajendran, Ramji; Haas, Naomi B

    2017-02-01

    In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

    Narayan, Vivek [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Vapiwala, Neha [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Mick, Rosemarie [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Subramanian, Pearl [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Haas, Naomi B., E-mail: naomi.haas@uphs.upenn.edu [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2017-02-01

    Purpose: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. Methods and Materials: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Results: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Conclusions: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

  7. Ganciclovir-Resistant Cytomegalovirus Infection in a Kidney Transplant Recipient Successfully Treated with Foscarnet and Everolimus.

    Menghi, Viola; Comai, Giorgia; Baraldi, Olga; Liviano D'Arcangelo, Giovanni; Lazzarotto, Tiziana; La Manna, Gaetano

    2016-01-01

    Cytomegalovirus (CMV) infection remains a major cause of morbidity, graft failure, and death in kidney transplant recipients. We describe a case of a 53-year-old CMV-seronegative man who underwent renal transplant from a CMV-positive donor and who developed ganciclovir- (GCV-) resistant CMV infection. Foscarnet was started while immunosuppressive therapy was modified with the introduction of everolimus minimizing tacrolimus dosage. Only two weeks after the start of this treatment regimen was the patient's viral load negative. At two-year follow-up the patient has no clinical or laboratory signs of CMV infection and a good and stable renal function or graft survival. In our case, administration of an mTOR inhibitor combined with foscarnet led to rapid and persistent viral clearance without compromising short- and medium-term graft function. This combination therapy supports the need for the kidney transplant community to individualize a target therapy for each type of GCV-resistant CMV infection.

  8. Effects of everolimus on macrophage-derived foam cell behavior

    Hsu, Steven; Koren, Eugen; Chan, Yen; Koscec, Mirna; Sheehy, Alexander; Kolodgie, Frank; Virmani, Renu; Feder, Debra

    2014-01-01

    Purpose: The purpose of this study was to investigate the effects of everolimus on foam cell (FC) viability, mRNA levels, and inflammatory cytokine production to better understand its potential inhibitory effects on atheroma progression. Methods and materials: Human THP1 macrophage-derived FC were formed using acetylated LDL (acLDL, 100 μg/mL) for 72 hours, followed by everolimus treatment (10 -5 –10 -11 M) for 24 hours. FC viability was quantified using fluorescent calcein AM/DAPI staining. FC lysates and media supernatants were analyzed for apoptosis and necrosis using a Cell Death ELISA PLUS assay. FC lysates and media supernatants were also analyzed for inflammatory cytokine (IL1β, IL8, MCP1, TNFα) mRNA levels and protein expression using quantitative reverse transcription real-time polymerase chain reaction (QPCR) and a Procarta® immunoassay, respectively. mRNA levels of autophagy (MAP1LC3), apoptosis (survivin, clusterin), and matrix degradation (MMP1, MMP9) markers were evaluated by Quantigene® Plex assay and verified with QPCR. Additionally, hypercholesterolemic rabbits received everolimus-eluting stents (EES) for 28 or 60 days. RAM-11 immunohistochemical staining was performed to compare %RAM-11 positive area between stented sections and unstented proximal sections. Statistical significance was calculated using one-way ANOVA (p ≤ 0.05). Results: Calcein AM/DAPI staining showed that FC exposed to everolimus (10 -5 M) had significantly decreased viability compared to control. FC apoptosis was significantly increased at a high dose of everolimus (10 -5 M), with no necrotic effects at any dose tested. Everolimus did not affect endothelial (HUVEC) and smooth muscle (HCASMC) cell apoptosis or necrosis. Everolimus (10 -5 M) significantly increased MAP1LC3, caused an increased trend in clusterin (p = 0.10), and significantly decreased survivin and MMP1 mRNA levels in FC. MCP1 cytokine mRNA levels and secreted protein expression was significantly decreased

  9. Effects of everolimus on macrophage-derived foam cell behavior

    Hsu, Steven, E-mail: steven.hsu@av.abbott.com [Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054 (United States); Koren, Eugen; Chan, Yen; Koscec, Mirna; Sheehy, Alexander [Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054 (United States); Kolodgie, Frank; Virmani, Renu [CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878 (United States); Feder, Debra [Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054 (United States)

    2014-07-15

    Purpose: The purpose of this study was to investigate the effects of everolimus on foam cell (FC) viability, mRNA levels, and inflammatory cytokine production to better understand its potential inhibitory effects on atheroma progression. Methods and materials: Human THP1 macrophage-derived FC were formed using acetylated LDL (acLDL, 100 μg/mL) for 72 hours, followed by everolimus treatment (10{sup -5}–10{sup -11} M) for 24 hours. FC viability was quantified using fluorescent calcein AM/DAPI staining. FC lysates and media supernatants were analyzed for apoptosis and necrosis using a Cell Death ELISA{sup PLUS} assay. FC lysates and media supernatants were also analyzed for inflammatory cytokine (IL1β, IL8, MCP1, TNFα) mRNA levels and protein expression using quantitative reverse transcription real-time polymerase chain reaction (QPCR) and a Procarta® immunoassay, respectively. mRNA levels of autophagy (MAP1LC3), apoptosis (survivin, clusterin), and matrix degradation (MMP1, MMP9) markers were evaluated by Quantigene® Plex assay and verified with QPCR. Additionally, hypercholesterolemic rabbits received everolimus-eluting stents (EES) for 28 or 60 days. RAM-11 immunohistochemical staining was performed to compare %RAM-11 positive area between stented sections and unstented proximal sections. Statistical significance was calculated using one-way ANOVA (p ≤ 0.05). Results: Calcein AM/DAPI staining showed that FC exposed to everolimus (10{sup -5} M) had significantly decreased viability compared to control. FC apoptosis was significantly increased at a high dose of everolimus (10{sup -5} M), with no necrotic effects at any dose tested. Everolimus did not affect endothelial (HUVEC) and smooth muscle (HCASMC) cell apoptosis or necrosis. Everolimus (10{sup -5} M) significantly increased MAP1LC3, caused an increased trend in clusterin (p = 0.10), and significantly decreased survivin and MMP1 mRNA levels in FC. MCP1 cytokine mRNA levels and secreted protein

  10. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II)

    Serruys, Patrick W; Chevalier, Bernard; Sotomi, Yohei

    2016-01-01

    BACKGROUND: No medium-term data are available on the random comparison between everolimus-eluting bioresorbable vascular scaffolds and everolimus-eluting metallic stents. The study aims to demonstrate two mechanistic properties of the bioresorbable scaffold: increase in luminal dimensions as a re...

  11. Effect of Post-Dilatation Following Primary PCI With Everolimus-Eluting Bioresorbable Scaffold Versus Everolimus-Eluting Metallic Stent Implantation

    Yamaji, Kyohei; Brugaletta, Salvatore; Sabaté, Manel

    2017-01-01

    OBJECTIVES: This study sought to investigate the effect of post-dilatation on angiographic and intracoronary imaging parameters in the setting of primary percutaneous coronary intervention comparing the everolimus-eluting bioresorbable scaffold (BRS) with the everolimus-eluting metallic stent (EE...

  12. Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

    Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M; Largiadèr, Carlo R; Mohacsi, Paul; Sistonen, Johanna

    2015-12-01

    Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts. While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction. Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Efficacy of everolimus in ABO-incompatible kidney transplantation: a retrospective study

    Tsujimura K

    2017-09-01

    Full Text Available Kazuma Tsujimura,1 Morihito Ota,1 Kiyoshi Chinen,1 Kiyomitsu Nagayama,2 Masato Oroku,2 Morikuni Nishihira,2 Yoshiki Shiohira,2 Kunitoshi Iseki,3 Hideki Ishida,4 Kazunari Tanabe4 1Department of Surgery, 2Department of Nephrology, 3Clinical Research Support Center, Tomishiro Central Hospital, Okinawa, Japan; 4Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan Background: There are limited reports on the use of everolimus for maintaining immunosuppression in ABO-incompatible (ABOi kidney transplantation (KT. As everolimus (EVR is effective for preventing calcineurin inhibitor (CNI nephrotoxicity without increasing the risk of chronic rejection and viral infection, we aimed to assess the efficacy of EVR in ABOi KT.Patients and methods: We retrospectively studied 22 patients who underwent KT and received EVR. Patients in the ABOi KT group (n=7 were compared with those in the ABO-compatible kidney transplantation group (ABOc KT; n=15. We recorded the frequency of CNI nephrotoxicity, chronic rejection, and viral infection in the 2 groups.Results: CNI nephrotoxicity, chronic rejection, and viral infection occurred in the ABOi KT and ANOc KT groups at rates of 28.3% (2/7 patients and 13.3% (2/15 patients (P=0.388, 28.3% (2/7 patients and 26.7% (4/15 patients (P=0.926, and 14.3% (1/7 patients and 26.7% (4/15 patients (P=0.517, respectively.Conclusion: Administration of EVR is effective in preventing CNI nephrotoxicity after KT. The rate of CNI nephrotoxicity was lower in the ABOc KT group than in the ABOi KT group. The rate of chronic rejection and viral infection was comparable between the groups. This study was conducted in a small cohort of patients. Hence, further evaluation with large sample sizes is necessary in the future to confirm the outcomes. Keywords: blood group incompatibility, immunosuppression, kidney transplantation

  14. Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers.

    Thudium, Karen; Gallo, Jorge; Bouillaud, Emmanuel; Sachs, Carolin; Eddy, Simantini; Cheung, Wing

    2015-01-01

    The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets. Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8-14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs). Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35-1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02-1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects. Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.

  15. Everolimus for Primary Intestinal Lymphangiectasia With Protein-Losing Enteropathy.

    Ozeki, Michio; Hori, Tomohiro; Kanda, Kaori; Kawamoto, Norio; Ibuka, Takashi; Miyazaki, Tatsuhiko; Fukao, Toshiyuki

    2016-03-01

    Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is an exudative enteropathy resulting from morphologic abnormalities in the intestinal lymphatics. In this article, we describe a 12-year-old boy with PIL that led to protein-losing enteropathy characterized by diarrhea, hypoalbuminemia associated with edema (serum albumin level: 1.0 g/dL), and hypogammaglobulinemia (serum IgG level: 144 mg/dL). Severe hypoalbuminemia, electrolyte abnormalities, and tetany persisted despite a low-fat diet and propranolol. Everolimus (1.6 mg/m(2)/day) was added to his treatment as an antiangiogenic agent. With everolimus treatment, the patient's diarrhea resolved and replacement therapy for hypoproteinemia was less frequent. Hematologic and scintigraphy findings also improved (serum albumin level: 2.5 g/dL). There were no adverse reactions during the 12-month follow-up. To the best of our knowledge, this is the first report of everolimus use in a patient with PIL. Copyright © 2016 by the American Academy of Pediatrics.

  16. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

    Jun Aono, MD, PhD

    2016-01-01

    Full Text Available Proliferation of smooth muscle cells (SMCs during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT, indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT.

  17. Early Introduction of Everolimus Immunosuppressive Regimen in Liver Transplantation with Extra-Anatomic Aortoiliac-Hepatic Arterial Graft Anastomosis

    Emanuele Felli

    2014-01-01

    Full Text Available Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage.

  18. Cabozantinib Versus Everolimus in Patients with Advanced Renal Cell Carcinoma: Results of a Randomised Phase III Trial (METEOR

    Toni Choueiri

    2015-11-01

    Full Text Available The METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma (RCC was reported by Prof Choueiri at the European Cancer Congress 2015. This presentation follows the publication in the New England Journal of Medicine of the METEOR trial back-to-back with the CheckMate 025 trial of nivolumab versus everolimus in the same patient setting. Excitingly, these trials demonstrated, for the first time, significant benefits over the standard of care for heavily pre-treated patients with advanced RCC. Cabozantinib, an oral multi-targeted tyrosine kinase inhibitor (TKI aims to address the challenge of resistance to targeted therapy with TKIs. While the METEOR trial has not yet reached its final analysis of overall survival (OS, the clear progression-free survival (PFS benefit, acceptable safety profile, and similar tolerability to other TKIs shown by cabozantinib indicate that this represents a promising new treatment option for second-line or subsequent therapy for patients with advanced RCC.

  19. Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors.

    Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya

    2014-11-14

    The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

  20. Comparison of medical costs and healthcare resource utilization of post-menopausal women with HR+/HER2- metastatic breast cancer receiving everolimus-based therapy or chemotherapy: a retrospective claims database analysis.

    Li, Nanxin; Hao, Yanni; Koo, Valerie; Fang, Anna; Peeples, Miranda; Kageleiry, Andrew; Wu, Eric Q; Guérin, Annie

    2016-01-01

    To analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among post-menopausal women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). Patients with HR+/HER2- mBC who discontinued a non-steroidal aromatase inhibitor and began a new line of treatment with everolimus-based therapy or chemotherapy (index therapy/index date) between July 20, 2012 and April 30, 2014 were identified from two large claims databases. All-cause, BC-related, and adverse event (AE)-related medical costs (in 2014 USD) and all-cause HRU per patient per month (PPPM) were analyzed for both treatment groups across patients' first four lines of therapies for mBC. Adjusted differences in costs and HRU between the everolimus and chemotherapy treatment group were estimated pooling all lines and using multivariable generalized linear models, accounting for difference in patient characteristics. A total of 3298 patients were included: 902 everolimus-treated patients and 2636 chemotherapy-treated patients. Compared to chemotherapy, everolimus was associated with significantly lower all-cause (adjusted mean difference = $3455, p well as significantly lower HRU (emergency room incidence rate ratio [IRR] = 0.83; inpatient IRR = 0.74; inpatient days IRR = 0.65; outpatient IRR = 0.71; BC-related outpatient IRR = 0.57; all p chemotherapy.

  1. 18F-FDG and 18F-FLT-PET imaging for monitoring everolimus effect on tumor-growth in neuroendocrine tumors: studies in human tumor xenografts in mice.

    Camilla Bardram Johnbeck

    Full Text Available The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily for 10 days. PET/CT scans were repeated at day 1,3 and 10.Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016, day 7 (164±7% vs. 226±13%; p<0.001 and at day 10 (194±10% vs. 281±18%; p<0.001. Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034, 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019 and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001 and day 10 (r2 = 0.58; P = 0.027.Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.

  2. Comparative effectiveness of everolimus-based therapy versus endocrine monotherapy among postmenopausal women with HR+/HER2- metastatic breast cancer: a retrospective chart review in community oncology practices in the US.

    Xie, Jipan; Hao, Yanni; Li, Nanxin; Lin, Peggy L; Ohashi, Erika; Koo, Valerie; Signorovitch, James E; Wu, Eric Q; Yardley, Denise A

    2015-06-01

    Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents. This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan-Meier analyses and Cox proportional hazards models adjusting for baseline characteristics. A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51-0.87) and PFS (HR = 0.75, 95% CI: 0.57-0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52-1.27). Results stratified by line of therapy were generally consistent with the overall results. Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review. Among a nationwide sample of postmenopausal HR+/HER2- m

  3. Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

    Hao, Yanni; Lin, Peggy L; Xie, Jipan; Li, Nanxin; Koo, Valerie; Ohashi, Erika; Wu, Eric Q; Rogerio, Jaqueline

    2015-08-01

    Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

  4. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.

    Aono, Jun; Ruiz-Rodriguez, Ernesto; Qing, Hua; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-01-01

    The present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase. Proliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated. We first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus. Inhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC

  5. Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor-positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

    Jyoti Bajpai

    2017-01-01

    Full Text Available Introduction: Biomarkers predictive of response to mechanistic target of rapamycin (mTOR inhibitor, everolimus, in endocrine receptor (ER-positive metastatic breast cancer (MBC are a work in progress. We evaluated the feasibility of directly measuring mTOR activity and phosphatase and tensin homolog (PTEN expression and correlating their expression with response and survival. Materials and Methods: MBC patients who received everolimus with endocrine therapy (ET after progression on an aromatase inhibitor and had adequate tissue preservation for estimation of mTOR activity and PTEN expression were selected for analysis from a prospectively maintained database. Progression-free survival (PFS and overall survival (OS were estimated by Kaplan–Meier method, and correlation between mTOR activity and PTEN expression with survival was done by log-rank test. Results: Thirteen ER-positive MBC patients were available for analysis. PTEN expression was lost in 11/13 (84.6% patients and retained in 2/13 patients (15.4%. mTOR activity was absent in four patients (30.7%, weak in six patients (46.1%, and moderate in 3 patients (23.2%. Median PFS for the entire population was 2.5 months while median OS was not reached. Patients with an absent mTOR activity showed a longer PFS (5 vs. 1.5 vs. 2 months than those with weak and moderate activity, respectively (P = 0.043. There was no correlation between loss of PTEN expression and PFS. Conclusions: Measurement of direct mTOR activity in patients with MBC receiving everolimus/ET combination appears feasible. Absent mTOR activity may predict for longer PFS with everolimus-ET combination and requires further study.

  6. Evaluation of the Impact of the Cancer Therapy Everolimus on the Central Nervous System in Mice

    Dubois, Martine; Le Joncour, Vadim; Tonon, Marie-Christine; Anouar, Youssef; Proust, François; Morin, Fabrice; Gandolfo, Pierrick; Joly, Florence; Hilber, Pascal; Castel, Hélène

    2014-01-01

    Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as

  7. Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.

    Martine Dubois

    Full Text Available Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated

  8. Everolimus-induced Pneumonitis after Drug-eluting Stent Implantation: A Case Report

    Sakamoto, Susumu, E-mail: susumu1029@gmail.com; Kikuchi, Naoshi; Ichikawa, Atsuo; Sano, Go; Satoh, Keita; Sugino, Keishi; Isobe, Kazutoshi; Takai, Yujiro [Toho University School of Medicine, Department of Respiratory Medicine (Japan); Shibuya, Kazutoshi [Toho University School of Medicine, Department of Pathology (Japan); Homma, Sakae [Toho University School of Medicine, Department of Respiratory Medicine (Japan)

    2013-08-01

    Despite the wide use of everolimus as an antineoplastic coating agent for coronary stents to reduce the rate of restenosis, little is known about the health hazards of everolimus-eluting stents (EES). We describe a case of pneumonitis that developed 2 months after EES implantation for angina. Lung pathology demonstrated an organizing pneumonia pattern that responded to corticosteroid therapy. Although the efficacy of EES for ischemic heart disease is well established, EES carries a risk of pneumonitis.

  9. Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat.

    Rahul Bohra

    Full Text Available Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL and sirolimus (SRL alone, and in combination with cyclosporine (CsA, on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination. After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with (1H-magnetic resonance spectroscopy (MRS and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.

  10. Randomised comparison of a bioresorbable everolimus-eluting scaffold with a metallic everolimus-eluting stent for ischaemic heart disease caused by de novo native coronary artery lesions

    Chevalier, Bernard; Onuma, Yoshinobu; van Boven, Ad J

    2016-01-01

    AIMS: The one-year randomised data of the ABSORB II trial showed that the everolimus-eluting bioresorbable scaffold and the everolimus-eluting metallic stent were comparable for the composite secondary clinical outcomes of patient-oriented composite endpoint (PoCE) and device-oriented composite...... Clara, CA, USA) or treatment with an everolimus-eluting metallic stent (XIENCE; Abbott Vascular). The trial enrolled 501 patients. Clinical follow-up at two years was available in 320 patients in the Absorb BVS arm and 160 patients in the XIENCE arm. At two years, the PoCE for the Absorb and XIENCE arms......-six percent and 34% of patients remained on DAPT at two years, respectively. Ninety-two percent of patients in both arms remained on aspirin. CONCLUSIONS: Two-year clinical results demonstrate sustained low rates of PoCE, MACE, DoCE and TVF with the Absorb BVS as compared to the XIENCE stent....

  11. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma

    Escudier, Bernard; Sharma, Padmanee; McDermott, David F

    2017-01-01

    /kg every 2 wk or everolimus 10mg once daily. RESULTS AND LIMITATIONS: The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer...... Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age

  12. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

    Costanza Bogani

    Full Text Available BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN, usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001 and an ATP-competitive (PP242 mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib. mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with

  13. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, single-blind, multicentre clinical trial

    Serruys, Patrick W.; Chevalier, Bernard; Sotomi, Yohei; Cequier, Angel; Carrié, Didier; Piek, Jan J.; van Boven, Ad J.; Dominici, Marcello; Dudek, Dariusz; McClean, Dougal; Helqvist, Steffen; Haude, Michael; Reith, Sebastian; de Sousa Almeida, Manuel; Campo, Gianluca; Iñiguez, Andrés; Sabaté, Manel; Windecker, Stephan; Onuma, Yoshinobu

    2016-01-01

    No medium-term data are available on the random comparison between everolimus-eluting bioresorbable vascular scaffolds and everolimus-eluting metallic stents. The study aims to demonstrate two mechanistic properties of the bioresorbable scaffold: increase in luminal dimensions as a result of

  14. mTOR inhibitors in urinary bladder cancer.

    Pinto-Leite, R; Arantes-Rodrigues, R; Sousa, Nuno; Oliveira, P A; Santos, L

    2016-09-01

    Despite the great scientific advances that have been made in cancer treatment, there is still much to do, particularly with regard to urinary bladder cancer. Some of the drugs used in urinary bladder cancer treatment have been in use for more than 30 years and show reduced effectiveness and high recurrence rates. There have been several attempts to find new and more effective drugs, to be used alone or in combination with the drugs already in use, in order to overcome this situation.The biologically important mammalian target of rapamycin (mTOR) pathway is altered in cancer and mTOR inhibitors have raised many expectations as potentially important anticancer drugs. In this article, the authors will review the mTOR pathway and present their experiences of the use of some mTOR inhibitors, sirolimus, everolimus and temsirolimus, in isolation and in conjunction with non-mTOR inhibitors cisplatin and gemcitabine, on urinary bladder tumour cell lines. The non-muscle-invasive cell line, 5637, is the only one that exhibits a small alteration in the mTOR and AKT phosphorylation after rapalogs exposure. Also, there was a small inhibition of cell proliferation. With gemcitabine plus everolimus or temsirolimus, the results were encouraging as a more effective response was noticed with both combinations, especially in the 5637 and T24 cell lines. Cisplatin associated with everolimus or temsirolimus also gave promising results, as an antiproliferative effect was observed when the drugs were associated, in particular on the 5637 and HT1376 cell lines. Everolimus or temsirolimus in conjunction with gemcitabine or cisplatin could have an important role to play in urinary bladder cancer treatment, depending on the tumour grading.

  15. Everolimus in clinical practice after liver transplantation: a single-center experience

    O. A. Gerasimova

    2017-01-01

    Full Text Available Aim. Single-center analysis of everolimus treatment after liver transplantation. Materials and methods. 23 patients having received Certican after OLT in RSCRST were observed in period from 6 months to 5 years; comparison group consisted of 50 patients who received immunosuppressive scheme with tacrolimus. Conversion to everolimus was performed in the period from 1 month after OLT after discharge and at later time according to the indications: hepatocellular cancer, cumulative CNI nephrotoxicity, the development of malignancies, and intolerance to CNI. The concentrations of CNI and everolimus in the blood (target concentration of tacrolimus 1.5–2 ng/ml, everolimus 3–8 ng/ml were monitored. Glomerular filtration rate (GFR was determined using the CKD-EPI equation. Adverse events of everolimus were evaluated. Results. The immunosuppressive scheme with everolimus is presented; adverse events with dose-dependent hypercholesterolemia (34.7% as the main; the average level of blood cholesterol was not significantly different from that in the control group, 5.6 ± 0.9 vs 5.1 ± 1.4 mmol/l (Z = 1.3, p = 0.17. Renal function was stable throughout the observation period (35 ± 16 months. GFR (CKD-EPI before conversion was 75.8 ± 17.5 ml/min. 6 patients treated with Certican for 5 years had final GFR 96.6 ± 5.1 ml/min. GFR in the group of Certican at 12 months post conversion was 87.5 ± 16.3 ml/min vs 94.2 ± 16.8 ml/min (p = 0.08 in the control group. We revealed metastases to the liver and lungs in 5 patients from 13 patients with HCC, survival rate in this group depended on the compliance with the Milan criteria (Z = 2.4, p = 0.02. Conclusion. Everolimus allows maintaining of a stable renal function to prevent progression of renal failure; conversion should be initiated as early as possible. Combination of everolimus with reduced dose of CNI is optimal. Despite the fact that side effects are developing in most patients, adequate monitoring of

  16. Everolimus use and associated factors among post-menopausal women with hormonal receptor positive/human epidermal growth factor receptor 2 negative metastatic breast cancer.

    Li, Nanxin; Hao, Yanni; Xie, Jipan; Lin, Peggy L; Zhou, Zhou; Zhong, Yichen; Signorovitch, James E; Wu, Eric Q

    2015-08-01

    Everolimus has been shown to be an effective HR+/HER2- mBC treatment in both clinical trials and real-world practice. The current study aims at understanding factors associated with everolimus use and how it is used in the real world. A retrospective chart review was conducted among postmenopausal HR+/HER2- mBC women who received everolimus, endocrine therapy (ET), or chemotherapy (CT) for mBC between 1 July 2012 and 15 April 2013 after an NSAI failure. Factors associated with everolimus use versus ET or CT were identified using multivariable logistic regressions. Reasons for prescribing everolimus and everolimus treatment patterns were described. Liver metastasis and high tumor volume were associated with a higher likelihood of everolimus use versus ET (OR = 1.67, OR = 1.62) but a lower likelihood of everolimus use versus CT (OR = 0.43, OR = 0.30). Medicare-only insurance (OR = 0.30) as well as ECOG ≥2 (OR = 3.72) and prior CT in mBC (OR = 2.76) were associated with a lower and higher likelihood of everolimus use versus CT, respectively. The top reason for prescribing everolimus was efficacy (69-85%). About 15% and 29% of everolimus users in second line and third line or above received prior CT for mBC. Exemestane was the most common concomitant therapy with everolimus (56-87%). The majority of patients initiated everolimus at the labeled dose of 10 mg daily (>80%) and maintained this dose (>80%). In the real world, everolimus was used in more severe patients than ET but less severe patients than CT based on visceral metastasis, tumor volume, and performance status. The top reason for prescribing everolimus was efficacy. A large proportion of patients received first or second line CT before everolimus initiation. The majority of patients used everolimus according to the labeled combination and dose. Future studies are needed to determine optimal sequencing of everolimus, ET, and CT for HR+/HER2- mBC.

  17. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents

    Serruys, Patrick W; Silber, Sigmund; Garg, Scot

    2010-01-01

    New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed...

  18. Cost utility analysis of everolimus in the treatment of metastatic renal cell cancer in the Netherlands

    Mihajlović, J.; Minović, I.; Bruinsma, A.; Postma, M.J.

    2013-01-01

    Objectives: Metastatic renal cell cancer (mRCC) is becoming an important part of Dutch health care expenditure due to expensive pharmaceutical options for disease control and lack of adequate prevention methods. New targeted therapeutics, such as sunitinib, sorafenib and everolimus, have recently

  19. Incidence and Potential Mechanism(s) of Post-Procedural Rise of Cardiac Biomarker in Patients With Coronary Artery Narrowing After Implantation of an Everolimus-Eluting Bioresorbable Vascular Scaffold or Everolimus-Eluting Metallic Stent

    Ishibashi, Yuki; Muramatsu, Takashi; Nakatani, Shimpei

    2015-01-01

    OBJECTIVES: This study sought to evaluate the mechanism of post-procedural cardiac biomarker (CB) rise following device implantation. BACKGROUND: A fully bioresorbable Absorb scaffold, compared with everolimus-eluting metallic stents (EES), might be associated with a higher incidence...

  20. The SYNERGY biodegradable polymer everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety study.

    Wilson, Gregory J; Marks, Angela; Berg, Kimberly J; Eppihimer, Michael; Sushkova, Natalia; Hawley, Steve P; Robertson, Kimberly A; Knapp, David; Pennington, Douglas E; Chen, Yen-Lane; Foss, Aaron; Huibregtse, Barbara; Dawkins, Keith D

    2015-11-15

    SYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly-lactide-co-glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent. SYNERGY stents were implanted in arteries of domestic swine. Devices were explanted at predetermined time points (up to 120 days) and the extent of PLGA coating or everolimus remaining on the stents was quantified. Everolimus levels in the arterial tissue were also evaluated. A pathological analysis on coronary arteries of single and overlapping stents was performed at time points between 5 and 270 days. PLGA bioabsorption began immediately after implantation, and drug release was essentially complete by 90 days; PLGA absorption was substantially complete by 120 days (>90% of polymer was absorbed) leaving a bare metal SYNERGY stent. Vascular response was similar among SYNERGY and control stents (bare metal, polymer-only, and 3× polymer-only). Mild increases in para-strut fibrin were seen for SYNERGY at an early time point with no significant differences in all other morphological and morphometric parameters through 270 days or endothelial function (eNOS immunostaining) at 90 or 180 days. Inflammation was predominantly minimal to mild for all device types. In a swine model, everolimus was released by 90 days and PLGA bioabsorption was complete shortly thereafter. The SYNERGY stent and its biodegradable polymer, even at a 3× safety margin, demonstrated vascular compatibility similar to bare metal stent controls. © 2015 Wiley Periodicals, Inc.

  1. The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

    Gustafsson, Finn; Barth, David; Delgado, Diego H

    2009-01-01

    CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P 2) = 0.98), there was poor correlation...... between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). CONCLUSION: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus........ METHODS: Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). RESULTS: There was a highly significant correlation between blood...

  2. Risk evaluation and mitigation strategies: a focus on the mammalian target of rapamycin inhibitors.

    Gabardi, Steven

    2013-03-01

    To review the history of risk evaluation and mitigation strategies (REMS) with the mammalian target of rapamycin (mToR) inhibitors, evaluate their required REMS elements, and delineate the reasons for them being released from their REMS requirements. Articles were identified through a literature search of MEDLINE and EMBASE (January 2007-July 2012) using the search terms: risk evaluation and mitigation strategies, REMS, everolimus, sirolimus and organ transplant (individual organs also were searched). Information from the Federal Register, the Food and Drug Administration, and the manufacturers of the mToR inhibitors was also evaluated. REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. The mToR inhibitors have been associated with several potential risks, including proteinuria, graft thrombosis, and wound-healing complications. The Food and Drug Administration approved REMS programs for both sirolimus and everolimus. The manufacturers of both medications complied with the components of their approved REMS, but after less than 2 years, both medications have been relieved of their REMS obligations. The only element of the sirolimus REMS was a medication guide, whereas the everolimus REMS consisted of a medication guide and a communication plan. The sirolimus REMS was implemented more than 10 years after its initial approval by the Food and Drug Administration, but was released from its REMS requirement within 7 months of its implementation. The everolimus REMS was instituted upon initial approval and was removed approximately 2 years later. Both medications' REMS were always intended to educate health care providers and patients about the potential risks associated with this transplant immunosuppressant. Transplant practitioners should be familiar with the mToR inhibitors' associated risks and properly educate patients regarding the

  3. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis.

    Fazio, Nicola; Buzzoni, Roberto; Delle Fave, Gianfranco; Tesselaar, Margot E; Wolin, Edward; Van Cutsem, Eric; Tomassetti, Paola; Strosberg, Jonathan; Voi, Maurizio; Bubuteishvili-Pacaud, Lida; Ridolfi, Antonia; Herbst, Fabian; Tomasek, Jiri; Singh, Simron; Pavel, Marianne; Kulke, Matthew H; Valle, Juan W; Yao, James C

    2018-01-01

    In the phase III RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), non-functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783). © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  4. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

    Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

    2015-01-01

    Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

  5. Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.

    Ribas, Ricardo; Pancholi, Sunil; Rani, Aradhana; Schuster, Eugene; Guest, Stephanie K; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Thornhill, Allan; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

    2018-06-08

    Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER

  6. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4.

    Buzzoni, Roberto; Carnaghi, Carlo; Strosberg, Jonathan; Fazio, Nicola; Singh, Simron; Herbst, Fabian; Ridolfi, Antonia; Pavel, Marianne E; Wolin, Edward M; Valle, Juan W; Oh, Do-Youn; Yao, James C; Pommier, Rodney

    2017-01-01

    Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35-0.67; P <0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity. ClinicalTrials.gov identifier: NCT01524783. Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported. A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37-0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36-0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19-0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42-0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24-0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42-0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%-65%), fatigue (27%-35%), and diarrhea (24%-34%) among the subgroups. These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET.

  7. Critical appraisal of the role of everolimus in advanced neuroendocrine tumors of pancreatic origin

    Mulet-Margalef N

    2012-09-01

    Full Text Available Núria Mulet-Margalef, Jaume CapdevilaMedical Oncology Department, Vall d'Hebron University Hospital, Barcelona, SpainAbstract: For many years, the treatment of advanced pancreatic neuroendocrine tumors (pNETs has been limited almost entirely to somatostatin analogs and streptozocin-based chemotherapy, with modest benefit. Increasing knowledge of the biologic features of pNETs has allowed the design of molecular-based clinical trials, which have taken a step forward in the management of these tumors. In this review, we discuss the molecular rationale for the development of everolimus for patients with advanced pNETs, critically review the clinical data obtained by the main studies in this setting, and discuss essential considerations based on recent findings in pNET biology for future drug development involving the phosphatidylinositol 3' kinase-AKT-mTOR pathway.Keywords: pancreatic neuroendocrine tumors, everolimus, targeted therapies

  8. Vascular Response of the Segments Adjacent to the Proximal and Distal Edges of the ABSORB Everolimus-Eluting Bioresorbable Vascular Scaffold

    Gogas, Bill D; Serruys, Patrick W; Diletti, Roberto

    2012-01-01

    This study sought to investigate in vivo the vascular response at the proximal and distal edges of the second-generation ABSORB everolimus-eluting bioresorbable vascular scaffold (BVS).......This study sought to investigate in vivo the vascular response at the proximal and distal edges of the second-generation ABSORB everolimus-eluting bioresorbable vascular scaffold (BVS)....

  9. A randomized comparison of a durable polymer Everolimus-eluting stent with a bare metal coronary stent: The SPIRIT first trial

    Serruys, Patrick W.; Ong, Andrew T. L.; Piek, Jan J.; Neumann, Franz-Josef; van der Giessen, Willem J.; Wiemer, Marcus; Zeiher, Andreas; Grube, Eberhard; Haase, Jürgen; Thuesen, Leif; Hamm, Christian; Otto-Terlouw, Patricia C.

    2005-01-01

    Background: Everolimus is a sirolimus analogue with similar efficacy in animal models, and has been previously successfully tested in humans using an erodable polymer.Methods: This first-in-man single blind multi-centre randomized controlled trial assessed the safety and efficacy of everolimus

  10. A randomised comparison of an everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent:the SPIRIT II trial

    Serruys, Patrick W.; Ruygrok, Peter; Neuzner, Jörg; Piek, Jan J.; Seth, Ashok; Schofer, Joachim J.; Richardt, Gert; Wiemer, Marcus; Carrié, Didier; Thuesen, Leif; Boone, Els; Miquel-Herbert, Karine; Daemen, Joost

    2006-01-01

    Background: Everolimus has been successfully tested in humans using both an erodable and a durable polymer in small previous studies.Methods: This single blind multi-centre non-inferiority randomised (3:1) controlled trial evaluated the safety and performance of the XIENCE V Everolimus Eluting

  11. The prognostic utility of the SYNTAX score on 1-year outcomes after revascularization with zotarolimus- and everolimus-eluting stents: a substudy of the RESOLUTE All Comers Trial

    Garg, Scot; Serruys, Patrick W; Silber, Sigmund

    2011-01-01

    This study assessed the ability of the SYNTAX score (SXscore) to stratify risk in patients treated with percutaneous coronary intervention (PCI) using zotarolimus-eluting or everolimus-eluting stents.......This study assessed the ability of the SYNTAX score (SXscore) to stratify risk in patients treated with percutaneous coronary intervention (PCI) using zotarolimus-eluting or everolimus-eluting stents....

  12. Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study.

    John J Bissler

    Full Text Available We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.Following favorable results from the double-blind core phase of EXIST-2 (NCT00790400, patients were allowed to receive open-label everolimus (extension phase. Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety.Of the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3% achieved angiomyolipoma response. Almost all patients (97% experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3% patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%, hypercholesterolemia (30.4%, acne (25.9%, aphthous stomatitis and nasopharyngitis (each 21.4%. Ten (8.9% patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time.Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use

  13. ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

    Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

    2018-05-01

    Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

  14. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

    Choueiri, Toni K; Escudier, Bernard; Powles, Thomas

    2015-01-01

    BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to an...

  15. Comparison of in vivo acute stent recoil between the bioabsorbable everolimus-eluting coronary stent and the everolimus-eluting cobalt chromium coronary stent: insights from the ABSORB and SPIRIT trials

    Tanimoto, Shuzou; Serruys, Patrick W; Thuesen, Leif

    2007-01-01

    OBJECTIVES: This study sought to evaluate and compare in vivo acute stent recoil of a novel bioabsorbable stent and a metallic stent. BACKGROUND: The bioabsorbable everolimus-eluting coronary stent (BVS) is composed of a poly-L-lactic acid backbone, coated with a bioabsorbable polymer containing...... the antiproliferative drug, everolimus, and expected to be totally metabolized and absorbed in the human body. Because the BVS is made from polymer, it may have more acute recoil than metallic stents in vivo. METHODS: A total of 54 patients, who underwent elective stent implantation for single de novo native coronary...... artery lesions, were enrolled: 27 patients treated with the BVS and 27 patients treated with the everolimus-eluting cobalt chromium stent (EES). Acute absolute recoil, assessed by quantitative coronary angiography, was defined as the difference between mean diameter of the last inflated balloon...

  16. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4

    Buzzoni R

    2017-10-01

    Full Text Available Roberto Buzzoni,1 Carlo Carnaghi,2 Jonathan Strosberg,3 Nicola Fazio,4 Simron Singh,5 Fabian Herbst,6 Antonia Ridolfi,7 Marianne E Pavel,8 Edward M Wolin,9 Juan W Valle,10 Do-Youn Oh,11 James C Yao,12 Rodney Pommier13 1IRCCS Foundation, National Institute of Tumors, Milan, Italy; 2Humanitas Clinical and Research Center, Rozzano, Italy; 3Moffitt Cancer Center, Tampa, FL, USA; 4European Institute of Oncology, Milan, Italy; 5Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 6Novartis AG, Basel, Switzerland; 7Novartis Pharma S.A.S., Rueil-Malmaison, France; 8Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 9Montefiore Einstein Center for Cancer Care, Bronx, NY, USA; 10Institute of Cancer Sciences, University of Manchester, The Christie Hospital, Manchester, UK; 11Seoul National University Hospital, Seoul, Republic of Korea; 12University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 13Oregon Health & Science University, Portland, OR, USA Background: Recently, everolimus was shown to improve median progression-free survival (PFS by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET of lung or gastrointestinal (GI tract compared with placebo (HR, 0.48; 95% CI, 0.35–0.67; P<0.00001 in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy on everolimus activity. Trial registration: ClinicalTrials.gov identifier: NCT01524783. Patients and methods: Patients were randomized (2:1 to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy were analyzed and reported. Results: A total of 302 patients were enrolled, of whom, 163 (54% had any prior SSA use (mostly for tumor control, 77 (25% received

  17. A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial

    Serruys, Patrick W.; Chevalier, Bernard; Dudek, Dariusz; Cequier, Angel; Carrié, Didier; Iniguez, Andres; Dominici, Marcello; van der Schaaf, René J.; Haude, Michael; Wasungu, Luc; Veldhof, Susan; Peng, Lei; Staehr, Peter; Grundeken, Maik J.; Ishibashi, Yuki; Garcia-Garcia, Hector M.; Onuma, Yoshinobu

    2015-01-01

    Despite rapid dissemination of an everolimus-eluting bioresorbable scaffold for treatment for coronary artery disease, no data from comparisons with its metallic stent counterpart are available. In a randomised controlled trial we aimed to compare an everolimus-eluting bioresorbable scaffold with an

  18. Everolimus-eluting bioresorbable stent vs. durable polymer everolimus-eluting metallic stent in patients with ST-segment elevation myocardial infarction

    Sabaté, Manel; Windecker, Stephan; Iñiguez, Andres

    2015-01-01

    AIMS: Patients with ST-segment elevation myocardial infarction (STEMI) feature thrombus-rich lesions with large necrotic core, which are usually associated with delayed arterial healing and impaired stent-related outcomes. The use of bioresorbable vascular scaffolds (Absorb) has the potential...... to overcome these limitations owing to restoration of native vessel lumen and physiology at long term. The purpose of this randomized trial was to compare the arterial healing response at short term, as a surrogate for safety and efficacy, between the Absorb and the metallic everolimus-eluting stent (EES...... was the 6-month optical frequency domain imaging healing score (HS) based on the presence of uncovered and/or malapposed stent struts and intraluminal filling defects. Main secondary endpoint included the device-oriented composite endpoint (DOCE) according to the Academic Research Consortium definition...

  19. Arterial healing following primary PCI using the Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) versus the durable polymer everolimus-eluting metallic stent (XIENCE) in patients with acute ST-elevation myocardial infarction

    Räber, Lorenz; Onuma, Yoshinobu; Brugaletta, Salvatore

    2015-01-01

    Aims: The Absorb bioresorbable vascular scaffold (Absorb BVS) provides similar clinical outcomes compared with a durable polymer-based everolimus-eluting metallic stent (EES) in stable coronary artery disease patients. ST-elevation myocardial infarction (STEMI) lesions have been associated with d...

  20. Differential Antitumoral Properties and Renal-Associated Tissue Damage Induced by Tacrolimus and Mammalian Target of Rapamycin Inhibitors in Hepatocarcinoma: In Vitro and In Vivo Studies.

    Elena Navarro-Villarán

    Full Text Available Orthotopic liver transplantation (OLT is the recommended treatment for patients at early stages of hepatocarcinoma (HCC with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2, being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.

  1. Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

    Mihajlovic, Jovan; Pechlivanoglou, Petros; Sabo, Ana; Tomic, Zdenko; Postma, Maarten J.

    2013-01-01

    Background: New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had

  2. Everolimus plus exemestane as first-line therapy in HR⁺, HER2⁻ advanced breast cancer in BOLERO-2.

    Beck, J Thaddeus; Hortobagyi, Gabriel N; Campone, Mario; Lebrun, Fabienne; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Masuda, Norikazu; Hart, Lowell; Melichar, Bohuslav; Dakhil, Shaker; Geberth, Matthias; Nunzi, Martina; Heng, Daniel Y C; Brechenmacher, Thomas; El-Hashimy, Mona; Douma, Shyanne; Ringeisen, Francois; Piccart, Martine

    2014-02-01

    The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.

  3. Dynamic tumor modeling of the dose–response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

    Stein, Andrew; Wang, Wenping; Carter, Alison A; Chiparus, Ovidiu; Hollaender, Norbert; Kim, Hyewon; Motzer, Robert J; Sarr, Celine

    2012-01-01

    The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose–response relationship of everolimus. The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and –15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose–response relationship

  4. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma.

    Escudier, Bernard; Sharma, Padmanee; McDermott, David F; George, Saby; Hammers, Hans J; Srinivas, Sandhya; Tykodi, Scott S; Sosman, Jeffrey A; Procopio, Giuseppe; Plimack, Elizabeth R; Castellano, Daniel; Gurney, Howard; Donskov, Frede; Peltola, Katriina; Wagstaff, John; Gauler, Thomas C; Ueda, Takeshi; Zhao, Huanyu; Waxman, Ian M; Motzer, Robert J

    2017-12-01

    The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  5. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

    Noguchi, Shinzaburo; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Puttawibul, Puttisak; Srimuninnimit, Vichien; Tokuda, Yutaka; Kuroi, Katsumasa; Iwase, Hirotaka; Inaji, Hideo; Ohsumi, Shozo; Noh, Woo-Chul; Nakayama, Takahiro; Ohno, Shinji; Rai, Yoshiaki; Park, Byeong-Woo; Panneerselvam, Ashok; El-Hashimy, Mona; Taran, Tetiana; Sahmoud, Tarek; Ito, Yoshinori

    2014-11-01

    The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

  6. Safety and Efficacy of Everolimus- Versus Sirolimus-Eluting Stents

    Jensen, Lisette Okkels; Thayssen, Per; Christiansen, Evald Høj

    2016-01-01

    BACKGROUND: Long-term safety and efficacy for everolimus-eluting stents (EES) versus those of sirolimus-eluting stents (SES) are unknown. OBJECTIVES: This study compared 5-year outcomes for EES with those for SES from the SORT OUT IV (Scandinavian Organization for Randomized Trials with Clinical...... rate was lower with EES (HR: 0.71, 95% CI: 0.55 to 0.90; p = 0.006; p interaction = 0.12). Definite stent thrombosis was lower with EES (0.4%) than with SES (2.0%; HR: 0.18, 95% CI: 0.07 to 0.46), with a lower risk of very late definite stent thrombosis in the EES group (0.2% vs. 1.4%, respectively; HR...... in Non-selected Patients With Coronary Heart Disease [SORT OUT IV]; NCT00552877)....

  7. Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus--results of a multicenter trial

    Arora, Stina Jørgensen; Erikstad, I; Ueland, T

    2012-01-01

    of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However...... with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal...

  8. A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

    Fury, Matthew G.; Lee, Nancy Y.; Sherman, Eric; Ho, Alan L.; Rao, Shyam; Heguy, Adriana; Shen, Ronglai; Korte, Susan; Lisa, Donna; Ganly, Ian; Patel, Snehal; Wong, Richard J.; Shaha, Ashok; Shah, Jatin; Haque, Sofia; Katabi, Nora; Pfister, David G.

    2013-01-01

    Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m 2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins

  9. A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

    Fury, Matthew G. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States); Lee, Nancy Y. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Sherman, Eric; Ho, Alan L. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States); Rao, Shyam [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Heguy, Adriana [Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Shen, Ronglai [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Korte, Susan; Lisa, Donna [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Ganly, Ian; Patel, Snehal; Wong, Richard J.; Shaha, Ashok; Shah, Jatin [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Haque, Sofia [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Katabi, Nora [Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Pfister, David G. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States)

    2013-11-01

    Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m{sup 2} weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.

  10. Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex.

    Steven Sparagana

    Full Text Available To determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients.A pooled analysis from 3 prospective studies consisting of a core phase (≥6 months and a long-term follow-up open-label extension.One phase 2 single-center and two phase 3 multicenter studies.Data were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus.Incidence of fertility events.A total of 43/112 patients (38.4% experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1% and irregular menstruation (17.0%. Seven patients (6.3% experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years. A total of 19/92 patients (20.7% who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%, and follicle-stimulating hormone levels were within normal limits for these patients.No new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex-associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus.ClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400.

  11. The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma.

    Bissler, John J; Franz, David N; Frost, Michael D; Belousova, Elena; Bebin, E Martina; Sparagana, Steven; Berkowitz, Noah; Ridolfi, Antonia; Kingswood, J Christopher

    2018-01-01

    Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney. This was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m 2 /day (target blood trough 5-15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged 20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed. Overall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7-88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity. Although everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.

  12. The Promus Premier everolimus-eluting platinum chromium stent with durable polymer evaluated in a real world all-comer population in Rotterdam cardiology hospital (the P-SEARCH registry)

    Lemmert, M.E.; Mieghem, N.M. van; Geuns, R.J.M. van; Diletti, R.; Bommel, R.J. van; Domburg, R.T. van; Jaegere, P.P. de; Regar, E.; Zijlstra, F.; Boersma, E.; Daemen, J.

    2017-01-01

    BACKGROUND: A new-generation everolimus eluting platinum-chromium stent (EePCS), offering improved radial strength, radiopacity and conformability compared to everolimus-eluting cobalt-chromium stents (EeCCS), was evaluated with regard to safety and efficacy in an all-comer cohort. METHODS: A total

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

    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.

  14. 1-year clinical outcomes of diabetic patients treated with everolimus-eluting bioresorbable vascular scaffolds: a pooled analysis of the ABSORB and the SPIRIT trials.

    Muramatsu, Takashi; Onuma, Yoshinobu; van Geuns, Robert-Jan; Chevalier, Bernard; Patel, Tejas M; Seth, Ashok; Diletti, Roberto; García-García, Hector M; Dorange, Cécile C; Veldhof, Susan; Cheong, Wai-Fung; Ozaki, Yukio; Whitbourn, Robert; Bartorelli, Antonio; Stone, Gregg W; Abizaid, Alexandre; Serruys, Patrick W

    2014-05-01

    The aim of this study was to evaluate 1-year clinical outcomes of diabetic patients treated with the Absorb bioresorbable vascular scaffold (BVS). Clinical outcomes of diabetic patients after BVS implantation have been unreported. This study included 101 patients in the ABSORB Cohort B trial and the first consecutive 450 patients with 1 year of follow-up in the ABSORB EXTEND trial. A total of 136 diabetic patients were compared with 415 nondiabetic patients. In addition, 882 diabetic patients treated with everolimus-eluting metal stents (EES) in pooled data from the SPIRIT trials (SPIRIT FIRST [Clinical Trial of the Abbott Vascular XIENCE V Everolimus Eluting Coronary Stent System], SPIRIT II [A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System], SPIRIT III [Clinical Trial of the XIENCE V Everolimus Eluting Coronary Stent System (EECSS)], SPIRIT IV Clinical Trial [Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System]) were used for the comparison by applying propensity score matching. The primary endpoint was a device-oriented composite endpoint (DoCE), including cardiac death, target vessel myocardial infarction, and target lesion revascularization at 1-year follow-up. The cumulative incidence of DoCE did not differ between diabetic and nondiabetic patients treated with the BVS (3.7% vs. 5.1%, p = 0.64). Diabetic patients treated with the BVS had a similar incidence of the DoCE compared with diabetic patients treated with EES in the matched study group (3.9% for the BVS vs. 6.4% for EES, p = 0.38). There were no differences in the incidence of definite or probable scaffold/stent thrombosis (0.7% for both diabetic and nondiabetic patients with the BVS; 1.0% for diabetic patients with the BVS vs. 1.7% for diabetic patients with EES in the matched study group). In the present analyses, diabetic patients treated with the BVS showed similar rates of DoCEs compared with nondiabetic patients treated with the BVS and

  15. Treatment options in HR⁺/HER2⁻ advanced breast cancer patients pretreated with nonsteroidal aromatase inhibitors: what does current evidence tell us?

    De Placido, Sabino; Pronzato, Paolo

    2015-01-01

    Many postmenopausal women with advanced or metastatic breast cancer (BC) receive nonsteroidal aromatase inhibitors (NSAIs). Virtually all of them experience progression, but may still gain benefit from a different endocrine or targeted agent. We indirectly compare the results of trials on endocrine or targeted treatment in HR(+)/HER2(-) mBC patients who progressed after a prior NSAI therapy. Although with the limitations of any indirect comparison, evidence suggests that only the combination of everolimus and exemestane is associated with a prolonged progression-free survival and a more evident clinical benefit than its comparators. We speculate that prior NSAI therapy can 'per se' individuate patients eligible to everolimus. More robust data from head-to-head trials will provide more grounded evidence on this issue.

  16. Everolimus plus exemestane versus bevacizumab-based chemotherapy for second-line treatment of hormone receptor-positive metastatic breast cancer in Greece: An economic evaluation study.

    Kourlaba, Georgia; Rapti, Vasiliki; Alexopoulos, Athanasios; Relakis, John; Koumakis, Georgios; Chatzikou, Magdalini; Maniadakis, Nikos; Georgoulias, Vassilis

    2015-08-05

    The objective of our study was to conduct a cost-effectiveness (CE) study of combined everolimus (EVE) and exemestane (EXE) versus the common clinical practice in Greece for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer (BC) progressing on nonsteroidal aromatase inhibitors (NSAI). The combinations of bevacizumab (BEV) plus paclitaxel (PACL) and BEV plus capecitabine (CAPE) were selected as comparators. A Markov model, consisting of three health states, was used to describe disease progression and evaluate the CE of the comparators from a third-party payer perspective over a lifetime horizon. Efficacy and safety data as well as utility values considered in the model were extracted from the relevant randomized Phase III clinical trials and other published studies. Direct medical costs referring to the year 2014 were incorporated in the model. A probabilistic sensitivity analysis was conducted to account for uncertainty and variation in the parameters of the model. Primary outcomes were patient survival (life-years), quality-adjusted life years (QALYs), total direct costs and incremental cost-effectiveness ratios (ICER). The discounted quality-adjusted survival of patients treated with EVE plus EXE was greater by 0.035 and 0.004 QALYs, compared to BEV plus PACL and BEV plus CAPE, respectively. EVE plus EXE was the least costly treatment in terms of drug acquisition, administration, and concomitant medications. The total lifetime cost per patient was estimated at €55,022, €67,980, and €62,822 for EVE plus EXE, BEV plus PACL, and BEV plus CAPE, respectively. The probabilistic analysis confirmed the deterministic results. Our results suggest that EVE plus EXE may be a dominant alternative relative to BEV plus PACL and BEV plus CAPE for the treatment of HR+/HER2- advanced BC patients failing initial therapy with NSAIs.

  17. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2.

    Pritchard, Kathleen I; Burris, Howard A; Ito, Yoshinori; Rugo, Hope S; Dakhil, Shaker; Hortobagyi, Gabriel N; Campone, Mario; Csöszi, Tibor; Baselga, José; Puttawibul, Puttisak; Piccart, Martine; Heng, Daniel; Noguchi, Shinzaburo; Srimuninnimit, Vichien; Bourgeois, Hugues; Gonzalez Martin, Antonio; Osborne, Karen; Panneerselvam, Ashok; Taran, Tetiana; Sahmoud, Tarek; Gnant, Michael

    2013-12-01

    Postmenopausal women with hormone receptor-positive (HR(+)) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR(+) advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest. BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR(+) advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up. Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths. Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+) advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in the United States.

    Xie, Jipan; Diener, Melissa; De, Gourab; Yang, Hongbo; Wu, Eric Q; Namjoshi, Madhav

    2013-01-01

    To estimate the budget impact of everolimus as the first and second treatment option after letrozole or anastrozole (L/A) failure for post-menopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). Pharmacy and medical budget impacts (2011 USD) were estimated over the first year of everolimus use in HR+, HER2- ABC from a US payer perspective. Epidemiology data were used to estimate target population size. Pre-everolimus entry treatment options included exemestane, fulvestrant, and tamoxifen. Pre- and post-everolimus entry market shares were estimated based on market research and assumptions. Drug costs were based on wholesale acquisition cost. Patients were assumed to be on treatment until progression or death. Annual medical costs were calculated as the average of pre- and post-progression medical costs weighted by the time in each period, adjusted for survival. One-way and two-way sensitivity analyses were conducted to assess the model robustness. In a hypothetical 1,000,000 member plan, 72 and 159 patients were expected to be candidates for everolimus treatment as first and second treatment option, respectively, after L/A failure. The total budget impact for the first year post-everolimus entry was $0.044 per member per month [PMPM] (pharmacy budget: $0.058 PMPM; medical budget: -$0.014 PMPM), assuming 10% of the target population would receive everolimus. The total budget impacts for the first and second treatment options after L/A failure were $0.014 PMPM (pharmacy budget: $0.018; medical budget: -$0.004) and $0.030 PMPM (pharmacy budget: $0.040; medical budget: -$0.010), respectively. Results remained robust in sensitivity analyses. Assumptions about some model input parameters were necessary and may impact results. Increased pharmacy costs for HR+, HER2- ABC following everolimus entry are expected to be partially offset by reduced medical service costs. Pharmacy and total

  19. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study.

    Campone, Mario; Bachelot, Thomas; Gnant, Michael; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Noguchi, Shinzaburo; Shtivelband, Mikhail; Pritchard, Kathleen I; Provencher, Louise; Burris, Howard A; Hart, Lowell; Melichar, Bohuslav; Hortobagyi, Gabriel N; Arena, Francis; Baselga, José; Panneerselvam, Ashok; Héniquez, Aurelia; El-Hashimyt, Mona; Taran, Tetiana; Sahmoud, Tarek; Piccart, Martine

    2013-08-01

    Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases. Copyright © 2013 The

  20. Plasma NGAL and glomerular filtration rate in cardiac transplant recipients treated with standard or reduced calcineurin inhibitor levels

    Gustafsson, Finn; Gude, Einar; Sigurdardottir, Vilborg

    2014-01-01

    GFR) at baseline (R(2) = 0.21; p year (median [25-75 % percentiles]: ΔmGFR 5.5 [-0.5-11.5] vs -1 [-7-4] ml/min/1.73 m(2); p = 0.006). Baseline P-NGAL predicted mGFR after 1 year (R(2) = 0.18; p ...: P-NGAL was measured in 88 cardiac transplantation patients (median 5 years post-transplant) with renal dysfunction randomized to continuation of conventional calcineurin inhibitor-based immunosuppression or switching to an everolimus-based regimen. RESULTS: P-NGAL correlated with measured GFR (m...

  1. Comparison of everolimus- and paclitaxel-eluting stents in patients with acute and stable coronary syndromes: pooled results from the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) Trials.

    Planer, David; Smits, Pieter C; Kereiakes, Dean J; Kedhi, Elvin; Fahy, Martin; Xu, Ke; Serruys, Patrick W; Stone, Gregg W

    2011-10-01

    This study sought to compare the clinical outcomes of everolimus-eluting stents (EES) versus paclitaxel-eluting stents (PES) in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD). Although randomized trials have shown superiority of EES to PES, the safety and efficacy of EES in ACS is unknown. We performed a patient-level pooled analysis from the prospective, randomized SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) II, III, IV, and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trials in which 2,381 patients with ACS and 4,404 patients with stable CAD were randomized to EES or to PES. Kaplan-Meier estimates of death, myocardial infarction (MI), ischemia-driven target lesion revascularization, and stent thrombosis were assessed at 2 years and stratified by clinical presentation (ACS vs. stable CAD). At 2 years, patients with ACS compared with stable CAD had higher rates of death (3.2% vs. 2.4%, hazard ratio [HR]: 1.37 [95% confidence interval (CI): 1.02 to 1.85], p = 0.04) and MI (4.9% vs. 3.4%, HR: 1.45 [95% CI: 1.14 to 1.85], p = 0.02). In patients with ACS, EES versus PES reduced the rate of death or MI (6.6% vs. 9.3%, HR: 0.70 [95% CI: 0.52 to 0.94], p = 0.02), stent thrombosis (0.7% vs. 2.9%, HR: 0.25 [95% CI: 0.12 to 0.52], p = 0.0002), and ischemia-driven target lesion revascularization (4.7% vs. 6.2%, HR: 0.69 [95% CI: 0.48 to 0.99], p = 0.04). In patients with stable CAD, EES reduced the rate of death or MI (4.5% vs. 7.1%, HR: 0.62 [95% CI: 0.48 to 0.80], p = 0.0002), stent thrombosis (0.7% vs. 1.8%, HR: 0.34 [95% CI: 0.19 to 0.62], p = 0.0002), and ischemia-driven target lesion revascularization (3.9% vs. 6.9%, HR: 0.55 [95% CI: 0.42 to 0.73], p SPIRIT II]; NCT00180310; SPIRIT III: A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the

  2. Effects of cobalt-chromium everolimus eluting stents or bare metal stent on fatal and non-fatal cardiovascular events: patient level meta-analysis.

    Valgimigli, Marco; Sabaté, Manel; Kaiser, Christoph; Brugaletta, Salvatore; de la Torre Hernandez, Jose Maria; Galatius, Soeren; Cequier, Angel; Eberli, Franz; de Belder, Adam; Serruys, Patrick W; Ferrante, Giuseppe

    2014-11-04

    To examine the safety and effectiveness of cobalt-chromium everolimus eluting stents compared with bare metal stents. Individual patient data meta-analysis of randomised controlled trials. Cox proportional regression models stratified by trial, containing random effects, were used to assess the impact of stent type on outcomes. Hazard ratios with 95% confidence interval for outcomes were reported. Medline, Embase, the Cochrane Central Register of Controlled Trials. Randomised controlled trials that compared cobalt-chromium everolimus eluting stents with bare metal stents were selected. The principal investigators whose trials met the inclusion criteria provided data for individual patients. The primary outcome was cardiac mortality. Secondary endpoints were myocardial infarction, definite stent thrombosis, definite or probable stent thrombosis, target vessel revascularisation, and all cause death. The search yielded five randomised controlled trials, comprising 4896 participants. Compared with patients receiving bare metal stents, participants receiving cobalt-chromium everolimus eluting stents had a significant reduction of cardiac mortality (hazard ratio 0.67, 95% confidence interval 0.49 to 0.91; P=0.01), myocardial infarction (0.71, 0.55 to 0.92; P=0.01), definite stent thrombosis (0.41, 0.22 to 0.76; P=0.005), definite or probable stent thrombosis (0.48, 0.31 to 0.73; Pstents the use of cobalt-chromium everolimus eluting stents improves global cardiovascular outcomes including cardiac survival, myocardial infarction, and overall stent thrombosis. © Valgimigli et al 2014.

  3. Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1.

    Toi, Masakazu; Shao, Zhimin; Hurvitz, Sara; Tseng, Ling-Ming; Zhang, Qingyuan; Shen, Kunwei; Liu, Donggeng; Feng, Jifeng; Xu, Binghe; Wang, Xiaojia; Lee, Keun Seok; Ng, Ting Ying; Ridolfi, Antonia; Noel-Baron, Florence; Ringeisen, Francois; Jiang, Zefei

    2017-04-11

    The current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial. Postmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR-) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety. In the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61-1.11)). In the HR- subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29-0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm. The efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population. ClinicalTrials.gov, NCT00876395 . Registered on 2 April 2009.

  4. A randomized study to compare bioactive titanium stents and everolimus-eluting stents in diabetic patients (TITANIC XV): 1-year results.

    López-Mínguez, José R; Nogales-Asensio, Juan M; Doncel-Vecino, Luis J; Merchán-Herrera, Antonio; Pomar-Domingo, Francisco; Martínez-Romero, Pedro; Fernández-Díaz, José A; Valdesuso-Aguilar, Raúl; Moreu-Burgos, José; Díaz-Fernández, José

    2014-07-01

    Up to 25% of patients who undergo a percutaneous coronary intervention show some limitation in the use of drug-eluting stents. The aim of this study was to evaluate if titanium-nitride-oxide-coated stents could be a good alternative to everolimus-eluting stents in diabetic patients. A total of 173 diabetic patients with lesions at moderate risk of restenosis (exclusion criteria: diameter 28 mm in vessels < 3mm, chronic occlusion) were randomized to a titanium group (83 patients) or an everolimus group (90 patients). Baseline characteristics were well balanced; 28.3% of patients were insulin dependent. At 1 year, the incidence of major adverse cardiac events (death, nonfatal myocardial infarction, stroke, or repeat target vessel revascularization) was significantly higher in the titanium group than in the everolimus group (total, 14.5% vs 4.4%; P = .02; noninsulin-dependent subgroup, 9.7% vs 3.2%; P = .14; insulin-dependent subgroup, 28.6% vs 7.1%; P = .04). The incidence of death, nonfatal myocardial infarction, stroke, or any revascularization was 16.9% in the titanium group and 7.8% in the everolimus group (P = .06). Target lesion and vessel revascularizations occurred in 8.4% compared with 3.3% (P = .15) and in 13.3% compared with 3.3% (P = .01) in the titanium and everolimus groups, respectively. Angiographic follow-up at 9 months showed significantly less late lumen loss in the everolimus group (in-segment, 0.52 [standard deviation, 0.58) mm vs -0.05 [0.32] mm; in-stent, 0.76 [0.54] mm vs 0.13 [0.31] mm; P < .0001). The everolimus-eluting stent is superior to the titanium stent for clinical and angiographic end points in diabetic patients with lesions at moderate risk of restenosis. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  5. Biodegradable-Polymer Biolimus-Eluting Stents versus Durable-Polymer Everolimus-Eluting Stents at One-Year Follow-Up: A Registry-Based Cohort Study.

    Parsa, Ehsan; Saroukhani, Sepideh; Majlessi, Fereshteh; Poorhosseini, Hamidreza; Lofti-Tokaldany, Masoumeh; Jalali, Arash; Salarifar, Mojtaba; Nematipour, Ebrahim; Alidoosti, Mohammad; Aghajani, Hassan; Amirzadegan, Alireza; Kassaian, Seyed Ebrahim

    2016-04-01

    We compared outcomes of percutaneous coronary intervention patients who received biodegradable-polymer biolimus-eluting stents with those who received durable-polymer everolimus-eluting stents. At Tehran Heart Center, we performed a retrospective analysis of the data from January 2007 through December 2011 on 3,270 consecutive patients with coronary artery disease who underwent percutaneous coronary intervention with the biodegradable-polymer biolimus-eluting stent or the durable-polymer everolimus-eluting stent. We excluded patients with histories of coronary artery bypass grafting or percutaneous coronary intervention, acute ST-segment-elevation myocardial infarction, or the implantation of 2 different stent types. Patients were monitored for 12 months. The primary endpoint was a major adverse cardiac event, defined as a composite of death, nonfatal myocardial infarction, and target-vessel and target-lesion revascularization. Durable-polymer everolimus-eluting stents were implanted in 2,648 (81%) and biodegradable-polymer biolimus-eluting stents in 622 (19%) of the study population. There was no significant difference between the 2 groups (2.7% vs 2.7%; P=0.984) in the incidence of major adverse cardiac events. The cumulative adjusted probability of major adverse cardiac events in the biodegradable-polymer biolimus-eluting stent group did not differ from that of such events in the durable-polymer everolimus-eluting stent group (hazard ratio=0.768; 95% confidence interval, 0.421-1.44; P=0.388). We conclude that in our patients the biodegradable-polymer biolimus-eluting stent was as effective and safe, during the 12-month follow-up period, as was the durable-polymer everolimus-eluting stent.

  6. Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.

    Perrin, Allison; Sherman, Steven; Pal, Sumanta; Chua, Andrew; Gorritz, Magdaliz; Liu, Zhimei; Wang, Xufang; Culver, Kenneth; Casciano, Roman; Garrison, Louis P

    2015-03-01

    Everolimus and axitinib are approved in the US to treat patients with advanced renal cell carcinoma (RCC) after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Two indirect comparisons performed to evaluate progression-free survival in patients treated with everolimus vs axitinib suggested similar efficacy between the two treatments. Therefore, this analysis compares the lifetime costs of these two therapies among sunitinib-refractory advanced RCC patients from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory advanced RCC patients and estimate the cost of treating patients with everolimus vs axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. The model included the following resources: active treatments, post-progression treatments, adverse events, physician and nurse visits, scans and tests, and palliative care. Resource utilization inputs were derived from a US claims database analysis. Additionally, a 3% annual discount rate was applied to costs, and the robustness of the model results was tested by conducting sensitivity analyses, including those on dosing scheme and post-progression treatment costs. Base case results demonstrated that patients treated with everolimus cost an average of $12,985 (11%) less over their lifetimes than patients treated with axitinib. The primary difference in costs was related to active treatment, which was largely driven by axitinib's higher dose intensity. RESULTS remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity and discount rates. The results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory advanced RCC patients in the US.

  7. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease

    Onuma, Yoshinobu; Dudek, Dariusz; Thuesen, Leif

    2013-01-01

    This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California).......This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California)....

  8. Health-related quality of life and disease symptoms in postmenopausal women with HR(+), HER2(-) advanced breast cancer treated with everolimus plus exemestane versus exemestane monotherapy.

    Campone, Mario; Beck, J Thaddeus; Gnant, Michael; Neven, Patrick; Pritchard, Kathleen I; Bachelot, Thomas; Provencher, Louise; Rugo, Hope S; Piccart, Martine; Hortobagyi, Gabriel N; Nunzi, Martina; Heng, Daniel Y C; Baselga, José; Komorowski, Anna; Noguchi, Shinzaburo; Horiguchi, Jun; Bennett, Lee; Ziemiecki, Ryan; Zhang, Jie; Cahana, Ayelet; Taran, Tetiana; Sahmoud, Tarek; Burris, Howard A

    2013-11-01

    Everolimus (EVE)+exemestane (EXE; n = 485) more than doubled median progression-free survival versus placebo (PBO) + EXE (n = 239), with a manageable safety profile and no deterioration in health-related quality-of-life (HRQOL) in patients with hormone-receptor-positive (HR(+)) advanced breast cancer (ABC) who recurred or progressed on/after nonsteroidal aromatase inhibitor (NSAI) therapy. To further evaluate EVE + EXE impact on disease burden, we conducted additional post-hoc analyses of patient-reported HRQOL. HRQOL was assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline and every 6 weeks thereafter until treatment discontinuation because of disease progression, toxicity, or consent withdrawal. Endpoints included the QLQ-C30 Global Health Status (QL2) scale, the QLQ-BR23 breast symptom (BRBS), and arm symptom (BRAS) scales. Between-group differences in change from baseline were assessed using linear mixed models with selected covariates. Sensitivity analysis using pattern-mixture models determined the effect of study discontinuation on/before week 24. Treatment arms were compared using differences of least squares mean (LSM) changes from baseline and 95% confidence intervals (CIs) at each timepoint and overall. Clinicaltrials.gov: NCT00863655. Progression-free survival, survival, response rate, safety, and HRQOL. Linear mixed models (primary model) demonstrated no statistically significant overall difference between EVE + EXE and PBO + EXE for QL2 (LSM difference = -1.91; 95% CI = -4.61, 0.78), BRBS (LSM difference = -0.18; 95% CI = -1.98, 1.62), or BRAS (LSM difference = -0.42; 95% CI = -2.94, 2.10). Based on pattern-mixture models, patients who dropped out early had worse QL2 decline on both treatments. In the expanded pattern-mixture model, EVE + EXE-treated patients who did not drop out early had stable BRBS and BRAS relative to PBO + EXE. HRQOL data were not collected after disease progression. These analyses confirm

  9. The Impact of Post-Procedural Asymmetry, Expansion, and Eccentricity of Bioresorbable Everolimus-Eluting Scaffold and Metallic Everolimus-Eluting Stent on Clinical Outcomes in the ABSORB II Trial.

    Suwannasom, Pannipa; Sotomi, Yohei; Ishibashi, Yuki; Cavalcante, Rafael; Albuquerque, Felipe N; Macaya, Carlos; Ormiston, John A; Hill, Jonathan; Lang, Irene M; Egred, Mohaned; Fajadet, Jean; Lesiak, Maciej; Tijssen, Jan G; Wykrzykowska, Joanna J; de Winter, Robbert J; Chevalier, Bernard; Serruys, Patrick W; Onuma, Yoshinobu

    2016-06-27

    The study sought to investigate the relationship between post-procedural asymmetry, expansion, and eccentricity indices of metallic everolimus-eluting stent (EES) and bioresorbable vascular scaffold (BVS) and their respective impact on clinical events at 1-year follow-up. Mechanical properties of a fully BVS are inherently different from those of permanent metallic stent. The ABSORB II (A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions) trial compared the BVS and metallic EES in the treatment of a de novo coronary artery stenosis. Protocol-mandated intravascular ultrasound imaging was performed pre- and post-procedure in 470 patients (162 metallic EES and 308 BVS). Asymmetry index (AI) was calculated per lesion as: (1 - minimum scaffold/stent diameter/maximum scaffold/stent diameter). Expansion index and optimal scaffold/stent expansion followed the definition of the MUSIC (Multicenter Ultrasound Stenting in Coronaries) study. Eccentricity index (EI) was calculated as the ratio of minimum and maximum scaffold/stent diameter per cross section. The incidence of device-oriented composite endpoint (DoCE) was collected. Post-procedure, the metallic EES group was more symmetric and concentric than the BVS group. Only 8.0% of the BVS arm and 20.0% of the metallic EES arm achieved optimal scaffold/stent expansion (p 0.30 is an independent predictor of DoCE (hazard ratio: 3.43; 95% confidence interval: 1.08 to 10.92; p = 0.037). BVS implantation is more frequently associated with post-procedural asymmetric and eccentric morphology compared to metallic EES. Post-procedural devices asymmetry were independently associated with DoCE following percutaneous coronary intervention. However, this approach should be viewed as hypothesis generating due to low event rates. (ABSORB II Randomized Controlled Trial [ABSORB II]; NCT01425281). Copyright © 2016 American

  10. Role of mTOR Inhibitors in Kidney Disease

    Moto Kajiwara

    2016-06-01

    Full Text Available The first compound that inhibited the mammalian target of rapamycin (mTOR, sirolimus (rapamycin was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui. Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1 and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild. To obtain compounds with more potent antiproliferative effects, ATP-competitive inhibitors of mTOR targeting both mTORC1 and mTORC2 have been developed and tested in clinical trials as anticancer drugs. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors, and immunosuppressive agents for transplantation of various organs. This review discusses the role of mTOR inhibitors in renal disease with a particular focus on renal cancer, diabetic nephropathy, and kidney transplantation.

  11. Safety and efficacy of everolimus-eluting stents for bare-metal in-stent restenosis

    Ota, Hideaki [Division of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC 20010 (United States); Mahmoudi, Michael [University of Surrey, Guildford Road, Surrey, GU2-7XH (United Kingdom); Torguson, Rebecca; Satler, Lowell F.; Suddath, William O.; Pichard, Augusto D. [Division of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC 20010 (United States); Waksman, Ron, E-mail: ron.waksman@medstar.net [Division of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC 20010 (United States)

    2015-04-15

    Objective: The aim of this study was to compare the safety and efficacy of the everolimus-eluting stents (EES) with the paclitaxel-eluting stent (PES) and sirolimus-eluting stent (SES) for the treatment of bare-metal in-stent restenosis. Background: The optimal treatment for bare-metal in-stent restenosis remains controversial. Methods: The study cohort comprised 322 consecutive patients (543 lesions) who presented with bare-metal in-stent restenosis to our institution and underwent coronary artery stent implantation with EES (114 patients; 181 lesions), PES (65 patients; 116 lesions) and SES (143 patients; 246 lesions). The analyzed clinical parameters were the 1-year rates of death, Q-wave myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), definite stent thrombosis (ST) and major adverse cardiac events (MACE) defined as the composite of death, MI, or TLR at 1-year. Results: The three groups were well matched for the conventional risk factors except for age and chronic kidney disease. The 1-year analyzed clinical parameters were similar in the three groups: death (EES = 3.5%, PES = 4.6%, SES = 4.2%; p = 0.94), MI (EES = 3.5%, PES = 6.3%, SES = 2.1%; p = 0.31), TLR (EES = 9.8%, PES = 9.5%, SES = 5.7%; p = 0.42), TVR (EES = 14.3%, PES = 11.1%, SES = 11.3%; p = 0.74), definite ST (EES = 0.9%, PES = 3.1%, SES = 3.5%; p = 0.38) and MACE (EES = 14.0%, PES = 15.4%, SES = 10.5%; p = 0.54). Male gender (hazard ratio = 0.47; 95% confidence interval = 0.25–0.88) and number of treated lesions (hazard ratio = 1.47; 95% confidence interval = 1.06–2.05) were found to be independent predictors of MACE. Conclusion: The results of the present study indicate that EES may provide similar safety and efficacy as first generation DES for the treatment of patients presenting with bare-metal in-stent restenosis.

  12. Clinical implications of recent studies using mTOR inhibitors to treat advanced hormone receptor-positive breast cancer

    Arena, Francis

    2014-01-01

    Breast cancer is a leading cause of cancer-related death worldwide. Approximately 75% of breast cancer is hormone receptor-positive (HR + ) and is managed with endocrine therapies. However, relapse or disease progression caused by primary or acquired endocrine resistance is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endocrine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when compared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising. Recently, everolimus was approved in combination with exemestane by the US Food and Drug Administration for treating postmenopausal women with advanced HR + breast cancer, based on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted agent approved for combating endocrine resistance

  13. Vitamins C and K3: A Powerful Redox System for Sensitizing Leukemia Lymphocytes to Everolimus and Barasertib.

    Ivanova, Donika; Zhelev, Zhivko; Lazarova, Dessislava; Getsov, Plamen; Bakalova, Rumiana; Aoki, Ichio

    2018-03-01

    Recent studies provided convincing evidence for the anticancer activity of combined application of vitamin C and pro-vitamin K3 (menadione). The molecular pathways underlying this process are still not well established. The present study aimed to investigate the effect of the combination of vitamin C plus pro-vitamin K3 on the redox status of leukemia and normal lymphocytes, as well as their sensitizing effect for a variety of anticancer drugs. Cytotoxicity of the substances was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by fluorescein isothiocyanate-annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen and nitrogen species and protein-carbonyl products. Combined administration of 300 μM vitamin C plus 3 μM pro-vitamin K3 reduced the viability of leukemia lymphocytes by ~20%, but did not influence the viability of normal lymphocytes. All combinations of anticancer drug plus vitamins C and K3 were characterized by synergistic cytotoxicity towards Jurkat cells, compared to cells treated with drug alone for 24 h. In the case of barasertib and everolimus, this synergistic cytotoxicity increased within 72 hours. It was accompanied by strong induction of apoptosis, but a reduction of level of hydroperoxides and moderately increased protein-carbonyl products in leukemia cells. Leukemia lymphocytes were more sensitive to combined administration of anticancer drug (everolimus or barasertib) plus vitamins C and K3, compared to normal lymphocytes. The combination of vitamin C plus K3 seems to be a powerful redox system that could specifically influence redox homeostasis of leukemia cells and sensitize them to conventional chemotherapy. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

    Casciano, Roman; Chulikavit, Maruit; Di Lorenzo, Giuseppe; Liu, Zhimei; Baladi, Jean-Francois; Wang, Xufang; Robertson, Justin; Garrison, Lou

    2011-01-01

    A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  15. FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

    Tedesco-Silva, H; Lorber, M I; Foster, C E; Sollinger, H W; Mendez, R; Carvalho, D B; Shapiro, R; Rajagopalan, P R; Mayer, H; Slade, J; Kahan, B D

    2009-01-01

    This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

  16. The evolving field of kinase inhibitors in thyroid cancer.

    Marotta, V; Sciammarella, C; Vitale, M; Colao, A; Faggiano, A

    2015-01-01

    Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis.

    Yang, Lin; Alyasova, Anna; Ye, Dingwei; Ridolfi, Antonia; Dezzani, Luca; Motzer, Robert J

    2018-02-17

    RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0-85.3) for Asian patients and 74.7% (95% CI 63.6-83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%). This RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small

  18. The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial.

    Randell, Elizabeth; McNamara, Rachel; Davies, D Mark; Owen-Jones, Eleri; Kirby, Nigel; Angel, Lianna; Drew, Cheney; Cannings-John, Rebecca; Smalley, Michelle; Saxena, Anurag; McDermott, Emer; Stockwell, Laura; de Vries, Petrus J; Hood, Kerry; Sampson, Julian R

    2016-08-11

    Tuberous sclerosis complex (TSC) is a genetic disorder affecting about 1 in 6000 people and is characterised by the development of tumours in many organs, including the skin and kidneys, and by a range of neurological and neuropsychiatric manifestations. TSC-associated neuropsychiatric disorders (TAND) occur in the majority of those with TSC, and they have a significant impact on patients and their families, given the everyday impact of TAND on education, employment, family and social life. The potential benefits of better treatment for TAND therefore include reduction in health care demands and wider benefits for patients and their carers. We have planned a single-centre, two-arm, individually randomised, phase II, double-blind, placebo-controlled trial of everolimus versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis. Everolimus is a licensed medicine in this patient group, but for a different target of effect. The present trial is a proof-of-principle study developed to provide effect size estimates which may be used to inform the design of subsequent trials. Forty-eight patients aged 16-60 years with tuberous sclerosis who have an IQ >60 and a significant deficit (at least -2 SD) in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to receive everolimus or placebo, respectively. Participants will be assessed for eligibility and then be started on study medication 4 weeks later. They will then be randomised and receive placebo or everolimus for 24 weeks. Neurocognitive and safety assessments will be carried out at baseline and weeks 4, 12, 24 and 36. This study is designed to determine the effect sizes of treatment with everolimus or placebo for 6 months on specific neurocognitive functions-recall memory (verbal and non-verbal) and executive function-in people affected by TSC who have significant deficits in these functions. These data will provide new evidence to determine whether

  19. Comparative vascular responses three months after paclitaxel and everolimus-eluting stent implantation in streptozotocin-induced diabetic porcine coronary arteries

    Sheehy Alexander

    2012-06-01

    Full Text Available Abstract Background Diabetes remains a significant risk factor for restenosis/thrombosis following stenting. Although vascular healing responses following drug-eluting stent (DES treatment have been characterized previously in healthy animals, comparative assessments of different DES in a large animal model with isolated features of diabetes remains limited. We aimed to comparatively assess the vascular response to paclitaxel-eluting (PES and everolimus-eluting (EES stents in a porcine coronary model of streptozotocin (STZ-induced type I diabetes. Method Twelve Yucatan swine were induced hyperglycemic with a single STZ dose intravenously to ablate pancreatic β-cells. After two months, each animal received one XIENCE V® (EES and one Taxus Liberte (PES stent, respectively, in each coronary artery. After three months, vascular healing was assessed by angiography and histomorphometry. Comparative in vitro effects of everolimus and paclitaxel (10-5 M–10-12 M after 24 hours on carotid endothelial (EC and smooth muscle (SMC cell viability under hyperglycemic (42 mM conditions were assayed by ELISA. Caspase-3 fluorescent assay was used to quantify caspase-3 activity of EC treated with everolimus or paclitaxel (10-5 M, 10-7 M for 24 hours. Results After 3 months, EES reduced neointimal area (1.60 ± 0.41 mm, p vs. 0.08 ± 0.05, greater medial necrosis grade (0.52 ± 0.26 vs. 0.0 ± 0.0, and persistently elevated fibrin scores (1.60 ± 0.60 vs. 0.63 ± 0.41 with PES compared to EES (p In vitro, paclitaxel significantly increased (p -7 M, while everolimus did not affect EC/SMC apoptosis/necrosis within the dose range tested. In ECs, paclitaxel (10-5 M significantly increased caspase-3 activity (p  Conclusion After 3 months, both DES exhibited signs of delayed healing in a STZ-induced diabetic swine model. PES exhibited greater neointimal area, increased inflammation, greater medial necrosis, and

  20. Alternative signaling pathways as potential therapeutic targets for overcoming EGFR and c-Met inhibitor resistance in non-small cell lung cancer.

    Jason T Fong

    Full Text Available The use of tyrosine kinase inhibitors (TKIs against EGFR/c-Met in non-small cell lung cancer (NSCLC has been shown to be effective in increasing patient progression free survival (PFS, but their efficacy is limited due to the development of resistance and tumor recurrence. Therefore, understanding the molecular mechanisms underlying development of drug resistance in NSCLC is necessary for developing novel and effective therapeutic approaches to improve patient outcome. This study aims to understand the mechanism of EGFR/c-Met tyrosine kinase inhibitor (TKI resistance in NSCLC. H2170 and H358 cell lines were made resistant to SU11274, a c-Met inhibitor, and erlotinib, an EGFR inhibitor, through step-wise increases in TKI exposure. The IC50 concentrations of resistant lines exhibited a 4-5 and 11-22-fold increase for SU11274 and erlotinib, respectively, when compared to parental lines. Furthermore, mTOR and Wnt signaling was studied in both cell lines to determine their roles in mediating TKI resistance. We observed a 2-4-fold upregulation of mTOR signaling proteins and a 2- to 8-fold upregulation of Wnt signaling proteins in H2170 erlotinib and SU11274 resistant cells. H2170 and H358 cells were further treated with the mTOR inhibitor everolimus and the Wnt inhibitor XAV939. H358 resistant cells were inhibited by 95% by a triple combination of everolimus, erlotinib and SU11274 in comparison to 34% by a double combination of these drugs. Parental H2170 cells displayed no sensitivity to XAV939, while resistant cells were significantly inhibited (39% by XAV939 as a single agent, as well as in combination with SU11274 and erlotinib. Similar results were obtained with H358 resistant cells. This study suggests a novel molecular mechanism of drug resistance in lung cancer.

  1. [Syk inhibitors].

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  2. The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

    Schult, Catrin; Boldt, Sonja; Wolkenhauer, Olaf; Neri, Luca Maria; Freund, Mathias; Junghanss, Christian; Dahlhaus, Meike; Ruck, Sabine; Sawitzky, Mandy; Amoroso, Francesca; Lange, Sandra; Etro, Daniela; Glass, Aenne; Fuellen, Georg

    2010-01-01

    Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells

  3. Syk inhibitors.

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  4. The Additional Costs per Month of Progression-Free Survival and Overall Survival: An Economic Model Comparing Everolimus with Cabozantinib, Nivolumab, and Axitinib for Second-Line Treatment of Metastatic Renal Cell Carcinoma.

    Swallow, Elyse; Messali, Andrew; Ghate, Sameer; McDonald, Evangeline; Duchesneau, Emilie; Perez, Jose Ricardo

    2018-04-01

    When considering optimal second-line treatments for metastatic renal cell carcinoma (mRCC), clinicians and payers seek to understand the relative clinical benefits and costs of treatment. To use an economic model to compare the additional cost per month of overall survival (OS) and of progression-free survival (PFS) for cabozantinib, nivolumab, and axitinib with everolimus for the second-line treatment of mRCC from a third-party U.S. payer perspective. The model evaluated mean OS and PFS and costs associated with drug acquisition/administration; adverse event (AE) treatment; monitoring; and postprogression (third-line treatment, monitoring, and end-of-life costs) over 1- and 2-year horizons. Efficacy, safety, and treatment duration inputs were estimated from regimens' pivotal clinical trials; for everolimus, results were weighted across trials. Mean 1- and 2-year OS and mean 1-year PFS were estimated using regimens' reported OS and PFS Kaplan-Meier curves. Dosing and administration inputs were consistent with approved prescribing information and the clinical trials used to estimate efficacy and safety inputs. Cost inputs came from published literature and public data. Additional cost per additional month of OS or PFS was calculated using the ratio of the cost difference per treated patient and the corresponding difference in mean OS or PFS between everolimus and each comparator. One-way sensitivity analyses were conducted by varying efficacy and cost inputs. Compared with everolimus, cabozantinib, nivolumab, and axitinib were associated with 1.6, 0.3, and 0.5 additional months of PFS, respectively, over 1 year. Cabozantinib and nivolumab were associated with additional months of OS compared with everolimus (1 year: 0.7 and 0.8 months; 2 years: 1.6 and 2.3 months; respectively); axitinib was associated with fewer months (1 year: -0.2 months; 2 years: -0.7 months). The additional costs of treatment with cabozantinib, nivolumab, or axitinib versus everolimus over 1

  5. The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415

    Zhang, Wei; Chen, Bingyu; Zhang, Yu; Li, Kaiqiang; Hao, Ke; Jiang, Luxi; Wang, Ying; Mou, Xiaozhou; Xu, Xiaodong; Wang, Zhen

    2017-01-01

    Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma (HCC) represents a valuable treatment target. Recent studies have developed a highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM concentrations of CZ415 efficiently inhibited survival and induced apoptosis in HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes. Mechanistic studies showed that CZ415 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in HepG2 cells. Meanwhile, activation of mTORC1 (p-S6K1) and mTORC2 (p-AKT, Ser-473) was almost blocked by CZ415. In vivo studies revealed that oral administration of CZ415 significantly suppressed HepG2 xenograft tumor growth in severe combined immuno-deficient (SCID) mice. Activation of mTORC1/2 was also largely inhibited in CZ415-treated HepG2 tumor tissue. Together, these results show that CZ415 blocks mTORC1/2 activation and efficiently inhibits HCC cell growth in vitro and in vivo. - Highlights: • CZ415 is anti-survival and pro-apoptotic to hepatocellular carcinoma (HCC) cells. • CZ415 inhibits HCC cell proliferation, more efficiently than mTORC1 inhibitors. • CZ415 blocks assembly and activation of both mTORC1 and mTORC2 in HCC cells. • CZ415 oral administration inhibits HepG2 tumor growth in SCID mice. • mTORC1/2 activation in HepG2 tumor is inhibited with CZ415 administration.

  6. Simultaneous Determination of Cyclosporine A, Tacrolimus, Sirolimus, and Everolimus in Whole-Blood Samples by LC-MS/MS

    Mustafa Karapirli

    2012-01-01

    Full Text Available Objectives. Cyclosporine A (CyA, tacrolimus (TRL, sirolimus (SIR, and everolimus (RAD are immunosuppressive drugs frequently used in organ transplantation. Our aim was to confirm a robust sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS method for determination of CyA, TRL, SIR, and RAD in whole-blood samples. Materials and Methods. We used an integrated online solid-phase extraction-LC-MS/MS system and atmospheric pressure ionization tandem mass spectrometry (API-MS/MS in the multiple reaction monitoring (MRM detection mode. CyA, TRL, SIR, and RAD were simultaneously analyzed in whole blood treated with precipitation reagent taken from transplant patients. Results. System performance parameters were suitable for using this method as a high-throughput technique in clinical practice. The high concentration of one analyte in the sample did not affect the concentration of other analytes. Total analytical time was 2.5 min, and retention times of all analytes were shorter than 2 minutes. Conclusion. This LC-MS/MS method can be preferable for therapeutic drug monitoring of these immunosuppressive drugs (CyA, TRL, SRL, and RAD in whole blood. Sample preparation was too short and simple in this method, and it permits robust, rapid, sensitive, selective, and simultaneous determination of these drugs.

  7. Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.

    Royce, Melanie; Bachelot, Thomas; Villanueva, Cristian; Özgüroglu, Mustafa; Azevedo, Sergio J; Cruz, Felipe Melo; Debled, Marc; Hegg, Roberto; Toyama, Tatsuya; Falkson, Carla; Jeong, Joon; Srimuninnimit, Vichien; Gradishar, William J; Arce, Christina; Ridolfi, Antonia; Lin, Chinjune; Cardoso, Fatima

    2018-03-22

    Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4

  8. Clinical Application of Everolimus in Field of Organ Transplantation%依维莫司在器官移植领域的临床应用

    刘丽; 王华光

    2015-01-01

    Objective To summary the clinical application of everolimus in the field of organ transplantation by describing the action mechanism, pharmacokinetics, influence factors, clinical evaluation, adverse reaction, and so on. Methods By consulting the literatures about the mechanism, pharmacokinetics and clinical researches of everolimus in recent years, the important informations were extracted, analyzed and summarized for conducting this review. Results and Conclusion Everolimus can maintain better renal function in the as-pect of organ transplantation;various factors, such as food, drugs, can affect its pharmacokinetic properties. With the existing research clin-ical treatment regimen as the guidance, individualized medication regime and monitoring its blood concentration can increase the curative effect and reduce the adverse reactions.%目的:从作用机制、药代动力学性质及影响因素、临床评价、不良反应等方面简述依维莫司在器官移植领域的临床应用。方法查阅近几年文献,提取重要信息,通过分析、归纳进行综述。结果与结论依维莫司用于器官移植能维持较好的肾功能。食物、药物等多种因素均能影响其药代动力学性质。以已有的研究性临床治疗方案为指导,采用依维莫司个体化给药方案,监测其血药浓度,可提高疗效、降低不良反应。

  9. Risk and timing of clinical events according to diabetic status of patients treated with everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting stent: 2-year results from a propensity score matched comparison of ABSORB EXTEND and SPIRIT trials.

    Campos, Carlos M; Caixeta, Adriano; Franken, Marcelo; Bartorelli, Antonio L; Whitbourn, Robert J; Wu, Chiung-Jen; Li Paul Kao, Hsien; Rosli, Mohd Ali; Carrie, Didier; De Bruyne, Bernard; Stone, Gregg W; Serruys, Patrick W; Abizaid, Alexandre

    2018-02-15

    to compare the occurrence of clinical events in diabetics treated with the Absorb bioresorbable vascular scaffold (Absorb BVS; Abbott Vascular, Santa Clara, CA) versus everolimus-eluting metal stents (EES; XIENCE V; Abbott Vascular, Santa Clara, CA) BACKGROUND: There are limited data dedicated to clinical outcomes of diabetic patients treated with bioresorbable scaffolds (BRS) at 2-year horizon. The present study included 812 patients in the ABSORB EXTEND study in which a total of 215 diabetic patients were treated with Absorb BVS. In addition, 882 diabetic patients treated with EES in pooled data from the SPIRIT clinical program (SPIRIT II, SPIRIT III and SPIRIT IV trials) were used for comparison by applying propensity score matching using 29 different variables. The primary endpoint was ischemia driven major adverse cardiac events (ID-MACE), including cardiac death, myocardial infarction (MI), and ischemia driven target lesion revascularization (ID-TLR). After 2 years, the ID-MACE rate was 6.5% in the Absorb BVS vs. 8.9% in the Xience group (P = 0.40). There was no difference for MACE components or definite/probable device thrombosis (HR: 1.43 [0.24,8.58]; P = 0.69). The occurrence of MACE was not different for both diabetic status (insulin- and non-insulin-requiring diabetes) in all time points up to the 2-year follow-up for the Absorb and Xience groups. In this largest ever patient-level pooled comparison on the treatment of diabetic patients with BRS out to two years, individuals with diabetes treated with the Absorb BVS had a similar rate of MACE as compared with diabetics treated with the Xience EES. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  10. Rationale and Design of a Randomized Clinical Comparison of Everolimus-Eluting (Xience V/Promus) and Sirolimus-Eluting (Cypher Select+) Coronary Stents in Unselected Patients with Coronary Heart Disease

    Jensen, Lisette Okkels; Thayssen, Per; Tilsted, Hans Henrik

    2010-01-01

    with Clinical Outcome (SORT OUT) IV trial was designed as a prospective, multi-center, open-label, all-comer, two-arm, randomized, non-inferiority study comparing the everolimus-eluting stent with the sirolimus-eluting stent in the treatment of atherosclerotic coronary artery lesions. Based on a non...

  11. Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial

    Gutiérrez-Chico, Juan Luis; van Geuns, Robert Jan; Regar, Evelyn

    2011-01-01

    To compare the tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent (ZES) vs. a fluoropolymer-coated everolimus-eluting stent (EES) at 13 months, using optical coherence tomography (OCT) in an 'all-comers' population of patients, in order to clarify the mechanism of eventual...

  12. Long-Term Follow-Up of Patients after Percutaneous Coronary Intervention with Everolimus-Eluting Bioresorbable Vascular Scaffold.

    Meneguz-Moreno, Rafael Alexandre; Costa, José de Ribamar; Moscoso, Freddy Antônio Britto; Staico, Rodolfo; Tanajura, Luiz Fernando Leite; Centemero, Marinella Patrizia; Chaves, Auréa Jacob; Abizaid, Andrea Claudia Leão de Sousa; Sousa, Amanda Guerra de Moraes Rego E; Abizaid, Alexandre Antonio Cunha

    2017-02-01

    Bioresorbable vascular scaffolds (BVS) were developed to improve the long-term results of percutaneous coronary intervention, restoring vasomotion. To report very late follow-up of everolimus-eluting Absorb BVS (Abbott Vascular, Santa Clara, USA) in our center. Observational retrospective study, in a single Brazilian center, from August 2011 to October 2013, including 49 patients submitted to Absorb BVS implantation. Safety and efficacy outcomes were analyzed in the in-hospital and very late follow-up phases (> 2 years). All 49 patients underwent a minimum follow-up of 2.5 years and a maximum of 4.6 years. Mean age was 56.8 ± 7.6 years, 71.4% of the patients were men, and 26.5% were diabetic. Regarding clinical presentation, the majority (94%) had stable angina or silent ischemia. Device success was achieved in 100% of cases with 96% overall procedure success rate. Major adverse cardiovascular events rate was 4% at 30 days, 8.2% at 1 year, and 12.2% at 2 years, and there were no more events until 4.6 years. There were 2 cases of thrombosis (1 subacute and 1 late). In this preliminary analysis, Absorb BVS showed to be a safe and effective device in the very late follow-up. Establishing the efficacy and safety profiles of these devices in more complex scenarios is necessary. Os suportes vasculares bioabsorvíveis (SVB) foram desenvolvidos com o intuito de melhorar os resultados da intervenção coronária percutânea a longo prazo, restabelecendo-se a vasomotricidade. Reportar o seguimento muito tardio do implante do SVB eluidor de everolimus Absorb® (Abbot Vascular, Santa Clara, EUA) em nosso centro. Estudo observacional, retrospectivo, em um único centro brasileiro, que incluiu 49 pacientes submetidos ao implante do SVB Absorb® entre agosto/2011 e outubro/2013. Foram analisados os desfechos de segurança e eficácia na fase hospitalar e bastante tardia (> 2 anos). Todos os 49 pacientes completaram um seguimento mínimo de 2,5 anos, sendo o máximo de 4,6 anos

  13. Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

    Gianluigi Zaza

    2013-01-01

    Full Text Available The mammalian target of rapamycin inhibitors (mTOR-I, sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR, a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

  14. The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

    Pinelopi Argyriou

    2012-01-01

    Full Text Available Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

  15. Differentiated analysis of an everolimus-eluting stent and a paclitaxel-eluting stent among higher risk subgroups for restenosis: results from the SPIRIT II trial.

    Khattab, Ahmed A; Richardt, Gert; Verin, Vitali; Kelbaek, Henning; Macaya, Carlos; Berland, Jacques; Miquel-Hebert, Karine; Dorange, Cécile; Serruys, Patrick W

    2008-03-01

    Restenosis is higher among certain subpopulations when subjected to percutaneous coronary interventions even when using drug-eluting stents. The randomised SPIRIT II trial demonstrated the superiority of the XIENCE V Everolimus Eluting Coronary Stent System over the TAXUS Paclitaxel-Eluting Stent System in terms of in-stent late loss at six months among 300 patients treated for de novo native coronary artery lesions. In this post-hoc analysis of SPIRIT II we focused on six-month angiographic outcomes of diabetic patients (n=69), left anterior descending arteries (n=149), long lesions >20 mm (n=43), small vessels B2 and C lesions (n=233). In-stent late loss was consistently less among all subgroups when treated by everolimus-eluting stents compared to paclitaxel-eluting stents: diabetics 0.15+/-0.26 mm versus 0.39+/-0.34 mm, p=0.006; LAD 0.12+/-0.23 mm versus 0.44+/-0.37 mm, pB2/C lesions 0.12+/-0.31 mm versus 0.36+/-0.36 mm, pSPIRIT II trial population.

  16. Effect of everolimus vs calcineurin inhibitors on quality of life in heart transplant recipients during a 3-year follow-up

    Relbo Authen, Anne; Grov, Ingelin; Karason, Kristjan

    2017-01-01

    or a standard CsA dosage (CsA group). This study assessed quality of life (QoL), based on the Short Form-36, EuroQol-5D, and Beck Depression Inventory (BDI). Assessments were performed pre-HTx and 12 and 36 months post-HTx. At 12 and 36 months, the groups showed similar improvements in Short Form-36 measures......BDI (EVR: 10.9±10.2, 5.4±4.7, and 8.1±9.0; P

  17. Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

    Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

    2013-02-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

  18. Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

    Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

    2013-01-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

  19. The SPIRIT V study: a clinical evaluation of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery lesions.

    Grube, Eberhard; Chevalier, Bernard; Smits, Peter; Džavík, Vladimir; Patel, Tejas M; Mullasari, Ajit S; Wöhrle, Jochen; Stuteville, Marrianne; Dorange, Cécile; Kaul, Upendra

    2011-02-01

    The SPIRIT V (A Clinical Evaluation of the XIENCE V Everolimus-Eluting Coronary Stent System in the Treatment of Patients With De Novo Coronary Artery Lesions) study is a post-market surveillance experience of the XIENCE V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) in patients with higher-risk coronary anatomy. Previous pre-approval studies have shown the safety and efficacy of EES in highly selected groups of patients. The SPIRIT V trial is a prospective, open label, single arm, multicenter study. Two thousand seven hundred patients with multiple de novo coronary artery lesions suitable for treatment with a planned maximum of 4 EES were enrolled at 93 centers in Europe, Asia Pacific, Canada, and South Africa. Lesions had a reference vessel diameter between 2.25 and 4.0 mm and a length of ≤ 28 mm by visual estimation. An independent clinical events committee adjudicated all end point-related events. The primary end point was the composite rate of all death, myocardial infarction (MI), and target vessel revascularization at 30 days. Secondary end points included stent thrombosis and acute success (clinical device and procedure success). At 30 days, the primary composite end point of all death, MI, and target vessel revascularization was 2.7%. At 1 year, rates of cardiac death, overall MI, and target lesion revascularization were 1.1%, 3.5%, and 1.8%, respectively. The cumulative rate of definite and probable stent thrombosis was low at 0.66% at 1 year. Use of EES in patients with multiple, complex de novo lesions yielded 1-year major adverse cardiac events, stent thrombosis, and target lesion revascularization rates that are comparable to those of the more controlled SPIRIT II and SPIRIT III trials-which included patients with restricted inclusion/exclusion criteria-and other all-comer population, physician-initiated studies like the X-SEARCH (Xience Stent Evaluated At Rotterdam Cardiology Hospital) and COMPARE (A Randomized

  20. Comparison of Outcomes in Patients With Versus Without Diabetes Mellitus After Revascularization With Everolimus- and Sirolimus-Eluting Stents (from the SORT OUT IV Trial)

    Jensen, Lisette Okkels; Thayssen, Per; Junker, Anders

    2012-01-01

    Diabetes is associated with increased risk of major adverse cardiac events (MACEs) after percutaneous coronary intervention. The purpose of this substudy of the SORT OUT IV trial was to compare clinical outcomes in patients with and without diabetes mellitus treated with everolimus-eluting stents...... (EESs) or sirolimus-eluting stents (SESs). In total 2,774 patients (390 with diabetes, 14.1%) were randomized to stent implantation with EESs (n = 1,390, diabetes in 14.0%) or SESs (n = 1,384, diabetes in 14.2%). Randomization was stratified by presence/absence of diabetes. The primary end point...... was MACEs, a composite of cardiac death, myocardial infarction, definite stent thrombosis, or target vessel revascularization within 18 months. MACEs were higher in diabetic than in nondiabetic patients (13.1% vs 6.4%, hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.51 to 2.86). In diabetic patients...

  1. An everolimus-eluting stent versus a paclitaxel-eluting stent in small vessel coronary artery disease: a pooled analysis from the SPIRIT II and SPIRIT III trials.

    Bartorelli, Antonio L; Serruys, Patrick W; Miquel-Hébert, Karine; Yu, Shui; Pierson, Wes; Stone, Gregg W

    2010-07-01

    To evaluate the safety and efficacy of the XIENCE V everolimus-eluting stent compared to the TAXUS paclitaxel-eluting stent in small vessels. The XIENCE V everolimus-eluting stent (EES) has been shown to improve angiographic and clinical outcomes after percutaneous myocardial revascularization, but its performance in small coronary arteries has not been investigated. In this pooled analysis, we studied a cohort of 541 patients with small coronary vessels (reference diameter SPIRIT II and SPIRIT III studies. TAXUS Express (73% of lesions) and TAXUS Liberté (27% of lesions) paclitaxel-eluting stents (PES) were used as controls in SPIRIT II. In SPIRIT III, Taxus Express(2) PES was the control. Mean angiographic in-stent and in-segment late loss was significantly less in the EES group compared with the PES group, (0.15 +/- 0.37 mm vs. 0.30 +/- 0.44 mm; P = 0.011 for in-stent; 0.10 +/- 0.38 mm vs. 0.21 +/- 0.34 mm; P = 0.034 for in-segment). EES also resulted in a significant reduction in composite major adverse cardiac events at 1 year (19/366 [5.2%] vs. 17/159 [10.7%]; P = 0.037), due to fewer non-Q-wave myocardial infarctions and target lesion revascularizations. At 1 year, the rate of non-Q-wave myocardial infarction was significantly lower in the EES group compared with that of the PES group (6/366 [1.6%] vs. 8/159 [5.0%]; P = 0.037). In patients with small vessel coronary arteries, the XIENCE V EES was superior to the TAXUS PES. (c) 2010 Wiley-Liss, Inc.

  2. Serial optical coherence tomography assessment of malapposed struts after everolimus-eluting stent implantation. A subanalysis from the HEAL-EES study

    Ishida, Kohki [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain); Otsuki, Shuji [Division of Cardiology, Teikyo University Hospital, Tokyo (Japan); Giacchi, Giuseppe; Ortega-Paz, Luis [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain); Shiratori, Yoshitaka [Division of Cardiology, Teikyo University Hospital, Tokyo (Japan); Freixa, Xavier; Martín-Yuste, Victoria; Masotti, Mónica; Sabaté, Manel [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain); Brugaletta, Salvatore, E-mail: sabrugal@clinic.ub.es [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain)

    2017-01-15

    Background: Incomplete stent apposition (ISA) is related to stent thrombosis, which is a serious adverse event. We aim to assess the time-course of ISA after 2nd generation everolimus-eluting stent (EES) implantation. Methods: In HEAL-EES study, we enrolled 36 patients who underwent percutaneous coronary intervention (PCI) with EES. OCT imaging was performed at baseline and follow-up. Patients were randomized 1:1:1 into 3 groups according to the time in which follow-up was performed: group A (6-month), group B (9-month), and group C (12-month). In this subanalysis, patients who had ISA segments at baseline and/or follow-up OCT were analyzed. Result: At baseline, among 41 lesions in 36 patients, 20 lesions in 18 patients had ISA segments and were analyzed. At baseline, there were 3.0% ISA struts in group A (n = 8), 2.8% in group B (n = 4), and 4.5% in group C (n = 8). At follow-up, ISA struts were present in 0.09%, 0.16% and 0.64%; respectively in groups A, B, and C. At follow-up, there was a significant decrease in the frequency of ISA: group A 3.0% vs. 0.09% (p < 0.001), group B 2.8% vs. 0.16% (p < 0.001), and group C 4.5% vs. 0.64% (p < 0.001). In group A, there was one late acquired ISA at follow-up. Conclusions: In patients undergoing 2nd generation EES implantation, area of acute ISA assessed by OCT, was almost resolved at 6-month follow-up. - Highlights: • Time-course of incomplete stent apposition of everolimus-eluting stent was assessed. • Serial optical coherence tomography images at baseline and follow-up were evaluated. • Acute incomplete stent apposition was almost resolved as early as at 6 months.

  3. Overtime evaluation of the vascular HEALing process after everolimus-eluting stent implantation by optical coherence tomography. The HEAL-EES study

    Otsuki, Shuji; Brugaletta, Salvatore, E-mail: sabrugal@clinic.ub.es; Sabaté, Manel; Shiratori, Yoshitaka; Gomez-Monterrosas, Omar; Scalone, Giancarla; Romero-Villafañe, Sebastian; Hernández-Enríquez, Marco; Freixa, Xavier; Martín-Yuste, Victoria; Masotti, Mónica

    2016-06-15

    Purpose: Second-generation drug-eluting stent (DES) have shown a better safety and efficacy as compared to first generation DES due to an improved vascular healing process. This process has not been so far evaluated in vivo in an overtime fashion by optical coherent tomography (OCT). We sought to evaluate the vascular healing process after everolimus-eluting stent (EES) implantation at 6, 9 and 12 months, by OCT. Methods: Consecutive 36 patients undergoing percutaneous coronary intervention with EES were randomized 1:1:1 to receive OCT imaging at 6 (group A), 9 (group B) or 12-month follow-up (group C). One patient from group C was excluded because of target lesion revascularization at 1-month, whereas 5 patients withdraw the informed consent. Finally, 30 patients were analyzed. Results: Neointimal thickness was not different between 3 groups (group A: 99.50 [94.06–127.79] μm, group B: 107.26 [83.48–133.59] μm, group C: 127.67 [102.51–138.49] μm; p = 0.736). Although the percentage of “uncovered struts” was significantly higher in group A as compared to the other groups (8.0% vs. 4.4% vs. 2.9%, respectively; p = 0.180), the ratio of uncovered to total struts per section < 30% was similar between 3 groups (0.3% vs. 0.3% vs. 0%, respectively; p = 1.000). Conclusion: Healing process following EES implantation seems almost completed at 6-month follow-up. These data, which need to be confirmed in a larger study, may support the decision to shorten dual antiplatelet therapy. - Highlights: • Healing process following everolimus-eluting stent implantation is complete at 6-month • There are no difference in RUTTS > 30% between 6, 9 and 12 months analyses. • This finding may support to shorten dual antiplatelet therapy in this context.

  4. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.

    Rugo, Hope S; Seneviratne, Lasika; Beck, J Thaddeus; Glaspy, John A; Peguero, Julio A; Pluard, Timothy J; Dhillon, Navneet; Hwang, Leon Christopher; Nangia, Chaitali; Mayer, Ingrid A; Meiller, Timothy F; Chambers, Mark S; Sweetman, Robert W; Sabo, J Randy; Litton, Jennifer K

    2017-05-01

    Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently

  5. Intimal hyperplasia and vascular remodeling after everolimus-eluting and sirolimus-eluting stent implantation in diabetic patients the randomized diabetes and drug-eluting stent (DiabeDES) IV intravascular ultrasound trial

    Antonsen, Lisbeth; Maeng, Michael; Thayssen, Per

    2013-01-01

    OBJECTIVE: To evaluate the effects of the everolimus-eluting Xience™/Promus™ stent (EES) and the sirolimus-eluting Cypher™ stent (SES) on intimal hyperplasia (IH) in diabetic patients. BACKGROUND: Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent...... implantation due to intimal hyperplasia (IH). METHODS: In a sub study of the Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated with Percutaneous Coronary Intervention (SORT OUT IV trial), serial intravascular ultrasound (IVUS) 10-month follow-up data were available...... in 88 patients, including 48 EES and 40 SES treated patients. IVUS endpoints included IH volume, in-stent % volume obstruction and changes in external elastic membrane (EEM) volume. RESULTS: Compared with the SES group, IH volume was increased in the EES group [median (interquartile range): 2.8 mm(3) (0...

  6. Lung cancer, intracellular signaling pathways, and preclinical models

    Mordant, P.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  7. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells.

    Pasquier, Benoit

    2015-04-03

    Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

  8. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial.

    Onuma, Yoshinobu; Dudek, Dariusz; Thuesen, Leif; Webster, Mark; Nieman, Koen; Garcia-Garcia, Hector M; Ormiston, John A; Serruys, Patrick W

    2013-10-01

    This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California). Multimodality imaging of the first-in-humans trial using a ABSORB BVS scaffold demonstrated at 2 years the bioresorption of the device while preventing restenosis. However, the long-term safety and efficacy of this therapy remain to be documented. In the ABSORB cohort A trial (ABSORB Clinical Investigation, Cohort A [ABSORB A] Everolimus-Eluting Coronary Stent System Clinical Investigation), 30 patients with a single de novo coronary artery lesion were treated with the fully resorbable everolimus-eluting Absorb scaffold at 4 centers. As an optional investigation in 3 of the 4 centers, the patients underwent multislice computed tomography (MSCT) angiography at 18 months and 5 years. Acquired MSCT data were analyzed at an independent core laboratory (Cardialysis, Rotterdam, the Netherlands) for quantitative analysis of lumen dimensions and was further processed for calculation of fractional flow reserve (FFR) at another independent core laboratory (Heart Flow, Redwood City, California). Five-year clinical follow-up is available for 29 patients. One patient withdrew consent after 6 months, but the vital status of this patient remains available. At 46 days, 1 patient experienced a single episode of chest pain and underwent a target lesion revascularization with a slight troponin increase after the procedure. At 5 years, the ischemia-driven major adverse cardiac event rate of 3.4% remained unchanged. Clopidogrel was discontinued in all but 1 patient. Scaffold thrombosis was not observed in any patient. Two noncardiac deaths were reported, 1 caused by duodenal perforation and the other from Hodgkin's disease. At 5 years, 18 patients underwent MSCT angiography. All scaffolds were patent, with a median minimal lumen area of 3

  9. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial

    Choueiri, Toni K; Escudier, Bernard; Powles, Thomas

    2016-01-01

    Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously...

  10. Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.

    Hisamatsu, Takeshi; Mabuchi, Seiji; Matsumoto, Yuri; Kawano, Mahiru; Sasano, Tomoyuki; Takahashi, Ryoko; Sawada, Kenjiro; Ito, Kimihiko; Kurachi, Hirohisa; Schilder, Russell J; Testa, Joseph R; Kimura, Tadashi

    2013-07-01

    The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

  11. The influence of immunosuppressive drugs on neural stem/progenitor cell fate in vitro

    Skardelly, Marco, E-mail: Marco.Skardelly@med.uni-tuebingen.de [Department of Neurosurgery, University Hospital, Leipzig (Germany); Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany); Glien, Anja; Groba, Claudia; Schlichting, Nadine [Department of Neurosurgery, University Hospital, Leipzig (Germany); Kamprad, Manja [Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig (Germany); Meixensberger, Juergen [Department of Neurosurgery, University Hospital, Leipzig (Germany); Milosevic, Javorina [Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany)

    2013-12-10

    In allogenic and xenogenic transplantation, adequate immunosuppression plays a major role in graft survival, especially over the long term. The effect of immunosuppressive drugs on neural stem/progenitor cell fate has not been sufficiently explored. The focus of this study is to systematically investigate the effects of the following four different immunotherapeutic strategies on human neural progenitor cell survival/death, proliferation, metabolic activity, differentiation and migration in vitro: (1) cyclosporine A (CsA), a calcineurin inhibitor; (2) everolimus (RAD001), an mTOR-inhibitor; (3) mycophenolic acid (MPA, mycophenolate), an inhibitor of inosine monophosphate dehydrogenase and (4) prednisolone, a steroid. At the minimum effective concentration (MEC), we found a prominent decrease in hNPCs' proliferative capacity (BrdU incorporation), especially for CsA and MPA, and an alteration of the NAD(P)H-dependent metabolic activity. Cell death rate, neurogenesis, gliogenesis and cell migration remained mostly unaffected under these conditions for all four immunosuppressants, except for apoptotic cell death, which was significantly increased by MPA treatment. - Highlights: • Four immunosuppresants (ISs) were tested in human neural progenitor cells in vitro. • Cyclosporine A and mycophenolic acid showed a prominent anti-proliferative activity • Mycophenolic acid exhibited a significant pro-apoptotic effect. • NAD(P)H-dependent metabolic activity was occasionally induced by ISs. • Neuronal differentiation and migration potential remained unaffected by ISs treatment.

  12. Evaluation of chemical stability of polymers of XIENCE everolimus-eluting coronary stents in vivo by pyrolysis-gas chromatography/mass spectrometry.

    Kamberi, Marika; Pinson, David; Pacetti, Stephen; Perkins, Laura E L; Hossainy, Syed; Mori, Hiroyoshi; Rapoza, Richard J; Kolodgie, Frank; Virmani, Renu

    2017-09-07

    The polymers poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly(n-butyl methacrylate) (PBMA) are employed in manufacturing the XIENCE family of coronary stents. PBMA serves as a primer and adheres to both the stent and the drug coating. PVDF-HFP is employed in the drug matrix layer to hold the drug everolimus on the stent and control its release. Chemical stability of the polymers of XIENCE stents in the in-vivo environment was evaluated by pyrolysis-gas chromatography with mass spectrometry (Py-GC/MS) detection. For this evaluation, XIENCE stents explanted from porcine coronary arteries and from human coronary artery specimens at autopsy after 2-4 and 5-7 years of implantation, respectively, were compared to freshly manufactured XIENCE stents (controls). The comparison of pyrograms of explanted stent samples and controls showed identical fragmentation fingerprints of polymers, indicating that PVDF-HFP and PBMA maintained their chemical integrity after multiple years of XIENCE coronary stent implantation. The findings of the present study demonstrate the chemical stability of PVDF-HFP and PBMA polymers of the XIENCE family of coronary stents in the in-vivo environment, and constitute a further proof of the suitability of PVDF-HFP as a drug carrier for the drug eluting stent applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017. © 2017 Wiley Periodicals, Inc.

  13. Monoamine Oxidase Inhibitors (MAOIs)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for ... www.uptodate.com/home. Accessed May 16, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  14. Effects of cobalt-chromium everolimus eluting stents or bare metal stent on fatal and non-fatal cardiovascular events

    Valgimigli, Marco; Sabaté, Manel; Kaiser, Christoph

    2014-01-01

    eluting stents with bare metal stents were selected. The principal investigators whose trials met the inclusion criteria provided data for individual patients. PRIMARY OUTCOMES: The primary outcome was cardiac mortality. Secondary endpoints were myocardial infarction, definite stent thrombosis, definite...... a significant reduction of cardiac mortality (hazard ratio 0.67, 95% confidence interval 0.49 to 0.91; P=0.01), myocardial infarction (0.71, 0.55 to 0.92; P=0.01), definite stent thrombosis (0.41, 0.22 to 0.76; P=0.005), definite or probable stent thrombosis (0.48, 0.31 to 0.73; P... coronary syndrome v stable coronary artery disease), diabetes mellitus, female sex, use of glycoprotein IIb/IIIa inhibitors, and up to one year v longer duration treatment with dual antiplatelets. CONCLUSIONS: This meta-analysis offers evidence that compared with bare metal stents the use of cobalt...

  15. SGLT2 inhibitors.

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Aromatase inhibitors in pediatrics.

    Wit, Jan M; Hero, Matti; Nunez, Susan B

    2011-10-25

    Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

  17. The REMEDEE-OCT Study: An Evaluation of the Bioengineered COMBO Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent Compared With a Cobalt-Chromium Everolimus-Eluting Stent in Patients With Acute Coronary Syndromes: Insights From Optical Coherence Tomography Imaging Analysis

    Jaguszewski, Milosz; Aloysius, Romila; Wang, Wei; Bezerra, Hiram G.; Hill, Jonathan; de Winter, Robbert J.; Karjalainen, Pasi P.; Verheye, Stefan; Wijns, William; Lüscher, Thomas F.; Joner, Michael; Costa, Marco; Landmesser, Ulf

    2017-01-01

    The aim of the present study was to evaluate vascular healing of the bioengineered COMBO Dual Therapy Stent compared with a cobalt-chromium (CoCr) everolimus-eluting stent (EES) as assessed by optical coherence tomography in patients with acute coronary syndromes. CD34+ cells promote endothelial

  18. Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I): 2-Year Clinical and Imaging Results.

    Lammer, Johannes; Bosiers, Marc; Deloose, Koen; Schmidt, Andrej; Zeller, Thomas; Wolf, Florian; Lansink, Wouter; Sauguet, Antoine; Vermassen, Frank; Lauwers, Geert; Scheinert, Dierk; Popma, Jeffrey J; McGreevy, Robert; Rapoza, Richard; Schwartz, Lewis B; Jaff, Michael R

    2016-06-13

    This is the first-in-human study of a drug-eluting bioresorbable vascular scaffold (BVS) for treatment of peripheral artery disease (PAD) involving the external iliac artery (EIA) and superficial femoral artery (SFA). Drug-eluting BVS has shown promise in coronary arteries. The ESPRIT BVS system is a device-drug combination consisting of an everolimus-eluting poly-l-lactide scaffold. Safety and performance were evaluated in 35 subjects with symptomatic claudication. Lesions were located in the SFA (88.6%) and EIA (11.4%). Mean lesion length was 35.7 ± 16.0 mm. The study device was successfully deployed in 100% of cases, without recoil. Procedure-related minor complications were observed in 3 patients (groin hematoma, dissection). Within 2 years there was 1 unrelated death, but no patients in this cohort had an amputation. At 1 and 2 years, the binary restenosis rates were 12.1% and 16.1%, respectively, and target lesion revascularization was performed in 3 of 34 patients (8.8%) and 4 of 32 patients (11.8%), respectively. The ankle brachial index 0.75 ± 0.14 improved from pre-procedure to 0.96 ± 0.16 at 2 years' follow-up. At 2 years, 71.0% of the patients were Rutherford-Becker 0, and 93.5% achieved a maximum walking distance of 1,500 feet. The safety of the ESPRIT BVS was demonstrated with no procedure or device-related deaths or amputations within 2 years. The low occurrence of revascularizations was consistent with duplex-ultrasonography showing sustained patency at 2-years. (A Clinical Evaluation of the Abbott Vascular ESPRIT BVS [Bioresorbable Vascular Scaffold] System [ESPRIT I]; NCT01468974). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  19. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

    Gianluigi Zaza

    Full Text Available The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group, and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group.A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05. Flagellar motor switch protein (fliNY and type IV pilus assembly protein pilM (pilM were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

  20. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

    Zaza, Gianluigi; Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

    2017-01-01

    The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

  1. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen

    Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

    2017-01-01

    Background The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. Methods We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). Results A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Conclusions Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this

  2. Paclitaxel-eluting stents versus everolimus-eluting coronary stents in a diabetic population: two-year follow-up of the TUXEDO-India trial.

    Kaul, Upendra; Bhagwat, Ajit; Pinto, Brian; Goel, Praveen K; Jagtap, Prashant; Sathe, Shireesh; Wander, Gurpreet S; Arambam, Priyadarshini; Bangalore, Sripal

    2017-11-20

    The aim of this study was to report whether the superiority of the everolimus-eluting stent (EES) vs. the paclitaxel-eluting stent (PES) at one-year follow-up in the Taxus Element versus Xience Prime in a Diabetic Population (TUXEDO)-India trial was sustained at longer-term follow-up. One thousand eight hundred and thirty (1,830) patients with diabetes mellitus and coronary artery disease were randomised to EES vs. PES. Follow-up data up to two years were available in 1,701 (92.9%) patients. The primary endpoint was target vessel failure (TVF), defined as the composite of cardiac death, target vessel myocardial infarction (TV-MI), or ischaemia-driven target vessel revascularisation (TVR). Treatment with EES had a lower two-year rate of TVF (4.3% vs. 6.6%, p=0.03). Of the secondary endpoints, EES significantly reduced any MI (1.6% vs. 3.5%, p=0.01), TV-MI (0.7% vs. 3.1%, p=0.0001), ST (0.4% vs. 2.2%, p=0.001), cardiac death or target vessel MI (2.9% vs. 4.8%, p=0.04) and TLR (1.9% vs. 3.7%, p=0.02), compared with PES. Between one year and two years, no significant differences in the clinical outcomes were observed (pinteraction >0.05). In this adequately powered trial, the benefits of EES vs. PES in a diabetic population seen at one year were maintained at two years.

  3. A process for assessing the feasibility of a network meta-analysis: a case study of everolimus in combination with hormonal therapy versus chemotherapy for advanced breast cancer.

    Cope, Shannon; Zhang, Jie; Saletan, Stephen; Smiechowski, Brielan; Jansen, Jeroen P; Schmid, Peter

    2014-06-05

    The aim of this study is to outline a general process for assessing the feasibility of performing a valid network meta-analysis (NMA) of randomized controlled trials (RCTs) to synthesize direct and indirect evidence for alternative treatments for a specific disease population. Several steps to assess the feasibility of an NMA are proposed based on existing recommendations. Next, a case study is used to illustrate this NMA feasibility assessment process in order to compare everolimus in combination with hormonal therapy to alternative chemotherapies in terms of progression-free survival for women with advanced breast cancer. A general process for assessing the feasibility of an NMA is outlined that incorporates explicit steps to visualize the heterogeneity in terms of treatment and outcome characteristics (Part A) as well as the study and patient characteristics (Part B). Additionally, steps are performed to illustrate differences within and across different types of direct comparisons in terms of baseline risk (Part C) and observed treatment effects (Part D) since there is a risk that the treatment effect modifiers identified may not explain the observed heterogeneity or inconsistency in the results due to unexpected, unreported or unmeasured differences. Depending on the data available, alternative approaches are suggested: list assumptions, perform a meta-regression analysis, subgroup analysis, sensitivity analyses, or summarize why an NMA is not feasible. The process outlined to assess the feasibility of an NMA provides a stepwise framework that will help to ensure that the underlying assumptions are systematically explored and that the risks (and benefits) of pooling and indirectly comparing treatment effects from RCTs for a particular research question are transparent.

  4. Percutaneous coronary intervention with second-generation paclitaxel-eluting stents versus everolimus-eluting stents in United States contemporary practice (REWARDS TLX Trial).

    Waksman, Ron; Ghali, Magdi; Goodroe, Randy; Ryan, Thomas; Turco, Mark; Ring, Michael; McGarry, Thomas; Dobies, David; Shammas, Nicolas; Steinberg, Daniel H; Swymelar, Stacy; Kaneshige, Kimberly; Torguson, Rebecca

    2012-10-15

    Registry Experience at the Washington Hospital Center, DES - Taxus Liberte Versus Xience V (REWARDS TLX) is a physician-initiated, retrospective, real-world, multicenter, observational study for all patients >18 years of age subjected to percutaneous coronary intervention with everolimus-eluting stents (EESs) or paclitaxel-eluting stents (PESs). Outcomes of patients receiving a TAXUS Liberté or XIENCE V drug-eluting stent were compared. Baseline clinical, procedural, and follow-up data at 12 months were collected from 10 clinical centers by an electronic data capture system. The study's primary end point was major adverse cardiac events: a composite of all-cause death, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. The trial is registered with http://www.clinicaltrials.gov (NCT01134159). Data were entered for 1,195 patients (PES, n = 595; EES, n = 600). Baseline clinical characteristics were similar except for higher dyslipidemia, systemic hypertension, and family history of coronary artery disease in the EES group. In-hospital outcome was similar between groups, with an overall in-hospital stent thrombosis rate of 0.2%. The primary end point at 12 months was similar (EES 7.8% vs 10.8%, p = 0.082). Overall stent thrombosis rate was lower in the EES group (0.3% vs 1.2%, respectively, p = 0.107); however, target lesion revascularization was similar (PES, hazard ratio 1.46, 95% confidence interval 0.98 to 2.19, p = 0.064). There was no difference in overall mortality between groups. In conclusion, second-generation EESs and PESs demonstrated similar efficacy and safety profiles for broadened patient and lesion subsets compared to a selected population from the pivotal trials. However, for composite efficacy and safety end points, EESs outperformed second-generation PESs. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Safety and efficacy of everolimus-eluting stents compared with first-generation drug-eluting stents in patients undergoing primary percutaneous coronary intervention

    Escárcega, Ricardo O.; Baker, Nevin C.; Magalhaes, Marco A.; Lipinski, Michael J.; Minha, Sa’ar; Torguson, Rebecca; Satler, Lowell F.; Pichard, Augusto D.; Suddath, William O.; Waksman, Ron, E-mail: ron.waksman@medstar.net

    2014-09-15

    Objective: To assess the safety and efficacy everolimus-eluting stents (EES) compared with first-generation drug-eluting stents (DES) in patients with acute myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PCI). Background: EES have been associated with improved clinical outcomes compared to paclitaxel-eluting stents (PES) and with similar outcomes compared to sirolimus-eluting stents (SES). Methods: A total of 520 patients who presented with ST-elevation myocardial infarction (STEMI) from 2003 to 2013, who underwent primary PCI with DES, were retrospectively analyzed. Of these, 247 received SES, 136 PES, and 137 EES. Patients were followed up to 2 years for major adverse cardiac events (MACE). Univariate and multivariate models detected correlates to outcome. Results: EES implantation, compared with PES and SES, resulted in comparable rates of MACE (8.8% vs. 16.2%, p = 0.06 and 8.8% vs. 12.6%, respectively, p = 0.26), stent thrombosis, MI, and target lesion revascularization. Patients who received EES had lower rates of all-cause mortality (3.7% vs. 12.6% vs. 9.4%, p = 0.03) at 1-year follow up. However, in the univariate and multivariate analyses, stent type was not independently associated with the primary outcome or with all-cause mortality. Diabetes mellitus and number of stents implanted were independently associated with the primary outcome. Conclusion: While EES seem to be associated with better outcome when compared to PES, the main correlates of STEMI patients are the presence of diabetes and number of stents implanted, and not the type of stent used for intervention.

  6. Absorb bioresorbable vascular scaffold versus everolimus-eluting metallic stent in ST-segment elevation myocardial infarction: 1-year results of a propensity score matching comparison: the BVS-EXAMINATION Study (bioresorbable vascular scaffold-a clinical evaluation of everolimus eluting coronary stents in the treatment of patients with ST-segment elevation myocardial infarction).

    Brugaletta, Salvatore; Gori, Tommaso; Low, Adrian F; Tousek, Petr; Pinar, Eduardo; Gomez-Lara, Josep; Scalone, Giancarla; Schulz, Eberhard; Chan, Mark Y; Kocka, Viktor; Hurtado, Jose; Gomez-Hospital, Juan Antoni; Münzel, Thomas; Lee, Chi-Hang; Cequier, Angel; Valdés, Mariano; Widimsky, Petr; Serruys, Patrick W; Sabaté, Manel

    2015-01-01

    The purpose of this study was to compare the 1-year outcome between bioresorbable vascular scaffold (BVS) and everolimus-eluting metallic stent (EES) in ST-segment elevation myocardial infarction (STEMI) patients. The Absorb BVS (Abbott Vascular, Santa Clara, California) is a polymeric scaffold approved for treatment of stable coronary lesions. Limited and not randomized data are available on its use in ST-segment elevation myocardial infarction (STEMI) patients. This study included 290 consecutive STEMI patients treated by BVS, compared with either 290 STEMI patients treated with EES or 290 STEMI patients treated with bare-metal stents (BMS) from the EXAMINATION (A Clinical Evaluation of Everolimus Eluting Coronary Stents in the Treatment of Patients With ST-segment Elevation Myocardial Infarction) trial, by applying propensity score matching. The primary endpoint was a device-oriented endpoint (DOCE), including cardiac death, target vessel myocardial infarction, and target lesion revascularization, at 1-year follow-up. Device thrombosis, according to the Academic Research Consortium criteria, was also evaluated. The cumulative incidence of DOCE did not differ between the BVS and EES or BMS groups either at 30 days (3.1% vs. 2.4%, hazard ratio [HR]: 1.31 [95% confidence interval (CI): 0.48 to 3.52], p = 0.593; vs. 2.8%, HR: 1.15 [95% CI: 0.44 to 2.30], p = 0.776, respectively) or at 1 year (4.1% vs. 4.1%, HR: 0.99 [95% CI: 0.23 to 4.32], p = 0.994; vs. 5.9%, HR: 0.50 [95% CI: 0.13 to 1.88], p = 0.306, respectively). Definite/probable BVS thrombosis rate was numerically higher either at 30 days (2.1% vs. 0.3%, p = 0.059; vs. 1.0%, p = 0.324, respectively) or at 1 year (2.4% vs. 1.4%, p = 0.948; vs. 1.7%, p = 0.825, respectively), as compared with EES or BMS. At 1-year follow-up, STEMI patients treated with BVS showed similar rates of DOCE compared with STEMI patients treated with EES or BMS, although rate of scaffolds thrombosis, mostly clustered in the early phase

  7. Biodegradable Polymer Biolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report From the COMPARE II Trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent).

    Vlachojannis, Georgios J; Smits, Pieter C; Hofma, Sjoerd H; Togni, Mario; Vázquez, Nicolás; Valdés, Mariano; Voudris, Vassilis; Slagboom, Ton; Goy, Jean-Jaques; den Heijer, Peter; van der Ent, Martin

    2017-06-26

    This analysis investigates the 5-year outcomes of the biodegradable polymer biolimus-eluting stent (BP-BES) and durable polymer everolimus-eluting stent (DP-EES) in an all-comers population undergoing percutaneous coronary intervention. Recent 1- and 3-year results from randomized trials have indicated similar safety and efficacy outcomes of BP-BES and DP-EES. Whether benefits of the biodegradable polymer device arise over longer follow-up is unknown. Moreover, in-depth, prospective, long-term follow-up data on metallic drug-eluting stents with durable or biodegradable polymers are scarce. The COMPARE II trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent) was a prospective, randomized, multicenter, all-comers trial in which 2,707 patients were randomly allocated (2:1) to BP-BES or DP-EES. The pre-specified endpoint at 5 years was major adverse cardiac events, a composite of cardiac death, nonfatal myocardial infarction, or target vessel revascularization. Five-year follow-up was available in 2,657 patients (98%). At 5 years, major adverse cardiac events occurred in 310 patients (17.3%) in the BP-BES group and 142 patients (15.6%) in the DP-EES group (p = 0.26). The rate of the combined safety endpoint all-cause death or myocardial infarction was 15.0% in the BP-BES group versus 14.8% in the DP-EES group (p = 0.90), whereas the efficacy measure target vessel revascularization was 10.6% versus 9.0% (p = 0.18), respectively. Interestingly, definite stent thrombosis rates did not differ between groups (1.5% for BP-BES vs. 0.9% for DP-EES; p = 0.17). The 5-year analysis comparing biodegradable polymer-coated BES and the durable polymer-coated EES confirms the initial early- and mid-term results regarding similar safety and efficacy outcomes in this all-comers percutaneous coronary intervention population. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights

  8. JAK inhibitors in autoinflammation.

    Hoffman, Hal M; Broderick, Lori

    2018-06-11

    Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

  9. Cathepsin D inhibitors

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  10. Outcome of everolimus eluting bioabsorbable vascular scaffold (BVS) compared to non BVS drug eluting stent in the management of ST-segment elevation myocardial infarction (STEMI) — A comparative study

    Chakraborty, Rabin; Patra, Soumya, E-mail: dr_soumyapatra@rediffmail.com; Banerjee, Suvro; Pande, Arindam; Khan, Aftab; Mandol, Prakash Chandra; Ghosh, Debashish; De, Swapan Kumar; Das, Sankha Subhro; Nag, Raja

    2016-04-15

    Background: The safety and efficacy of everolimus eluting bioabsorbable vascular scaffold (BVS) in the management of “ST” segment elevation myocardial infarction (STEMI) are yet to be established. Aims: To evaluate immediate and short term safety and efficacy of the everolimus-eluting ABSORB BVS compared with non BVS drug eluting stent (DES) in patients with STEMI. Methods: From December 2013 to December 2014, 220 patients with STEMI were included in this study. Among them, 35 patients treated with BVS were compared with a control group composed of 180 patients who underwent non BVS DES implantation in the same time period. The incidence of major adverse cardiac events (MACE: stent thrombosis: death, non-fatal myocardial infarction, or target vessel/lesion revascularization) before discharge and up to six months was evaluated. Results: 1 vessel disease was more frequent whereas, 2 and 3 vessel disease was less frequent in BVS group. Procedural characteristics were also similar between groups, except for the use of post dilation (p = 0.04). Procedural success, in-hospital, and up to six-month MACE rates were similar between both groups. Definite or probable stent thrombosis did not occur (according to the ARC criteria) in BVS patients, though two patients during the index admission and another two patients in the first month after DES implantation had stent thrombosis. Conclusion: The use of the ABSORB BVS for STEMI is feasible and associated with good procedural safety, and angiographic success rate.

  11. Outcome of everolimus eluting bioabsorbable vascular scaffold (BVS) compared to non BVS drug eluting stent in the management of ST-segment elevation myocardial infarction (STEMI) — A comparative study

    Chakraborty, Rabin; Patra, Soumya; Banerjee, Suvro; Pande, Arindam; Khan, Aftab; Mandol, Prakash Chandra; Ghosh, Debashish; De, Swapan Kumar; Das, Sankha Subhro; Nag, Raja

    2016-01-01

    Background: The safety and efficacy of everolimus eluting bioabsorbable vascular scaffold (BVS) in the management of “ST” segment elevation myocardial infarction (STEMI) are yet to be established. Aims: To evaluate immediate and short term safety and efficacy of the everolimus-eluting ABSORB BVS compared with non BVS drug eluting stent (DES) in patients with STEMI. Methods: From December 2013 to December 2014, 220 patients with STEMI were included in this study. Among them, 35 patients treated with BVS were compared with a control group composed of 180 patients who underwent non BVS DES implantation in the same time period. The incidence of major adverse cardiac events (MACE: stent thrombosis: death, non-fatal myocardial infarction, or target vessel/lesion revascularization) before discharge and up to six months was evaluated. Results: 1 vessel disease was more frequent whereas, 2 and 3 vessel disease was less frequent in BVS group. Procedural characteristics were also similar between groups, except for the use of post dilation (p = 0.04). Procedural success, in-hospital, and up to six-month MACE rates were similar between both groups. Definite or probable stent thrombosis did not occur (according to the ARC criteria) in BVS patients, though two patients during the index admission and another two patients in the first month after DES implantation had stent thrombosis. Conclusion: The use of the ABSORB BVS for STEMI is feasible and associated with good procedural safety, and angiographic success rate.

  12. Transglutaminase inhibitor from milk

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  13. Inhibitors of histone demethylases

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  14. Acid corrosion inhibitor

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  15. Benzoylurea Chitin Synthesis Inhibitors.

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  16. Zotarolimus-eluting Resolute Integrity versus everolimus-eluting Xience Xpedition stents in the management of very long (>30 mm) de novo coronary artery stenosis

    Patra, Soumya, E-mail: dr_soumyapatra@rediffmail.com; Chakraborty, Rabindra Nath; Pande, Arindam; Banerjee, Suvro; Jena, Manabhanjan; Mandal, Prakash Chandra; De, Swapan Kumar; Khan, Aftab; Das, Sankha Suvro; Ghosh, Debashish; Nag, Raja

    2017-04-15

    Background: Procedural and clinical outcomes in patients with very long (>30 mm) coronary lesions who underwent stent-based percutaneous coronary interventions are still unfavorable. Therefore, we compared the relative efficacy and safety of resolute zotarolimus-eluting stents (R-ZES) and Xpedition everolimus-eluting stents (X-EES) for patients with de novo very long coronary lesions. Methods: This comparative single-centre, retrospective study compared long R-ZES and X-EES in consecutive patients admitted with very long (≥30 mm) native ACC/AHA type C coronary lesions in 2014. All patients were followed up clinically at 1, 3, 6 and 12 months. In this study, only symptom-driven angiogram was advised. The study end point was to evaluate immediate procedural success and one-year rate of target lesion failure (TLF), which is a composite of cardiac death, target lesion myocardial infarction, or target lesion revascularization (TLR). Results: Total number of patients enrolled in this study was 185 (R-ZES = 107; X-EES = 78). The baseline characteristics and post procedural success rate were similar between R-ZES and X-EES groups, including the post stenting lesion lengths (36.6 ± 1.92 mm vs 40.71 ± 6.175 mm, P = 0.09). At 12-month follow-up, there were no significant between-group differences in the rate of adverse clinical events (death, myocardial infarction, stent thrombosis, target lesion revascularization, and composite outcomes). Procedural success was achieved in 94% in R-ZES group and 93% in X-EES group (P = 0.24). The incidence of TLF was 5% in R-ZES and 4% in X-EES groups (HR-1.25; 95% CI-0.86-5.6; P = 0.19). Conclusion: Patients with de novo long coronary artery disease, R-ZES implantation showed similar clinical outcome as compared with X-EES implantation. - Highlights: • This is the first study comparing between R-ZES (Resolute Integrity) and X-EES (Xience Xpedition) used in PCI for long coronary artery disease. Here, single stent length of more than 30

  17. Quality-of-Life After Everolimus-Eluting Stents or Bypass Surgery for Left-Main Disease: Results From the EXCEL Trial.

    Baron, Suzanne J; Chinnakondepalli, Khaja; Magnuson, Elizabeth A; Kandzari, David E; Puskas, John D; Ben-Yehuda, Ori; van Es, Gerrit-Anne; Taggart, David P; Morice, Marie-Claude; Lembo, Nicholas J; Brown, W Morris; Banning, Adrian; Simonton, Charles A; Kappetein, A Pieter; Sabik, Joseph F; Serruys, Patrick W; Stone, Gregg W; Cohen, David J

    2017-12-26

    The EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial compared outcomes in patients with unprotected left main coronary artery disease (LMCAD) treated with coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) using everolimus-eluting stents. Whereas rates of death, stroke, and myocardial infarction were similar at 36 months, event timing and repeat revascularization rates differed by treatment group. To understand the effects of revascularization strategy from the patient's perspective, a prospective quality of life (QoL) substudy was performed alongside the EXCEL trial. Between September 2010 and March 2014, 1,905 patients with LMCAD were randomized to undergo CABG or PCI, of whom 1,788 participated in the QoL substudy. QoL was assessed at baseline and 1, 12, and 36 months using the Seattle Angina Questionnaire, the 12-Item Short Form Health Survey, the Rose Dyspnea Scale, the Patient Health Questionnaire-8, and the EQ-5D. Differences between PCI and CABG were assessed using longitudinal random-effect growth curve models. Over 36 months, both PCI and CABG were associated with significant improvements in QoL compared with baseline. At 1 month, PCI was associated with better QoL than CABG. By 12 months though, these differences were largely attenuated, and by 36 months, there were no significant QoL differences between PCI and CABG. Among selected patients with LMCAD, both PCI and CABG result in similar QoL improvement through 36 months, although a greater early benefit is seen with PCI. Taken together with the 3-year clinical results of EXCEL, these findings suggest that PCI and CABG provide similar intermediate-term outcomes for patients with LMCAD. (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization [EXCEL]; NCT01205776). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier

  18. Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for primary percutaneous coronary revascularisation of acute myocardial infarction.

    Pilgrim, Thomas; Piccolo, Raffaele; Heg, Dik; Roffi, Marco; Tüller, David; Vuilliomenet, André; Muller, Olivier; Cook, Stéphane; Weilenmann, Daniel; Kaiser, Christoph; Jamshidi, Peiman; Khattab, Ahmed A; Taniwaki, Masanori; Rigamonti, Fabio; Nietlispach, Fabian; Blöchlinger, Stefan; Wenaweser, Peter; Jüni, Peter; Windecker, Stephan

    2016-12-10

    Our aim was to compare the safety and efficacy of a novel, ultrathin strut, biodegradable polymer sirolimus-eluting stent (BP-SES) with a thin strut, durable polymer everolimus-eluting stent (DP-EES) in a pre-specified subgroup of patients with acute ST-segment elevation myocardial infarction (STEMI) enrolled in the BIOSCIENCE trial. The BIOSCIENCE trial is an investigator-initiated, single-blind, multicentre, randomised non-inferiority trial (NCT01443104). Randomisation was stratified according to the presence or absence of STEMI. The primary endpoint, target lesion failure (TLF), is a composite of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularisation within 12 months. Between February 2012 and May 2013, 407 STEMI patients were randomly assigned to treatment with BP-SES or DP-EES. At one year, TLF occurred in seven (3.4%) patients treated with BP-SES and 17 (8.8%) patients treated with DP-EES (RR 0.38, 95% CI: 0.16-0.91, p=0.024). Rates of cardiac death were 1.5% in the BP-SES group and 4.7% in the DP-EES group (RR 0.31, 95% CI: 0.08-1.14, p=0.062); rates of target vessel myocardial infarction were 0.5% and 2.6% (RR 0.18, 95% CI: 0.02-1.57, p=0.082), respectively, and rates of clinically indicated target lesion revascularisation were 1.5% in the BP-SES group versus 2.1% in the DP-EES group (RR 0.69, 95% CI: 0.16-3.10, p=0.631). There was no difference in the risk of definite stent thrombosis. In this pre-specified subgroup analysis, BP-SES was associated with a lower rate of target lesion failure at one year compared to DP-EES in STEMI patients. These findings require confirmation in a dedicated STEMI trial.

  19. A national, multicenter, non-interventional, observational study on treatment patterns in patients with metastatic renal cell carcinoma in Turkey – NOTES study

    Yalcin Ş

    2018-03-01

    histologically confirmed mRCC were enrolled in the study from 11 centers between June 2012 and March 2014 (70 males and 30 females. Efficacy was assessed on the basis of progression-free survival and overall survival; safety of everolimus was assessed on the basis of adverse event occurrence. Results: The study results showed that the median progression-free survival with everolimus treatment was 8.1 months (95% CI: 5.1–11.1 and the median overall survival was 17.6 months (95% CI: 10.1–25.1, thus indicating a better overall response based on survival durations than those from the randomized Phase III REnal Cell cancer treatment with Oral RAD001 given Daily study results (4.9 and 14.8 months, respectively. Conclusion: The study showed that everolimus treatment is a safe and effective treatment option in the treatment of mRCC after VEGF-TKI, with an acceptable safety and tolerability profile in real-life settings. Keywords: metastatic renal cell carcinoma, mTOR inhibitors, everolimus, observational study, real-life setting, treatment patterns

  20. UV-visible spectroscopy as an alternative to liquid chromatography for determination of everolimus in surfactant-containing dissolution media: a useful approach based on solid-phase extraction.

    Kamberi, Marika; Tran, Thu-Ngoc

    2012-11-01

    High-throughput 96-well solid phase extraction (SPE) plate with C-18 reversed phase sorbent followed by UV-visible (UV-Vis) microplate reader was applied to the analysis of hydrophobic drugs in surfactant-containing dissolution media, which are often used to evaluate the in-vitro drug release of drug eluting stents (DES). Everolimus and dissolution medium containing Triton X-405 were selected as representatives, and the appropriate SPE conditions (adsorption, washing and elution) were investigated to obtain a practical and reliable sample clean-up. It was shown that the developed SPE procedure was capable of removing interfering components (Triton X-405 and its impurities), allowing for an accurate automated spectrophotometric analysis to be performed. The proposed UV-Vis spectrophotometric method yielded equivalent results compared to a classical LC analysis method. Linear regression analysis indicated that both methods have the ability to obtain test results that are directly proportional to the concentration of analyte in the sample within the selected range of 1.0-10 μg/ml for everolimus, with a coefficient of correlation (r(2)) value of >0.998 and standard deviation of the residuals (Syx) of UV-Vis spectrophotometric method and from 98 to 102 for the HPLC method, respectively. The 95% CI of the mean recovery for the UV-Vis spectrophotometric method was 99-102% and for the HPLC method was 99-101%. No statistical difference was found between the mean recoveries of the methods (p=0.42). Hence the methods are free from interference due to Triton and other chemicals present in the dissolution medium. The variation in the amount of everolimus estimated by UV-Vis spectrophotometric and HPLC methods was ≤3.5%, and the drug release profiles obtained by both methods were found to be equivalent by evaluation with two-one-sided t-test (two-tailed, p=0.62; mean of differences, 0.17; 95% CI, 0.62-0.96) and similarity factor f2 (f2 value, 87). The excellent conformity of

  1. Economic Outcomes of Bioresorbable Vascular Scaffolds Versus Everolimus-Eluting Stents in Patients Undergoing Percutaneous Coronary Intervention: 1-Year Results From the ABSORB III Trial.

    Baron, Suzanne J; Lei, Yang; Chinnakondepalli, Khaja; Vilain, Katherine; Magnuson, Elizabeth A; Kereiakes, Dean J; Ellis, Stephen G; Stone, Gregg W; Cohen, David J

    2017-04-24

    The purpose of this study was to evaluate the economic impact of the Absorb bioresorbable vascular scaffold compared with the Xience everolimus-eluting stent in patients undergoing percutaneous coronary intervention. The ABSORB III trial (Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease) demonstrated that the Absorb scaffold was noninferior to the Xience stent with respect to target lesion failure at 1 year. Whether health care costs differ between the Absorb scaffold and the Xience stent is unknown. We performed a prospective health economic study alongside the ABSORB III trial, in which patients undergoing percutaneous coronary intervention for stable or unstable angina were randomized to receive the Absorb scaffold (n = 1,322) or Xience stent (n = 686). Resource use data were collected through 1 year of follow-up. Costs were assessed using resource-based accounting (for procedures), MedPAR data (for other index hospitalization costs), and Medicare reimbursements (for follow-up costs and physician fees). Initial procedural costs were higher with the Absorb scaffold than the Xience stent ($6,316 ± 1,892 vs. $6,103 ± 1,895; p = 0.02), driven mainly by greater balloon catheter use and the higher cost of the scaffold in the Absorb group. Nonetheless, index hospitalization costs ($15,035 ± 2,992 for Absorb vs. $14,903 ± 3,449 for Xience; p = 0.37) and total 1-year costs ($17,848 ± 6,110 for Absorb vs. $17,498 ± 7,411 for Xience; p = 0.29) were similar between the 2 groups. Although initial procedural costs were higher with the Absorb scaffold, there were no differences in total 1-year health care costs between the 2 cohorts. Longer term follow-up is needed to determine whether meaningful cost savings emerge after scaffold resorption. (A Clinical Evaluation of Absorb™ BVS, the Everolimus-Eluting Bioresorbable Vascular Scaffold in the Treatment of Subjects With de Novo Native Coronary Artery Lesions; NCT01751906). Copyright © 2017

  2. Long-term forecasting and comparison of mortality in the Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial: prospective validation of the SYNTAX Score II.

    Campos, Carlos M; van Klaveren, David; Farooq, Vasim; Simonton, Charles A; Kappetein, Arie-Pieter; Sabik, Joseph F; Steyerberg, Ewout W; Stone, Gregg W; Serruys, Patrick W

    2015-05-21

    To prospectively validate the SYNTAX Score II and forecast the outcomes of the randomized Evaluation of the Xience Everolimus-Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) Trial. Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization is a prospective, randomized multicenter trial designed to establish the efficacy and safety of percutaneous coronary intervention (PCI) with the everolimus-eluting stent compared with coronary artery bypass graft (CABG) surgery in subjects with unprotected left-main coronary artery (ULMCA) disease and low-intermediate anatomical SYNTAX scores (EXCEL, the SYNTAX Score II was prospectively applied to predict 4-year mortality in the CABG and PCI arms. The 95% prediction intervals (PIs) for mortality were computed using simulation with bootstrap resampling (10 000 times). For the entire study cohort, the 4-year predicted mortalities were 8.5 and 10.5% in the PCI and CABG arms, respectively [odds ratios (OR) 0.79; 95% PI 0.43-1.50). In subjects with low (≤22) anatomical SYNTAX scores, the predicted OR was 0.69 (95% PI 0.34-1.45); in intermediate anatomical SYNTAX scores (23-32), the predicted OR was 0.93 (95% PI 0.53-1.62). Based on 4-year mortality predictions in EXCEL, clinical characteristics shifted long-term mortality predictions either in favour of PCI (older age, male gender and COPD) or CABG (younger age, lower creatinine clearance, female gender, reduced left ventricular ejection fraction). The SYNTAX Score II indicates at least an equipoise for long-term mortality between CABG and PCI in subjects with ULMCA disease up to an intermediate anatomical complexity. Both anatomical and clinical characteristics had a clear impact on long-term mortality predictions and decision making between CABG and PCI. Published on behalf of the European Society of Cardiology. All rights reserved. © The

  3. Long-Term Results of Everolimus-Eluting Stents Versus Drug-Eluting Balloons in Patients With Bare-Metal In-Stent Restenosis: 3-Year Follow-Up of the RIBS V Clinical Trial.

    Alfonso, Fernando; Pérez-Vizcayno, María José; García Del Blanco, Bruno; Otaegui, Imanol; Masotti, Mónica; Zueco, Javier; Veláquez, Maite; Sanchís, Juan; García-Touchard, Arturo; Lázaro-García, Rosa; Moreu, José; Bethencourt, Armando; Cuesta, Javier; Rivero, Fernando; Cárdenas, Alberto; Gonzalo, Nieves; Jiménez-Quevedo, Pilar; Fernández, Cristina

    2016-06-27

    The aim of this study was to compare the long-term efficacy of everolimus-eluting stents (EES) and drug-eluting balloons (DEB) in patients with bare-metal stent in-stent restenosis (ISR). The relative long-term clinical efficacy of current therapeutic modalities in patients with ISR remains unknown. The 3-year clinical follow-up (pre-specified endpoint) of patients included in the RIBS V (Restenosis Intra-Stent of Bare-Metal Stents: Drug-Eluting Balloon vs Everolimus-Eluting Stent Implantation) randomized clinical trial was analyzed. All patients were followed yearly using a pre-defined structured questionnaire. A total of 189 patients with bare-metal stent ISR were allocated to either EES (n = 94) or DEB (n = 95). Clinical follow-up at 1, 2, and 3 years was obtained in all patients (100%). Compared with patients treated with DEB, those treated with EES obtained better angiographic results, including larger minimal luminal diameter at follow-up (primary study endpoint; 2.36 ± 0.6 mm vs. 2.01 ± 0.6 mm; p 1 year) target vessel (3 [3.2%] vs. 3 [3.2%]; p = 0.95) and target lesion (1 [1%] vs. 2 [2.1%]; p = 0.54) revascularization was low and similar in the 2 arms. Rates of definite or probable stent thrombosis (1% vs. 0%) were also similar in the 2 arms. The 3-year clinical follow-up of the RIBS V clinical trial confirms the sustained safety and efficacy of EES and DEB in patients treated for bare-metal stent ISR. In this setting, EES reduce the need for target lesion revascularization at very long-term follow-up. (RIBS V [Restenosis Intra-Stent of Bare Metal Stents: Paclitaxel-Eluting Balloon vs Everolimus-Eluting Stent] [RIBS V]; NCT01239953). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  4. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice.

    Adam L Hartman

    Full Text Available The mammalian target of rapamycin (mTOR pathway integrates signals from different nutrient sources, including amino acids and glucose. Compounds that inhibit mTOR kinase activity such as rapamycin and everolimus can suppress seizures in some chronic animal models and in patients with tuberous sclerosis. However, it is not known whether mTOR inhibitors exert acute anticonvulsant effects in addition to their longer term antiepileptogenic effects. To gain insights into how rapamycin suppresses seizures, we investigated the anticonvulsant activity of rapamycin using acute seizure tests in mice.Following intraperitoneal injection of rapamycin, normal four-week-old male NIH Swiss mice were evaluated for susceptibility to a battery of acute seizure tests similar to those currently used to screen potential therapeutics by the US NIH Anticonvulsant Screening Program. To assess the short term effects of rapamycin, mice were seizure tested in ≤ 6 hours of a single dose of rapamycin, and for longer term effects of rapamycin, mice were tested after 3 or more daily doses of rapamycin.The only seizure test where short-term rapamycin treatment protected mice was against tonic hindlimb extension in the MES threshold test, though this protection waned with longer rapamycin treatment. Longer term rapamycin treatment protected against kainic acid-induced seizure activity, but only at late times after seizure onset. Rapamycin was not protective in the 6 Hz or PTZ seizure tests after short or longer rapamycin treatment times. In contrast to other metabolism-based therapies that protect in acute seizure tests, rapamycin has limited acute anticonvulsant effects in normal mice.The efficacy of rapamycin as an acute anticonvulsant agent may be limited. Furthermore, the combined pattern of acute seizure test results places rapamycin in a third category distinct from both fasting and the ketogenic diet, and which is more similar to drugs acting on sodium channels.

  5. A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial.

    de Winter, Robbert J; Katagiri, Yuki; Asano, Taku; Milewski, Krzysztof P; Lurz, Philipp; Buszman, Pawel; Jessurun, Gillian A J; Koch, Karel T; Troquay, Roland P T; Hamer, Bas J B; Ophuis, Ton Oude; Wöhrle, Jochen; Wyderka, Rafał; Cayla, Guillaume; Hofma, Sjoerd H; Levesque, Sébastien; Żurakowski, Aleksander; Fischer, Dieter; Kośmider, Maciej; Goube, Pascal; Arkenbout, E Karin; Noutsias, Michel; Ferrari, Markus W; Onuma, Yoshinobu; Wijns, William; Serruys, Patrick W

    2018-02-03

    MiStent is a drug-eluting stent with a fully absorbable polymer coating containing and embedding a microcrystalline form of sirolimus into the vessel wall. It was developed to overcome the limitation of current durable polymer drug-eluting stents eluting amorphous sirolimus. The clinical effect of MiStent sirolimus-eluting stent compared with a durable polymer drug-eluting stents has not been investigated in a large randomised trial in an all-comer population. We did a randomised, single-blind, multicentre, phase 3 study (DESSOLVE III) at 20 hospitals in Germany, France, Netherlands, and Poland. Eligible participants were any patients aged at least 18 years who underwent percutaneous coronary intervention in a lesion and had a reference vessel diameter of 2·50-3·75 mm. We randomly assigned patients (1:1) to implantation of either a sirolimus-eluting bioresorbable polymer stent (MiStent) or an everolimus-eluting durable polymer stent (Xience). Randomisation was done by local investigators via web-based software with random blocks according to centre. The primary endpoint was a non-inferiority comparison of a device-oriented composite endpoint (DOCE)-cardiac death, target-vessel myocardial infarction, or clinically indicated target lesion revascularisation-between the groups at 12 months after the procedure assessed by intention-to-treat. A margin of 4·0% was defined for non-inferiority of the MiStent group compared with the Xience group. All participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02385279. Between March 20, and Dec 3, 2015, we randomly assigned 1398 patients with 2030 lesions; 703 patients with 1037 lesions were assigned to MiStent, of whom 697 received the index procedure, and 695 patients with 993 lesions were asssigned to Xience, of whom 690 received the index procedure. At 12 months, the primary endpoint had occurred in 40 patients (5·8%) in the sirolimus-eluting stent group and in 45

  6. DGAT inhibitors for obesity.

    Matsuda, Daisuke; Tomoda, Hiroshi

    2007-10-01

    Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis. Two isozymes of DGAT, DGAT1 and DGAT2, have been reported. Increased DGAT2 activity has a role in steatosis, while DGAT1 plays a role in very (V)LDL synthesis; increased plasma VLDL concentrations may promote obesity and thus DGAT1 is considered a potential therapeutic target of inhibition for obesity control. Several DGAT inhibitors of natural and synthetic origin have been reported, and their future prospect as anti-obesity drugs is discussed in this review.

  7. Efficacy and Safety of the Absorb Everolimus-Eluting Bioresorbable Scaffold for Treatment of Patients With Diabetes Mellitus: Results of the Absorb Diabetic Substudy.

    Kereiakes, Dean J; Ellis, Stephen G; Kimura, Takeshi; Abizaid, Alexandre; Zhao, Weiying; Veldhof, Susan; Vu, Minh-Thien; Zhang, Zhen; Onuma, Yoshinobu; Chevalier, Bernard; Serruys, Patrick W; Stone, Gregg W

    2017-01-09

    The study sought to evaluate the efficacy and safety of the Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) (Abbott Vascular, Abbott Park, Illinois) in patients with diabetes mellitus. Randomized, controlled trials have demonstrated comparable clinical outcomes following percutaneous coronary intervention with either Absorb BVS or metallic Xience everolimus-eluting stent. However, these trials lack power required to provide reliable treatment effect estimates in this high-risk population. In a pre-specified, powered analysis, patients with diabetes who received ≥1 Absorb were pooled from the ABSORB II, III, and JAPAN randomized trials and from the single arm ABSORB EXTEND registry. The study composite primary endpoint was target lesion failure (TLF) at 1 year following Absorb BVS compared with a performance goal of 12.7%. Among 754 diabetic patients included in analysis (27.3% insulin treated), the 1-year TLF rate was 8.3% (upper 1-sided 95% confidence limit: 10.1%; p = 0.0001 vs. performance goal). Scaffold thrombosis (definite or probable) was observed in 2.3% of patients. Multivariable regression identified older age, insulin treatment, and smaller pre-procedure reference vessel diameter as significant independent predictors of 1-year TLF. The Absorb diabetic substudy suggests efficacy and safety of the Absorb BVS for treatment of patients with diabetes mellitus. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  8. Pulmonary Toxicity of Cholinesterase Inhibitors

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  9. Biological abatement of cellulase inhibitors

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  10. Proteinaceous alpha-araylase inhibitors

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    -amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha...

  11. Corrosion inhibitors. Manufacture and technology

    Ranney, M.W.

    1976-01-01

    Detailed information is presented relating to corrosion inhibitors. Areas covered include: cooling water, boilers and water supply plants; oil well and refinery operations; fuel and lubricant additives for automotive use; hydraulic fluids and machine tool lubes; grease compositions; metal surface treatments and coatings; and general processes for corrosion inhibitors

  12. Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification or HER3/4 Mutation

    2018-03-26

    Malignant Neoplasm of Breast; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract; Neoplasms of Uncertain or Unknown Behavior

  13. Drug Monographs: Atezolizumab and Everolimus.

    Green, Matthew A; Waddell, J Aubrey; Solimando, Dominic A

    2016-11-01

    The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The authors are not employees of, under contract to, recipients of funding to review products from, or in any other way affiliated with either Genentech, Inc. or Novartis Pharmaceuticals Corporation. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents.

  14. [ACE inhibitors and the kidney].

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  15. A randomized multicenter comparison of hybrid sirolimus-eluting stents with bioresorbable polymer versus everolimus-eluting stents with durable polymer in total coronary occlusion: rationale and design of the Primary Stenting of Occluded Native Coronary Arteries IV study

    Teeuwen Koen

    2012-12-01

    Full Text Available Abstract Background Percutaneous recanalization of total coronary occlusion (TCO was historically hampered by high rates of restenosis and reocclusions. The PRISON II trial demonstrated a significant restenosis reduction in patients treated with sirolimus-eluting stents compared with bare metal stents for TCO. Similar reductions in restenosis were observed with the second-generation zotarolimus-eluting stent and everolimus-eluting stent. Despite favorable anti-restenotic efficacy, safety concerns evolved after identifying an increased rate of very late stent thrombosis (VLST with drug-eluting stents (DES for the treatment of TCO. Late malapposition caused by hypersensitivity reactions and chronic inflammation was suggested as a probable cause of these VLST. New DES with bioresorbable polymer coatings were developed to address these safety concerns. No randomized trials have evaluated the efficacy and safety of the new-generation DES with bioresorbable polymers in patients treated for TCO. Methods/Design The prospective, randomized, single-blinded, multicenter, non-inferiority PRISON IV trial was designed to evaluate the safety, efficacy, and angiographic outcome of hybrid sirolimus-eluting stents with bioresorbable polymers (Orsiro; Biotronik, Berlin, Germany compared with everolimus-eluting stents with durable polymers (Xience Prime/Xpedition; Abbott Vascular, Santa Clara, CA, USA in patients with successfully recanalized TCOs. In total, 330 patients have been randomly allocated to each treatment arm. Patients are eligible with estimated duration of TCO ≥4 weeks with evidence of ischemia in the supply area of the TCO. The primary endpoint is in-segment late luminal loss at 9-month follow-up angiography. Secondary angiographic endpoints include in-stent late luminal loss, minimal luminal diameter, percentage of diameter stenosis, in-stent and in-segment binary restenosis and reocclusions at 9-month follow-up. Additionally, optical coherence

  16. Optical coherence tomography findings after chronic total occlusion interventions: Insights from the “AngiographiC evaluation of the everolimus-eluting stent in chronic Total occlusions” (ACE-CTO) study (NCT01012869)

    Sherbet, Daniel P.; Christopoulos, Georgios; Karatasakis, Aris; Danek, Barbara Anna; Kotsia, Anna; Navara, Rachita; Michael, Tesfaldet T.; Roesle, Michele; Rangan, Bavana V.; Haagen, Donald [VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, TX (United States); Garcia, Santiago [Minneapolis VA Healthcare System and University of Minnesota, Minneapolis, MN (United States); Maniu, Calin [Bon Secours Health System, Suffolk, VA (United States); Pershad, Ashish [Banner Good Samaritan Medical Center, Phoenix, AZ (United States); Abdullah, Shuaib M.; Hastings, Jeffrey L.; Kumbhani, Dharam J.; Luna, Michael; Addo, Tayo; Banerjee, Subhash [VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, TX (United States); Brilakis, Emmanouil S., E-mail: esbrilakis@gmail.com [VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, TX (United States)

    2016-10-15

    Background: There is limited information on optical coherence tomography (OCT) findings after percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). OCT allows high resolution imaging that can enhance understanding of the vascular response after stenting of chronically occluded vessels. Methods: The Angiographic Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO) study collected angiographic and clinical outcomes from 100 patients undergoing CTO PCI with the everolimus-eluting stent (EES). OCT was performed 8-months post stenting in 62 patients. Every third frame was analyzed throughout the course of the stented arterial segment. Lumen contours were semi-automatically traced and stent struts were manually delineated, with automatic measurement of the strut to lumen distance. Struts on the luminal side of the lumen contour were classified as malapposed if the distance to the lumen contour exceeded 0.108 mm. Results: A total of 44,450 struts in 6047 frames were analyzed, of which 4113 9.3%, 95% confidence intervals [CI] 9.0% to 9.5%) were malapposed and 1230 (2.8%, 95% CI 2.6% to 2.9%) were uncovered. Fifty-five of 62 patients (88.7%, 95% CI 78.5% to 98.4%) had at least one malapposed stent strut and 50 patients (80.7%, 95% CI 69.2% to 88.6%) had at least one uncovered stent strut. Mean strut-intimal thickness of the apposed and malapposed struts was 0.126 ± 0.140 mm and − 0.491 ± 0.440 mm, respectively. Conclusion: High rates of stent strut malapposition and incomplete stent strut coverage were observed after CTO PCI using EES, highlighting unique challenges associated with stent implantation in CTOs. - Highlights: • Percutaneous coronary intervention with drug-eluting stents for chronic total occlusion is associated with a 40% rate of binary in-stent restenosis at 8 months • Of patients who receive a drug eluting stent for a chronic total occlusion 88.7% will have stent strut malapposition and 80.7% will

  17. mTOR-inhibitor treatment of metastatic renal cell carcinoma: contribution of Choi and modified Choi criteria assessed in 2D or 3D to evaluate tumor response

    Lamuraglia, M. [Laboratoire d' Imagerie Biomedicale, Sorbonne Universites, UPMC Univ Paris 06, INSERM, CNRS, Paris (France); Raslan, S.; Penna, R.R.; Wagner, M. [Groupe Hospitalier Pitie-Salpetriere, APHP UPMC, Service de Radiologie Polyvalente et Oncologique, Paris Cedex 13 (France); Elaidi, R.; Oudard, S. [APHP, Oncology Unit, Georges-Pompidou Hospital, Paris (France); Escudier, B. [Gustave-Roussy Institute, Medical Oncology Department, Villejuif (France); Slimane, K. [Novartis Pharma, Rueil-Malmaison (France); Lucidarme, O. [Groupe Hospitalier Pitie-Salpetriere, APHP UPMC, Service de Radiologie Polyvalente et Oncologique, Paris Cedex 13 (France); Laboratoire d' Imagerie Biomedicale, Sorbonne Universites, UPMC Univ Paris 06, INSERM, CNRS, Paris (France)

    2016-01-15

    To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC). RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion. The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22-0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus. At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus. (orig.)

  18. A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

    Lorf Thomas

    2010-04-01

    Full Text Available Abstract Background Immunosuppression with calcineurin inhibitors (CNI increases the risk of renal dysfunction after orthotopic liver transplantation (OLT. Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. Methods/Design A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate, liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT, treatment failure, (i. e., re-introduction of CNI, incidence of adverse events, and mortality up to one year after OLT. Discussion This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation of this phase III trial. Trial registration number NCT00890253 (clinicaltrials.gov

  19. Percutaneous Coronary Intervention of Left Main Disease: Pre- and Post-EXCEL (Evaluation of XIENCE Everolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) and NOBLE (Nordic-Baltic-British Left Main Revascularization Study) Era.

    Park, Duk-Woo; Park, Seung-Jung

    2017-06-01

    For nearly half a century, coronary artery bypass grafting has been the standard treatment for patients with obstructive left main coronary artery (LMCA) disease. However, there has been considerable evolution in the field of percutaneous coronary intervention, and especially, percutaneous coronary intervention for LMCA disease has been rapidly expanded with adoption of drug-eluting stents. Some, but not all randomized trials, have shown that percutaneous coronary intervention with drug-eluting stents might be a suitable alternative for selected patients with LMCA disease instead of bypass surgery. However, none of previous trials involving early-generation drug-eluting stents was sufficiently powered and comparative trials using contemporary drug-eluting stents were limited. Recently, primary results of 2 new trials of EXCEL (Evaluation of XIENCE Everolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) and NOBLE (Nordic-Baltic-British Left Main Revascularization Study) were reported. However, these trials showed conflicting results, which might pose uncertainty on the optimal revascularization strategy for LMCA disease. In this article, with the incorporation of a key review on evolution of LMCA treatment, we summarize the similarity or disparity of the EXCEL and NOBLE trials, focus on how they relate to previous trials in the field, and finally speculate on how the treatment strategy may be changed or recommended for LMCA treatment. © 2017 American Heart Association, Inc.

  20. Metal corrosion inhibitors and ecology

    Krasts, H.; Svarce, J.; Berge, B.

    1999-01-01

    The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

  1. Positron emitter labeled enzyme inhibitors

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.; Langstrom, B.

    1990-01-01

    This invention involves a new strategy for imagining and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography

  2. ROCK inhibitors in ocular disease

    Eva Halasz

    2016-12-01

    Full Text Available Rho kinases (ROCKs have a crucial role in actin-cytoskeletal reorganization and thus are involved in broad aspects of cell motility, from smooth muscle contraction to neurite outgrowth. The first marketed ROCK inhibitor, called fasudil, has been used safely for treatment of cerebral vasospasm since 1995 in Japan. During the succeeding decades ROCK inhibitors have been applied in many pathological conditions from central nervous system disorders to cardiovascular disease as potential therapeutic agents or experimental tools to help understand the underlying (pathomechanisms. In 2014, a fasudil derivate named ripasudil was accepted for clinical use in glaucoma and ocular hypertension. Since ROCK kinases are widely expressed in ocular tissues, they have been implicated in the pathology of many ocular conditions such as corneal dysfunction, glaucoma, cataract, diabetic retinopathy, age-related macular degeneration, and retinal detachment. This paper aims to provide an overview of the most recent status/application of ROCK inhibitors in the field of eye disease.

  3. 3-Year Clinical Follow-Up of the RIBS IV Clinical Trial: A Prospective Randomized Study of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis in Coronary Arteries Previously Treated With Drug-Eluting Stents.

    Alfonso, Fernando; Pérez-Vizcayno, María José; Cuesta, Javier; García Del Blanco, Bruno; García-Touchard, Arturo; López-Mínguez, José Ramón; Masotti, Mónica; Zueco, Javier; Cequier, Angel; Velázquez, Maite; Moreno, Raúl; Mainar, Vicente; Domínguez, Antonio; Moris, Cesar; Molina, Eduardo; Rivero, Fernando; Jiménez-Quevedo, Pilar; Gonzalo, Nieves; Fernández-Pérez, Cristina

    2018-05-28

    This study sought to compare the long-term safety and efficacy of drug-eluting balloons (DEB) and everolimus-eluting stents (EES) in patients with in-stent restenosis (ISR) of drug-eluting stents (DES). Treatment of patients with DES-ISR remains a challenge. The RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents) trial is a prospective multicenter randomized clinical trial comparing DEB and EES in patients with DES-ISR. The pre-specified comparison of the 3-year clinical outcomes obtained with these interventions is the main objective of the present study. A total of 309 patients with DES-ISR were randomized to DEB (n = 154) or EES (n = 155). At angiographic follow-up, the in-segment minimal lumen diameter was larger in the EES arm (2.03 ± 0.7 mm vs. 1.80 ± 0.6 mm; p 1 year) target lesion revascularization (2.6% vs. 4%) and target vessel revascularization (4% vs. 6.6%) was similar in the 2 arms. Rates of cardiac death (3.9% vs. 3.2%), myocardial infarction (2.6% vs. 4.5%), and stent thrombosis (1.3% vs. 2.6%) at 3 years were also similar in both arms. The 3-year clinical follow-up of this randomized clinical trial demonstrates that in patients with DES-ISR, EES reduce the need for repeat interventions compared with DEB. (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents [RIBS IV]; NCT01239940). Published by Elsevier Inc.

  4. Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway.

    Chen, Dongshao; Lin, Xiaoting; Zhang, Cheng; Liu, Zhentao; Chen, Zuhua; Li, Zhongwu; Wang, Jingyuan; Li, Beifang; Hu, Yanting; Dong, Bin; Shen, Lin; Ji, Jiafu; Gao, Jing; Zhang, Xiaotian

    2018-01-26

    Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G 2 /M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.

  5. Azidoblebbistatin, a photoreactive myosin inhibitor

    Képiró, Miklós; Várkuti, Boglárka H.; Bodor, Andrea; Hegyi, György; Drahos, László; Kovács, Mihály; Málnási-Csizmadia, András

    2012-01-01

    Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-crosslinking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidoblebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC50 ≥ 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC50 = 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions. PMID:22647605

  6. Biological abatement of cellulase inhibitors.

    Cao, Guangli; Ximenes, Eduardo; Nichols, Nancy N; Zhang, Leyu; Ladisch, Michael

    2013-10-01

    Removal of enzyme inhibitors released during lignocellulose pretreatment is essential for economically feasible biofuel production. We tested bio-abatement to mitigate enzyme inhibitor effects observed in corn stover liquors after pretreatment with either dilute acid or liquid hot water at 10% (w/v) solids. Bio-abatement of liquors was followed by enzymatic hydrolysis of cellulose. To distinguish between inhibitor effects on enzymes and recalcitrance of the substrate, pretreated corn stover solids were removed and replaced with 1% (w/v) Solka Floc. Cellulose conversion in the presence of bio-abated liquors from dilute acid pretreatment was 8.6% (0.1x enzyme) and 16% (1x enzyme) higher than control (non-abated) samples. In the presence of bio-abated liquor from liquid hot water pretreated corn stover, 10% (0.1x enzyme) and 13% (1x enzyme) higher cellulose conversion was obtained compared to control. Bio-abatement yielded improved enzyme hydrolysis in the same range as that obtained using a chemical (overliming) method for mitigating inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Phosphodiesterase inhibitors in clinical urology.

    Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

    2013-05-01

    To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

  8. Inhibitors of mTOR

    Klümpen, Heinz-Josef; Beijnen, Jos H.; Gurney, Howard; Schellens, Jan H. M.

    2010-01-01

    Inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. The primary objective of this drug review is to provide pharmacokinetic and dynamic properties of the commonly used drugs

  9. Retroviral proteinases and their inhibitors

    Sedláček, Juraj

    2000-01-01

    Roč. 3, 3,4 (2000), s. 23-24 [ Proteolytic enzymes and their inhibitors in physiology and pathogenesis. 14.09.2000, Plzen] Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  10. Monoamine depletion by reuptake inhibitors

    Hinz M

    2011-10-01

    Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics Inc, Cape Coral, FL; 2Stein Orthopedic Associates, Plantation, FL; 3DBS Labs Inc, Duluth, MN, USABackground: Disagreement exists regarding the etiology of cessation of the observed clinical results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.Methods: Two groups were retrospectively evaluated. Group 1 was composed of subjects with depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors for appetite suppression.Results: In Group 1, 200 subjects with depression were treated with citalopram 20 mg per day. A total of 46.5% (n = 93 achieved relief of symptoms (Hamilton-D rating score ≤ 7, of whom 37 (39.8% of whom experienced recurrence of depression symptoms, at which point an amino acid precursor formula was started. Within 1–5 days, 97.3% (n = 36 experienced relief of depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198 achieved adequate appetite suppression. The appetite suppression ceased in all 198 subjects within 4–48 days. Administration of an amino acid precursor formula restored appetite suppression in 98.5% (n = 195 of subjects within 1–5 days.Conclusion: Reuptake inhibitors do not increase the total number of monoamine molecules in the central nervous system. Their mechanism of action facilitates redistribution of monoamines from one place to another. In the process, conditions are induced that facilitate depletion of monoamines. The "reuptake inhibitor monoamine depletion theory" of this paper

  11. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  12. Contemporary protease inhibitors and cardiovascular risk

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...

  13. Reduction rules for reset/inhibitor nets

    Verbeek, H.M.W.; Wynn, M.T.; Aalst, van der W.M.P.; Hofstede, ter A.H.M.

    2010-01-01

    Reset/inhibitor nets are Petri nets extended with reset arcs and inhibitor arcs. These extensions can be used to model cancellation and blocking. A reset arc allows a transition to remove all tokens from a certain place when the transition fires. An inhibitor arc can stop a transition from being

  14. Allosteric small-molecule kinase inhibitors

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  15. Comparison of the Absorbable Polymer Sirolimus-Eluting Stent (MiStent) to the Durable Polymer Everolimus-Eluting Stent (Xience) (from the DESSOLVE I/II and ISAR-TEST-4 Studies).

    Lansky, Alexandra J; Kastrati, Adnan; Edelman, Elazer R; Parise, Helen; Ng, Vivian G; Ormiston, John; Wijns, William; Byrne, Robert A

    2016-02-15

    We compared the outcomes of a novel, thin-strut, cobalt-chromium, absorbable, polymer sirolimus-eluting stent (APSES; MiStent) to the durable polymer cobalt-chromium everolimus-eluting stent (EES; Xience). A propensity-matched analysis was performed comparing data from the DES With Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With De Novo Lesions in the Native Coronary Arteries (DESSOLVE) I and II studies, evaluating the APSES to the EES arm of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4 study. Target lesion failure (TLF) and its components were evaluated at 12 months and annually to 3 years; 805 patients (APSES = 153; EES = 652) were included with propensity matching in 204 patients (APSES = 102; EES = 102). APSES compared with EES had lower TLF at 1 year (3.0% vs 8.0%, p = 0.12) driven by a difference in target lesion revascularization (TLR; 1% vs 6%, p = 0.05), with no difference in target vessel myocardial infarction (p = 0.56) or stent thrombosis (p = 0.31). At 3 years, TLF (5.0% vs 12.5%, p = 0.07) and TLR (2.0% vs 8.4%, p = 0.04) remained lower with APSES. By landmark analysis, there was no significant difference in TLF between 1 and 3 years (p = 0.36). In conclusion, in a propensity-matched analysis, the APSES demonstrated reduced clinically indicated TLR rates at 1 and 3 years compared with the durable polymer EES, with minimal accrual of events between 1 and 3 years. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Morphological and functional evaluation of the bioresorption of the bioresorbable everolimus-eluting vascular scaffold using IVUS, echogenicity and vasomotion testing at two year follow-up: a patient level insight into the ABSORB A clinical trial.

    Sarno, Giovanna; Bruining, Nico; Onuma, Yoshinobu; Garg, Scot; Brugaletta, Salvatore; De Winter, Sebastiaan; Regar, Evelyn; Thuesen, Leif; Dudek, Dariusz; Veldhof, Susan; Dorange, Cecile; Garcia-Garcia, Hector M; Ormiston, John A; Serruys, Patrick W

    2012-01-01

    The aim of this study was to describe vaso-reactivity (by Acetylcholine and Methergine tests) at 2 year follow-up in parallel with the individual changes in the echogenicity characteristics of the polymer struts of the everolimus eluting bioresorbable vascular scaffold (BVS), from post-treatment to 2 year follow-up, in patients enrolled in the ABSORB Cohort A study. Intravascular ultrasound assessment was performed with a phased array catheter (EagleEye, Volcano Corporation, Cordova, CA, USA) with automated pullback at 0.5 mm per second. The % ratio at 6 months and 2 years [(Scaffold Area post PCI- Lumen Area)/Scaffold Area post PCI] was calculated as a measure of scaffold shrinkage. The % change of hyperechogenicity was defined as: ([post-procedural hyperechogenicity] - [2 year follow up hyperechogenicity])/[post-procedural hyperechogenicity]) × 100. The vasomotion test with intracoronary acetylcholine (10(-6) M) or intravenous methergine (0.4 mg) was performed at 2 years. Overall nine patients received all these analyses and were enrolled in the present analysis. A 50-96% reduction in hyperechogenicity was observed between baseline and 2 years, which corresponded to a change in vasoreactivity between 2 and 22%. A vasoconstriction of the scaffolded segment was observed in the 5 patients, who underwent the methergine test, with a mean decrease in lumen diameter after methergine of 9 ± 7% (P = 0.06), while vasodilatation occurred in the 4 patients who underwent the acetylcholine test with a mean increase in lumen diameter after acetylcholine of 8 ± 5% (P = 0.125). Bioresorption of the BVS is accompanied by re-establishment of both endothelial and non-endothelial dependent vasomotion.

  17. Stent coverage and neointimal proliferation in bare metal stents postdilated with a Paclitaxel-eluting balloon versus everolimus-eluting stents: prospective randomized study using optical coherence tomography at 6-month follow-up.

    Poerner, Tudor C; Otto, Sylvia; Gassdorf, Johannes; Nitsche, Kristina; Janiak, Florian; Scheller, Bruno; Goebel, Björn; Jung, Christian; Figulla, Hans R

    2014-12-01

    In this randomized trial, strut coverage and neointimal proliferation of a therapy of bare metal stents (BMSs) postdilated with the paclitaxel drug-eluting balloon (DEB) was compared with everolimus drug-eluting stents (DESs) at 6-month follow-up using optical coherence tomography. We hypothesized sufficient stent coverage at follow-up. A total of 105 lesions in 90 patients were treated with either XIENCE V DES (n=51) or BMS postdilated with the SeQuent Please DEB (n=54). At follow-up, comparable results on the primary optical coherence tomography end point (percentage uncovered struts 5.64±9.65% in BMS+DEB versus 4.93±9.29% in DES; P=0.366) were found. Thus, BMS+DEB achieved the prespecified noninferiority margin of 5% uncovered struts versus DES (difference between treatment means, 0.71%; one-sided upper 95% confidence interval, 4.14%; noninferiority P=0.04). Optical coherence tomography analysis showed significantly more global neointimal proliferation in the BMS+DEB group (15.7±7.8 versus 11.0±5.2 mm(3) proliferation volume/cm stent length; P=0.002). No significant focal in-stent stenosis analyzed with angiography (percentage diameter stenosis at follow-up, 22.8±11.9 versus 16.9±10.4; P=0.014) and optical coherence tomography (peak local area stenosis, 39.5±13.8% versus 36.8±15.6%; P=0.409) was found. Good stent strut coverage of >94% was found in both therapy groups. Despite greater suppression of global neointimal growth in DES, both DES and BMS+DEB effectively prevented clinically relevant focal restenosis at 6-month follow-up. http://www.clinicaltrials.gov. Unique identifier: NCT01056744. © 2014 American Heart Association, Inc.

  18. Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

    Walker, J.B.; Hughes, B.; James, I.; Haddock, P.; Kluft, C.; Bajzar, L.

    2003-01-01

    Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged,

  19. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

    Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

  20. Calcineurin-inhibitor pain syndrome.

    Prommer, Eric

    2012-07-01

    There has been increased recognition of calcineurin, a phosphoprotein serine/threonine phosphatase enzyme, in the regulation of many physiologic systems. Calcineurin mediates activation of lymphocytes, which play a role in immune response. Widely distributed in the central nervous system, calcinuerin also plays an important role in sensory neural function, via its role in the regulation of newly discovered 2-pore potassium channels, which greatly influence neuronal resting membrane potentials. Calcinuerin inhibition is the mechanism of action of immunomodulatory drugs such as cyclosporine and tacrolimus, which are widely used in transplantation medicine to prevent rejection. While important for immunosuppression, the use of calcineurin inhibitors has been associated with the development of a new pain syndrome called the calcineurin pain syndrome, which appears to be an untoward complication of the interruption of the physiologic function of calcineurin. This is a narrative review focusing on the epidemiology, pathophysiology, characterization of a newly recognized pain syndrome associated with the use of calcineurin inhibitors. The use of immunosuppressants however is associated with several well-known toxicities to which the calcineurin pain syndrome can be added. The development of this syndrome most likely involves altered nociceptive processing due to the effect of calcineurin inhibition on neuronal firing, as well as effects of calcineurin on vascular tone. The most striking aspect of the treatment of this syndrome is the response to calcium channel blockers, which suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of the calcineurin pain syndrome. The calcineurin syndrome is a newly recognized complication associated with the use of calcineurin inhibitors. There is no standard therapy at this time but anecdotal reports suggest the effectiveness of calcium channel blockers.

  1. Crystallization inhibitors for amorphous oxides

    Reznitskij, L.A.; Filippova, S.E.

    1993-01-01

    Data for the last 10 years, in which experimental results of studying the temperature stabilization of x-ray amorphous oxides (including R 3 Fe 5 O 12 R-rare earths, ZrO 2 , In 2 O 3 , Sc 2 O 3 ) and their solid solution are presented, are generalized. Processes of amorphous oxide crystallization with the production of simple oxides, solid solutions and chemical compounds with different polyhedral structure, are investigated. Energy and crystallochemical criteria for selecting the doping inhibitor-components stabilizing the amorphous state are ascertained, temperatures and enthalpies of amorpous oxide crystallization are determined, examination of certain provisions of iso,orphous miscibility theory is conducted

  2. Inhibitors of plant hormone transport

    Klíma, Petr; Laňková, Martina; Zažímalová, Eva

    2016-01-01

    Roč. 253, č. 6 (2016), s. 1391-1404 ISSN 0033-183X R&D Projects: GA MŠk(CZ) LD15088 Institutional support: RVO:61389030 Keywords : polar auxin transport * acid-binding protein * gnom arf-gef * equilibrative nucleoside transporter * efflux carrier polarity * plasma-membrane-protein * cultured tobacco cells * arabidopsis-thaliana * gravitropic response * brefeldin-a * Plant hormones * Transport * Inhibitors * Auxin * Cytokinins * Strigolactones * Abscisic acid * Cell biology Subject RIV: ED - Physiology Impact factor: 2.870, year: 2016

  3. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  4. Vanadium Compounds as PTP Inhibitors

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  5. Proton pump inhibitors and osteoporosis

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  6. A randomized comparison of novel bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with acute coronary syndromes: The CENTURY II high risk ACS substudy

    Jiménez, Victor A.; Iñiguez, Andrés; Baz, José A.; Valdés, Mariano; Ortiz, Alberto; Vuilliomenet, André; Mainar, Vicente; Dudek, Dariusz; Banai, Shmuel; Tüller, David; Bonnet, Jean-Louis; De Miguel, Antonio; Bastos, Guillermo; Wijns, William; Saito, Shigeru

    2016-01-01

    Background: To investigate clinical outcomes of percutaneous coronary intervention using a sirolimus-eluting stent with bioresorbable polymer, Ultimaster (BP-SES) compared with a permanent polymer everolimus-eluting stent, Xience (PP-EES) in patients with high risk (ST-segment elevation and non-ST-segment elevation myocardial infarction) acute coronary syndromes (ACS) enrolled in the CENTURY II trial. Methods: CENTURY II is a prospective, multicenter, randomized, single blind, controlled trial comparing BP-SES and PP-EES, with primary endpoint of target lesion failure (TLF) at 9 month post-stent implantation. Out of 1123 patients enrolled in CENTURY II trial, 264 high risk ACS patients were included in this subgroup analysis, and the clinical outcomes including target lesion failure (TLF), target vessel failure (TVF), cardiac death, myocardial infarction, and stent thrombosis were evaluated at 24 months. Results: The baseline clinical, angiographic and procedural characteristics were similar between two groups. At 24 months, TLF occurred in 6.3% of patients receiving a BP-SES and 6.5% of patients receiving a PP-EES (P = 0.95); TVF was 6.3% in patients receiving a BP-SES and 9.4% in patients receiving a PP-EES (P = 0.36). There were no significant differences in cardiac death, myocardial infarction and stent thrombosis rate. Conclusions: BP-SES achieved similar safety and efficacy outcomes as PP-EES in this ACS subgroup of CENTURY II study, at 24-month follow-up. This finding is hypothesis-generating and needs to be confirmed in larger trials with longer follow-up. - Highlights: • This study reported the 24-month clinical outcomes of new-generation BP-SES compared with PP-EES in ACS subgroup from CENTURY II study. • This is a pre-specified subgroup analysis of a large randomized, prospective, multicenter clinical trial. • The BP-SES showed good and comparable clinical performance as PP-EES at 24 months. • This substudy has a relatively small sample size and

  7. Evaluation of XIENCE V everolimus-eluting and Taxus Express2 paclitaxel-eluting coronary stents in patients with jailed side branches from the SPIRIT IV trial at 2 years.

    Forrest, John K; Lansky, Alexandra J; Meller, Stephanie M; Hou, Liming; Sood, Poornima; Applegate, Robert J; Wang, John C; Skelding, Kimberly A; Shah, Aakar; Kereiakes, Dean J; Sudhir, Krishnankutty; Cristea, Ecaterina; Yaqub, Manejeh; Stone, Gregg W

    2013-06-01

    The aim of this study was to determine whether patients from the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions (SPIRIT) IV trial who underwent percutaneous coronary intervention, who had target lesions with jailed side branches, had improved clinical outcomes when treated with the XIENCE V versus Taxus Express(2) drug-eluting stent. In the SPIRIT III randomized trial, patients with target lesions with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had lower 2-year rates of major adverse cardiac events. The SPIRIT IV trial represents a larger more diverse patient population compared with SPIRIT III. In the large-scale, prospective, multicenter, randomized SPIRIT IV trial, 3,687 patients who underwent coronary stenting with up to 3 de novo native coronary artery lesions were randomized 2:1 to receive XIENCE V versus Taxus Express(2) stents. Two-year clinical outcomes of patients with or without jailed side branches after stenting were compared. A jailed side branch was defined as any side branch >1.0 mm in diameter within the target segment being stented, excluding bifurcations deemed to require treatment. Of the 3,687 patients in SPIRIT IV, a total of 1,426 had side branches that were jailed during angioplasty of the target lesion. Patients with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had significantly lower 2-year rates of target lesion failure (6.5% vs 11.9%, p = 0.001), major adverse cardiac events (6.6% vs 12.2%, p = 0.0008), ischemia-driven target vessel revascularization (4.1% vs 7.9%, p = 0.004), and stent thrombosis (0.6% vs 2.8%, p = 0.001). In conclusion, patients with jailed side branches after stenting with XIENCE V compared to Taxus Express(2) devices had superior clinical outcomes at 2 years in the large-scale randomized SPIRIT IV trial. Copyright © 2013 Elsevier Inc. All

  8. A randomized comparison of novel bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with acute coronary syndromes: The CENTURY II high risk ACS substudy

    Jiménez, Victor A., E-mail: victor.alfonso.jimenez.diaz@sergas.es [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Iñiguez, Andrés; Baz, José A. [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Valdés, Mariano [Hospital Universitario V. Arrixaca, Murcia (Spain); Ortiz, Alberto [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Vuilliomenet, André [Kantonsspital Aarau, Aarau (Switzerland); Mainar, Vicente [Department of Cardiology, University General Hospital of Alicante, Alicante (Spain); Dudek, Dariusz [Department of Interventional Cardiology, Jagiellonian University Medical College, Krakow (Poland); Banai, Shmuel [Tel Aviv Sourasky Medical Centre, Tel Aviv (Israel); Tüller, David [Department of Cardiology, Stadtspital Triemli, Zürich (Switzerland); Bonnet, Jean-Louis [Department of Cardiology, Hospital La Timone, Marseille (France); De Miguel, Antonio; Bastos, Guillermo [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Wijns, William [Cardiovascular Center Aalst, OLV Hospital, Aalst (Belgium); Saito, Shigeru [Department of Cardiology and Catheterization Laboratory, Shonan Kamakura General Hospital, Kamakura (Japan)

    2016-09-15

    Background: To investigate clinical outcomes of percutaneous coronary intervention using a sirolimus-eluting stent with bioresorbable polymer, Ultimaster (BP-SES) compared with a permanent polymer everolimus-eluting stent, Xience (PP-EES) in patients with high risk (ST-segment elevation and non-ST-segment elevation myocardial infarction) acute coronary syndromes (ACS) enrolled in the CENTURY II trial. Methods: CENTURY II is a prospective, multicenter, randomized, single blind, controlled trial comparing BP-SES and PP-EES, with primary endpoint of target lesion failure (TLF) at 9 month post-stent implantation. Out of 1123 patients enrolled in CENTURY II trial, 264 high risk ACS patients were included in this subgroup analysis, and the clinical outcomes including target lesion failure (TLF), target vessel failure (TVF), cardiac death, myocardial infarction, and stent thrombosis were evaluated at 24 months. Results: The baseline clinical, angiographic and procedural characteristics were similar between two groups. At 24 months, TLF occurred in 6.3% of patients receiving a BP-SES and 6.5% of patients receiving a PP-EES (P = 0.95); TVF was 6.3% in patients receiving a BP-SES and 9.4% in patients receiving a PP-EES (P = 0.36). There were no significant differences in cardiac death, myocardial infarction and stent thrombosis rate. Conclusions: BP-SES achieved similar safety and efficacy outcomes as PP-EES in this ACS subgroup of CENTURY II study, at 24-month follow-up. This finding is hypothesis-generating and needs to be confirmed in larger trials with longer follow-up. - Highlights: • This study reported the 24-month clinical outcomes of new-generation BP-SES compared with PP-EES in ACS subgroup from CENTURY II study. • This is a pre-specified subgroup analysis of a large randomized, prospective, multicenter clinical trial. • The BP-SES showed good and comparable clinical performance as PP-EES at 24 months. • This substudy has a relatively small sample size and

  9. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Elisabetta Abruzzese

    2014-04-01

    Full Text Available The management of patients with chronic myeloid leukemia (CML during pregnancy has became recently a matter of continuous debate.  The introduction of the Tyrosine Kinase Inhibitors (TKIs in clinical practice has dramatically changed the prognosis of CML patients.  Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy.  This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

  10. PARP Inhibitors in Ovarian Cancer.

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Genta, Sofia; Aglietta, Massimo; Sapino, Anna; Valabrega, Giorgio

    2018-03-05

    Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google.com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Olaparib, Niraparib and Rucaparib are already approved for treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Discovery and SAR of hydantoin TACE inhibitors

    Yu, Wensheng; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Chen, Lei; Dai, Chaoyang; Feltz, Robert J.; Girijavallabhan, Vinay M.; Kim, Seong Heon; Kozlowski, Joseph A.; Lavey, Brian J.; Li, Dansu; Lundell, Daniel; Niu, Xiaoda; Piwinski, John J.; Popovici-Muller, Janeta; Rizvi, Razia; Rosner, Kristin E.; Shankar, Bandarpalle B.; Shih, Neng-Yang; Siddiqui, M.A.; Sun, J.; Tong, L.; Umland, S.; Wong, M.K.; Yang, D.Y.; Zhou, G. (Merck)

    2010-09-03

    We disclose inhibitors of TNF-{alpha} converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

  12. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

    Bruyère, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia

    2010-01-01

    The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and...

  13. Electrochemical Behaviour of Environmentally Friendly Inhibitor of ...

    Electrochemical Behaviour of Environmentally Friendly Inhibitor of Aloe Secundiflora Extract in Corrosion Control of Carbon Steel in Soft Water Media. ... The investigation was performed at different inhibitor concentrations under static and dynamic conditions using a Rotating Disk Electrode (RDE). The impedance and ...

  14. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  15. Potential physiological role of plant glycosidase inhibitors

    Bellincampi, D.; Carmadella, L.; Delcour, J.A.

    2004-01-01

    Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens...... and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes. The continuing discovery of new inhibitors indicates that this research area is still unexplored and may lead to new exciting developments. To date, the role...... of the inhibitors is not completely understood. Here we review recent results obtained on the best characterised inhibitors, pointing to their possible biological role in vivo. Results recently obtained with plant transformation technology indicate that this class of inhibitors has potential biotechnological...

  16. The Wonders of Phosphodiesterase‑5 Inhibitors: A Majestic History

    A milestone in drug discovery was the selective inhibitors of. PDE‑5 that ... the pharmacotherapeutics of PDE‑5 inhibitors and the majestic history that led to their discovery. ..... including HIV protease inhibitors, ketoconazole, itraconazole,.

  17. Squash inhibitor family of serine proteinases

    Otlewski, J.; Krowarsch, D.

    1996-01-01

    Squash inhibitors of serine proteinases form an uniform family of small proteins. They are built of 27-33 amino-acid residues and cross-linked with three disulfide bridges. The reactive site peptide bond (P1-P1') is between residue 5 (Lys, Arg or Leu) and 6 (always Ile). High resolution X-ray structures are available for two squash inhibitors complexed with trypsin. NMR solution structures have also been determined for free inhibitors. The major structural motif is a distorted, triple-stranded antiparallel beta-sheet. A similar folding motif has been recently found in a number of proteins, including: conotoxins from fish-hunting snails, carboxypeptidase inhibitor from potato, kalata B1 polypeptide, and in some growth factors (e.g. nerve growth factor, transforming growth factor β2, platelet-derived growth factor). Squash inhibitors are highly stable and rigid proteins. They inhibit a number of serine proteinases: trypsin, plasmin, kallikrein, blood clotting factors: X a and XII a , cathepsin G. The inhibition spectrum can be much broadened if specific amino-acid substitutions are introduced, especially at residues which contact proteinase. Squash inhibitors inhibit proteinases via the standard mechanism. According to the mechanism, inhibitors are substrates which exhibit at neutral pH a high k cat /K m index for hydrolysis and resynthesis of the reactive site, and a low value of the hydrolysis constant. (author)

  18. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  19. Histone Deacetylase Inhibitors as Anticancer Drugs

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  20. Reverse transcriptase inhibitors as microbicides.

    Lewi, Paul; Heeres, Jan; Ariën, Kevin; Venkatraj, Muthusamy; Joossens, Jurgen; Van der Veken, Pieter; Augustyns, Koen; Vanham, Guido

    2012-01-01

    The CAPRISA 004 study in South Africa has accelerated the development of vaginal and rectal microbicides containing antiretrovirals that target specific enzymes in the reproduction cycle of HIV, especially reverse transcriptase inhibitors (RTI). In this review we discuss the potential relevance of HIV-1 RTIs as microbicides, focusing in the nucleotide RTI tenofovir and six classes of nonnucleoside RTIs (including dapivirine, UC781, urea and thiourea PETTs, DABOs and a pyrimidinedione). Although tenofovir and dapivirine appear to be most advanced in clinical trials as potential microbicides, several issues remain unresolved, e.g., the importance of nonhuman primates as a "gatekeeper" for clinical trials, the emergence and spread of drug-resistant mutants, the combination of microbicides that target different phases of viral reproduction and the accessibility to microbicides in low-income countries. Thus, here we discuss the latest research on RTI as microbicides in the light of the continuing spread of the HIV pandemic from the point of view of medicinal chemistry, virological, and pharmaceutical studies.

  1. AZT as a telomerase inhibitor

    Gomez, Daniel E.; Armando, Romina G.; Alonso, Daniel F.

    2012-01-01

    Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  2. Proton pump inhibitors and gastroenteritis

    Hassing, Robert-Jan; Verbon, Annelies; Visser, Herman de; Hofman, Albert; Stricker, Bruno H.

    2016-01-01

    An 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. The Rotterdam Study is a population-based cohort study among 14,926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a generalized estimating equations method in participants who handed-in a diagnostic stool sample. Furthermore, a nested case–control analysis was performed using the total cohort as a reference group. A bacterial microorganism was isolated in 125 samples, whereas 1174 samples were culture negative. In the generalized estimating equations analysis, we found that participants with a bacterial gastroenteritis were more likely than controls to be current users of PPIs (adjusted OR 1.94; 95 % CI 1.15–3.25). Different sensitivity analyses did not change this result. A considerably higher effect was observed (adjusted OR 6.14; 95 % CI 3.81–9.91), using the total cohort as a reference in a nested case–control analysis. Current PPI therapy is associated with an increased risk of bacterial gastroenteritis. However, by reducing the risk of selection and information bias in our study design, we demonstrated that the effect is lower than previously assumed.

  3. ALK inhibitors, a pharmaceutical perspective

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  4. SGLT2 Inhibitors May Predispose to Ketoacidosis.

    Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

    2015-08-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

  5. Enzyme structure and interaction with inhibitors

    London, R.E.

    1983-01-01

    This article reviews some of the results of studies on the 13 C-labeled enzyme dihydrofolate reductase (DHFR). Nuclear magnetic resonance (NMR) techniques are used in combination with isotopic labeling to learn about the structure and dynamics of this enzyme. 13 C-labeling is used for the purpose of studying enzyme/substrate and enzyme/inhibitor interactions. A second set of studies with DHFR was designed to investigate the basis for the high affinity between the inhibitor methotrexate and DHFR. The label was placed on the inhibitor, rather than the enzyme

  6. An Updated Review of Tyrosinase Inhibitors

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  7. Comparing Stent Thrombosis associated with Zotarolimus Eluting Stents versus Everolimus Eluting Stents at 1 year follow up: a systematic review and meta-analysis of 6 randomized controlled trials.

    Bundhun, Pravesh Kumar; Yanamala, Chandra Mouli; Huang, Wei-Qiang

    2017-03-16

    Two thousand fifteen has been a winning year for Drug Eluting Stents (DES). Increase in the number of patients with cardiovascular diseases treated by Percutaneous Coronary Intervention (PCI) has resulted to a high demand for second generation DES. This current analysis aimed to compare the different types of Stent Thrombosis (ST) associated with Zotarolimus Eluting Stents (ZES) versus Everolimus Eluting Stents (EES) at 1 year follow up. Electronic databases were searched for studies comparing ZES with EES. Different types of ST reported at 1 year follow up were considered as the primary endpoints in this analysis. Odds Ratios (OR) with 95% Confidence Intervals (CIs) were used as the statistical parameters and the pooled analyses were carried out by the RevMan 5 · 3 software. A total number of 10,512 patients were included in this analysis. No significant difference in any definite ST, acute definite ST, subacute definite ST, and late definite ST were observed between ZES and EES, at 1 year follow up with OR: 1.70, 95% CI: 0.92 - 3.16; P = 0.09, OR: 3.44, 95% CI: 0.82 - 14.43; P = 0.09, OR: 1.13, 95% CI: 0.43 - 2.95; P = 0.80 and OR: 2.39, 95% CI: 0.83 - 6.85; P = 0.11 respectively. Moreover, any definite or probable ST and definite/probable/possible ST were also not significantly different with OR: 1.39, 95% CI: 0.89 - 2.17; P = 0.15 and OR: 1.19, 95% CI: 0.84 - 1.70; P = 0.33 respectively. In addition, any probable ST, acute probable ST, late probable ST and possible ST were also not significantly different at 1 year follow up with OR: 1.11, 95% CI: 0.60 - 2.05; P = 0.75, OR: 0.53, 95% CI: 0.12 - 2.40; P = 0.41, OR: 1.67, 95% CI: 0.35 - 7.86; P = 0.52 and OR: 1.08, 95% CI: 0.64 - 1.82; P = 0.78 respectively. At 1 year follow up, ZES were not associated with significantly lower or higher definite and probable ST compared to EES. In addition, no significant difference was observed in acute, subacute and late

  8. Strategies for discontinuation of proton pump inhibitors

    Haastrup, Peter; Paulsen, Maja S; Begtrup, Luise M

    2014-01-01

    PURPOSE: Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS: Systematic review based on clinical studies investigating...

  9. Predicting the Performance of Organic Corrosion Inhibitors

    David A. Winkler

    2017-12-01

    Full Text Available The withdrawal of effective but toxic corrosion inhibitors has provided an impetus for the discovery of new, benign organic compounds to fill that role. Concurrently, developments in the high-throughput synthesis of organic compounds, the establishment of large libraries of available chemicals, accelerated corrosion inhibition testing technologies, and the increased capability of machine learning methods have made discovery of new corrosion inhibitors much faster and cheaper than it used to be. We summarize these technical developments in the corrosion inhibition field and describe how data-driven machine learning methods can generate models linking molecular properties to corrosion inhibition that can be used to predict the performance of materials not yet synthesized or tested. We briefly summarize the literature on quantitative structure–property relationships models of small organic molecule corrosion inhibitors. The success of these models provides a paradigm for rapid discovery of novel, effective corrosion inhibitors for a range of metals and alloys in diverse environments.

  10. Novel diamide-based inhibitors of IMPDH.

    Gu, Henry H; Iwanowicz, Edwin J; Guo, Junqing; Watterson, Scott H; Shen, Zhongqi; Pitts, William J; Dhar, T G Murali; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Witmer, Mark; Tredup, Jeffrey; Hollenbaugh, Diane

    2002-05-06

    A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.

  11. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol......%) and plasminogen activators (apparent recovery > 200%). Sodium lauryl sulfate eliminates the major fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery > 200%) and plasminogen activator, urokinase type (apparent recovery 130%). Methylamine affects only plasmin inhibition. We...

  13. Development of Radiosensitizer using farnesyltransferase inhibitors

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  14. Natural inhibitors of tumor-associated proteases

    Magdolen, U.; Krol, J.; Sato, S.; Schmitt, M.; Magdolen, V.; Krueger, A.; Mueller, M.M.; Sperl, S.

    2002-01-01

    The turnover and remodelling of extracellular matrix (ECM) is an essential part of many normal biological processes including development, morphogenesis, and wound healing. ECM turnover also occurs in severe pathological situations like artherosclerosis, fibrosis, tumor invasion and metastasis. The major proteases involved in this turnover are serine proteases (especially the urokinase-type plasminogen activator/plasmin system), matrix metalloproteases (a family of about 20 zinc-dependent endopeptidases including collagenases, gelatinases, stromelysins, and membrane-type metalloproteases), and cysteine proteases. In vivo, the activity of these proteases is tightly regulated in the extracellular space by zymogen activation and/or controlled inhibition. In the present review, we give an overview on the structure and biochemical properties of important tumor-associated protease inhibitors such as plasminogen activator inhibitor type 1 and type 2 (PAI-1, PAI-2), tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4), and the cysteine protease inhibitor cystatin C. Interestingly, some of these inhibitors of tumor-associated proteases display multiple functions which rather promote than inhibit tumor progression, when the presence of inhibitors in the tumor tissue is not balanced. (author)

  15. Emerging Corrosion Inhibitors for Interfacial Coating

    Mona Taghavikish

    2017-12-01

    Full Text Available Corrosion is a deterioration of a metal due to reaction with environment. The use of corrosion inhibitors is one of the most effective ways of protecting metal surfaces against corrosion. Their effectiveness is related to the chemical composition, their molecular structures and affinities for adsorption on the metal surface. This review focuses on the potential of ionic liquid, polyionic liquid (PIL and graphene as promising corrosion inhibitors in emerging coatings due to their remarkable properties and various embedment or fabrication strategies. The review begins with a precise description of the synthesis, characterization and structure-property-performance relationship of such inhibitors for anti-corrosion coatings. It establishes a platform for the formation of new generation of PIL based coatings and shows that PIL corrosion inhibitors with various heteroatoms in different form can be employed for corrosion protection with higher barrier properties and protection of metal surface. However, such study is still in its infancy and there is significant scope to further develop new structures of PIL based corrosion inhibitors and coatings and study their behaviour in protection of metals. Besides, it is identified that the combination of ionic liquid, PIL and graphene could possibly contribute to the development of the ultimate corrosion inhibitor based coating.

  16. Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

    Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

    Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

  17. Inactivation of proteinaceous protease inhibitors of soybeans by isolated fungi

    Meijer, M.M.T.; Spekking, W.T.J.; Sijtsma, L.; Bont, de J.A.M.

    1995-01-01

    Proteinaceous protease inhibitors, Kunitz Soybean Trypsin Inhibitor (KSTI) and Bowman Birk Inhibitor (BBI), in legume seeds reduce the digestibility of proteins in feed of monogastric animals. Enzymatic inactivation of these inhibitors will increase the nutritional value of the feed. The aim of this

  18. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  19. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

    Boutin Jean A

    2010-10-01

    Full Text Available Abstract Background Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts. Methods Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours. The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue. Results Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently. Conclusions In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.

  20. SGLT2 Inhibitors and the Diabetic Kidney.

    Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

    2016-08-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether

  1. Inhibitor chymotrypsynowy nasion wiechliny łąkowej (Poa pratensis [Chymotrypsin inhibitor from Poa pratensis seeds

    I. Lorenc-Kubis

    2015-01-01

    Full Text Available A chymotrypsin inhibitor was isolated from Poa pratensis seeds. The inhibitor showed also antytriptic activity. It is a termostable protein, soluble in water, sodium chloride, but insoluble in 5% trichloracetic acid and 0.15 M sulphosalicylic acid.

  2. SGLT2 inhibitors: are they safe?

    Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D; Elisaf, Moses S

    2018-01-01

    Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

  3. Aromatase inhibitors and breast cancer prevention.

    Litton, Jennifer Keating; Arun, Banu K; Brown, Powel H; Hortobagyi, Gabriel N

    2012-02-01

    Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

  4. Janus kinase inhibitors: jackpot or potluck?

    Pavithran Keechilat

    2012-06-01

    Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

  5. A cyclic peptidic serine protease inhibitor

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending......, in spite of a less favorable binding entropy and loss of a polar interaction. We conclude that increased flexibility of the peptide allows more favorable exosite interactions, which, in combination with the use of novel Arg analogues as P1 residues, can be used to manipulate the affinity and specificity...

  6. SGLT-2 Inhibitors and Cardiovascular Risk

    Cavender, Matthew A; Norhammar, Anna; Birkeland, Kåre I

    2018-01-01

    BACKGROUND: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown. OBJECTIVES: This study sought...... to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD. METHODS: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes...... evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)....

  7. New halogenated phenylcoumarins as tyrosinase inhibitors.

    Matos, Maria João; Santana, Lourdes; Uriarte, Eugenio; Delogu, Giovanna; Corda, Marcella; Fadda, Maria Benedetta; Era, Benedetta; Fais, Antonella

    2011-06-01

    With the aim to find out structural features for the tyrosinase inhibitory activity, in the present communication we report the synthesis and pharmacological evaluation of a new series of phenylcoumarin derivatives with different number of hydroxyl or ether groups and bromo substituent in the scaffold. The synthesized compounds 5-12 were evaluated as mushroom tyrosinase inhibitors showing, two of them, lower IC(50) than the umbelliferone. Compound 12 (IC(50)=215 μM) is the best tyrosinase inhibitor of this series. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Green inhibitors. Rare Earth based systems

    Aballe, A.; Bethencourt, M.; Botana, F.J.; Perez, J.; Rodriguez, M.A.; Marcos, M.

    1997-01-01

    Lanthanum, Cerium and Samarium chlorides have been investigated as uniform and pitting corrosion inhibitors of AISI 434 and AISI 304 stainless steels and AA 5083 Al-Mg alloy in 3.5% Na Cl aerated aqueous solutions. Their inhibitor power was evaluated by using electrochemical techniques such as Linear and Cyclic Polarisation. In each case, the highest protection degree was found in the solution dropped with 500 ppm of CeCl 3 . Similar results were obtained for additions of 500 ppm of LaCl 3 . Scanning Electron Microscopy and Energy Dispersive Spectroscopy allowed us to confirm the cathodic nature of the inhibition process. (Author) 27 refs

  9. 2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

    Zhong, Min; Bui, Minna; Shen, Wang; Baskaran, Subramanian; Allen, Darin A; Elling, Robert A; Flanagan, W Michael; Fung, Amy D; Hanan, Emily J; Harris, Shannon O; Heumann, Stacey A; Hoch, Ute; Ivy, Sheryl N; Jacobs, Jeffrey W; Lam, Stuart; Lee, Heman; McDowell, Robert S; Oslob, Johan D; Purkey, Hans E; Romanowski, Michael J; Silverman, Jeffrey A; Tangonan, Bradley T; Taverna, Pietro; Yang, Wenjin; Yoburn, Josh C; Yu, Chul H; Zimmerman, Kristin M; O'Brien, Tom; Lew, Willard

    2009-09-01

    This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

  10. Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German–Austrian ABSORB RegIstRy (GABI-R)

    Nef, Holger, E-mail: holger.nef@innere.med.uni-giessen.de [University of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen (Germany); Wiebe, Jens [University of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen (Germany); Achenbach, Stefan [University of Erlangen, Medizinische Klinik II, Department of Cardiology, Erlangen (Germany); Münzel, Thomas [Department of Medicine II, University Medical Center, Johannes Gutenberg University Mainz, Mainz (Germany); Naber, Christoph [Klinik für Kardiologie und Angiologie, Elisabeth-Krankenhaus, Essen (Germany); Richardt, Gert [Herzzentrum, Segeberger Kliniken GmbH, Bad Segeberg (Germany); Mehilli, Julinda [Department of Cardiology, Klinikum Großhadern, Ludwig- Maximilian Universität, Munich (Germany); Wöhrle, Jochen [Department of Internal Medicine II, University of Ulm, Ulm (Germany); Neumann, Till; Biermann, Janine [University of Essen, Department of Cardiology, Essen (Germany); Zahn, Ralf [Abteilung für Kardiologie, Herzzentrum Ludwigshafen, Ludwigshafen (Germany); Kastner, Johannes [Department of Cardiology, University of Vienna Medical School, Vienna (Austria); Schmermund, Axel [CCB, Cardioangiologisches Centrum Bethanien, Frankfurt (Germany); Pfannebecker, Thomas [Abbott Vascular Deutschland GmbH, Wetzlar (Germany); Schneider, Steffen; Limbourg, Tobias [Institut für Herzinfarktforschung, Ludwigshafen (Germany); Hamm, Christian W. [University of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen (Germany); Kerckhoff Heart and Thorax Center, Department of Cardiology, Bad Nauheim (Germany)

    2016-01-15

    Background: Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2–4 years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects. Methods/design: The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all-comers cohort will be evaluated in the prospective, non-interventional, multicenter German–Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5 years). Conclusion: Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information. - Highlights: • The GABI-R addresses a lack of data about bioresorbable scaffolds in daily practice. • 5000 patients with minimal in- and exclusion criteria at 100 sites will

  11. Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German–Austrian ABSORB RegIstRy (GABI-R)

    Nef, Holger; Wiebe, Jens; Achenbach, Stefan; Münzel, Thomas; Naber, Christoph; Richardt, Gert; Mehilli, Julinda; Wöhrle, Jochen; Neumann, Till; Biermann, Janine; Zahn, Ralf; Kastner, Johannes; Schmermund, Axel; Pfannebecker, Thomas; Schneider, Steffen; Limbourg, Tobias; Hamm, Christian W.

    2016-01-01

    Background: Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2–4 years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects. Methods/design: The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all-comers cohort will be evaluated in the prospective, non-interventional, multicenter German–Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5 years). Conclusion: Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information. - Highlights: • The GABI-R addresses a lack of data about bioresorbable scaffolds in daily practice. • 5000 patients with minimal in- and exclusion criteria at 100 sites will

  12. Synergistic apoptosis induction in leukemic cells by the phosphatase inhibitor salubrinal and proteasome inhibitors.

    Hannes C A Drexler

    Full Text Available Cells adapt to endoplasmic reticulum (ER-stress by arresting global protein synthesis while simultaneously activating specific transcription factors and their downstream targets. These processes are mediated in part by the phosphorylation-dependent inactivation of the translation initiation factor eIF2alpha. Following restoration of homeostasis protein synthesis is resumed when the serine/threonine-protein phosphatase PP1 dephosphorylates and reactivates eIF2alpha. Proteasome inhibitors, used to treat multiple myeloma patients evoke ER-stress and apoptosis by blocking the ER-associated degradation of misfolded proteins (ERAD, however, the role of eIF2alpha phosphorylation in leukemic cells under conditions of proteasome inhibitor-mediated ER stress is currently unclear.Bcr-Abl-positive and negative leukemic cell lines were used to investigate the functional implications of PP1-related phosphatase activities on eIF2alpha phosphorylation in proteasome inhibitor-mediated ER stress and apoptosis. Rather unexpectedly, salubrinal, a recently identified PP1 inhibitor capable to protect against ER stress in various model systems, strongly synergized with proteasome inhibitors to augment apoptotic death of different leukemic cell lines. Salubrinal treatment did not affect the phosphorlyation status of eIF2alpha. Furthermore, the proapoptotic effect of salubrinal occurred independently from the chemical nature of the proteasome inhibitor, was recapitulated by a second unrelated phosphatase inhibitor and was unaffected by overexpression of a dominant negative eIF2alpha S51A variant that can not be phosphorylated. Salubrinal further aggravated ER-stress and proteotoxicity inflicted by the proteasome inhibitors on the leukemic cells since characteristic ER stress responses, such as ATF4 and CHOP synthesis, XBP1 splicing, activation of MAP kinases and eventually apoptosis were efficiently abrogated by the translational inhibitor cycloheximide.Although PP1

  13. Structural Characterization of LRRK2 Inhibitors

    Gilsbach, Bernd K; Messias, Ana C; Ito, Genta; Sattler, Michael; Alessi, Dario R; Wittinghofer, Alfred; Kortholt, Arjan

    2015-01-01

    Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a

  14. Rational Design of Rho Protein Inhibitors

    Rojas, Rafael J

    2006-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  15. Rational Design of Rho Protein Inhibitors

    Rojas, Rafael J

    2005-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  16. [Mechanisms and efficacy of SGLT2 inhibitors].

    Shiba, Teruo

    2015-03-01

    SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

  17. Th17 Inhibitors in Active Psoriatic Arthritis

    Naik, Girish S; Ming, Wai K; Magodoro, Itai M

    2018-01-01

    BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α...

  18. Vildagliptin: the first innovative DDP-4 inhibitor

    Edvin Villkhauer

    2010-09-01

    Full Text Available A review of the main stages of investigation undertaken by Novartis Pharmaceuticals in search of a new molecule for the treatment of type 2 diabetesmellitus, dipeptidyl peptidase-4 (DPP-4 inhibitor (Vildaglyptin. The data on specificity and selectivity of the action of this molecule are presentedalong with the results of its comparison with another agent of this group (sitagliptin.

  19. Curcumin derivatives as HIV-1 protease inhibitors

    Sui, Z.; Li, J.; Craik, C.S.; Ortiz de Montellano, P.R. [Univ. of California, San Francisco, CA (United States)

    1993-12-31

    Curcumin, a non-toxic natural compound from Curcuma longa, has been found to be an HIV-1 protease inhibitor. Some of its derivatives were synthesized and their inhibitory activity against the HIV-1 protease was tested. Curcumin analogues containing boron enhanced the inhibitory activity. At least of the the synthesized compounds irreversibly inhibits the HIV-1 protease.

  20. Dissolution properties of cerium dibutylphosphate corrosion inhibitors

    Soestbergen, van M.; Erich, S.J.F.; Huinink, H.P.; Adan, O.C.G.

    2013-01-01

    The corrosion inhibitor cerium dibutylphosphate, Ce(dbp)3, prevents corrosion by cerium and dbp deposition at the alkaline cathode and acidic anode respectively. The pH dependent Ce(dbp)3 solubility seems to play an essential role in the inhibition degree. We found that Ce(dbp)3 scarcely dissolves

  1. SEARCH OF NEW SYNTHETIC INHIBITORS OF TYROSINASE

    Yu. Shesterenko

    2017-11-01

    Full Text Available Melanin pigmentation of skin plays the most important role in the protection of organism against UV-irradiation, but the excessive accumulation of melanin brings to toxic melanodermia, melasma, lentigo and other skin lesions. Tyrosinase is the key enzyme of skin melanin pigment biosynthesis. In spite of certain progress in investigation of natural and synthetic tyrosinase inhibitors, actuality of such studies is of a high level, because the existing inhibitors are in some cases unstable, expensive, toxic, requires complex methods of synthesis or isolation from natural sources. The aim of the work is screening of new tyrosinase inhibitors, using the enzyme, isolated from Agaricus bisporus. Tyrosinase was isolated from Agaricus bisporus mushrooms by a modified method. It was found, that the introduction of polyethylene glycol 4000 in the extraction process promotes 3-fold reduction of polyphenol content, which leads to increase purity of enzyme with an increase in its activity by 25%. A search for new tyrosinase inhibitors among a wide range of compounds, including derivatives of 3-chloro-1,4-naphthoquinone, isatin, 3-hydroxy-2-naphthoic acid, etc was conducted. The studied substances did not displayed inhibitory effect at concentration of 0,1-0,5 mmol/dm3.

  2. Peptide aldehyde inhibitors of bacterial peptide deformylases.

    Durand, D J; Gordon Green, B; O'Connell, J F; Grant, S K

    1999-07-15

    Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity. Copyright 1999 Academic Press.

  3. Immune checkpoint inhibitors for metastatic bladder cancer.

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Current and Novel Inhibitors of HIV Protease

    Pokorná, Jana; Machala, L.; Řezáčová, Pavlína; Konvalinka, Jan

    2009-01-01

    Roč. 1, č. 3 (2009), s. 1209-1239 ISSN 1999-4915 R&D Projects: GA MŠk 1M0508 Grant - others:GA AV ČR(CZ) IAAX00320901 Program:IA Institutional research plan: CEZ:AV0Z40550506 Keywords : HIV protease * protease inhibitor * HAART Subject RIV: CE - Biochemistry

  5. Proton pump inhibitors affect the gut microbiome

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Feenstra, Ettje T.; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or

  6. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Kudělová, J.; Fleischmannová, J.; Adamová, E.; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR(CZ) GA14-28254S Institutional support: RVO:68081715 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 2.804, year: 2015

  7. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Kudělová, J.; Fleischmannová, Jana; Adamová, Eva; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR GB14-37368G Institutional support: RVO:67985904 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.804, year: 2015

  8. Discovery of inhibitors of bacterial histidine kinases

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

  9. Novel peptide-based protease inhibitors

    Roodbeen, Renée

    of novel peptide-based protease inhibitors, efforts were made towards improved methods for peptide synthesis. The coupling of Fmoc-amino acids onto N-methylated peptidyl resins was investigated. These couplings can be low yielding and the effect of the use of microwave heating combined with the coupling...

  10. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor removal during reclamation of sewage to drinking water. ... Risks associated with sewage effluent and reclaimed sewage should be closely monitored; therefore water at the Gammams Sewage Treatment Plant (GSTP) inlet and outlet, as well as reclaimed water ...

  11. Dry eye syndrome in aromatase inhibitor users.

    Turaka, Kiran; Nottage, Jennifer M; Hammersmith, Kristin M; Nagra, Parveen K; Rapuano, Christopher J

    2013-04-01

    Aromatase inhibitors are frequently used as an adjuvant therapy in the treatment of breast cancer. We observed that several patients taking aromatase inhibitors presented with severe dry eye symptoms, and we investigated whether there is a relationship between aromatase inhibitors and dry eyes in these patients. Retrospective chart review. Forty-one women. A computerized search of health records was performed to identify patients using anastrazole, letrozole and exemestane seen by the Cornea Service from August 2008 to March 2011. The results were compared with age-matched controls. Ocular surface changes among aromatase inhibitors users. Of the 41 women, 39 were Caucasians. Thirty-nine patients had breast cancer (95%), one patient had ovarian cancer (2.5%) and one had an unknown primary cancer. Mean age was 68 ± 11.3 years (range 47-95). Most common presenting symptoms were blurred vision in 28 (68%) patients, irritation/foreign body sensation in 12 (29%) patients, redness in 9 (22%) patients, tearing in 6 (22%) patients and photosensitivity in 2 (5%) patients. Mean Schirmer's test measurement was 11 ± 5.8 mm (range 0.5-20 mm). Blepharitis was noted in 68 of 82 eyes (73%), decreased or poor tear function in 24 eyes (29%), conjunctival injection in 18 eyes (22%) and superficial punctate keratitis in 12 eyes (29%). Among an age-matched population (45-95 years), dry eye syndrome was found in only 9.5% of patients. Because the prevalence of ocular surface disease signs and symptoms appears to be higher in study group than control patients, aromatase inhibitors might be a contributing factor to the dry eye symptoms. © 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.

  12. RENAL SAFETY OF PROTON PUMP INHIBITORS

    A. I. Dyadyk

    2017-01-01

    Full Text Available Proton pump inhibitors are a widely used in clinical practice, and are taken by millions of patients around the world for a long time. While proton pump inhibitors are well-tolerated class of drugs, the number of publications has been raised about adverse renal effects, specially their association with acute tubulointerstitial nephritis. It is one of the leading causes of acute renal injury and have catastrophic long-term consequences called chronic kidney disease. In this review, we consider epidemiology, pathogenesis, diagnostic criteria (including biopsy and morphological pattern, clinical manifestations and treatment of proton pump inhibitors-induced acute tubulointerstitial nephritis. A subclinical course without classical manifestations of a cell-mediated hypersensitivity reaction (fever, skin rash, eosinophilia, arthralgia is characteristic of acute tubulointerstitial nephritis. Increased serum creatinine, decreased glomerular filtration rate, electrolyte disorders, pathological changes in urine tests are not highly specific indicators, but allow to suspect the development of acute tubulointerstitial nephritis. The “gold” standard of diagnosis is the intravital morphological examination of the kidney tissue. Timely diagnosis and immediate discontinuation of the potentially causative drug is the mainstay of therapy and the first necessary step in the early management of suspected or biopsy-proven drug-induced acute tubulointerstitial nephritis. The usage of proton pump inhibitors should be performed only on strict indications with optimal duration of treatment and careful monitoring of kidney function. Multiple comorbidities (older age, heart failure, diabetes, cirrhosis, chronic kidney disease, hypovolemia increase potential nephrotoxicity. Awareness of this iatrogenic complication will improve diagnosis of proton pump inhibitors-induced acute tubulointerstitial nephritis by multidisciplinary specialists and increase the possibility

  13. Cost of care of haemophilia with inhibitors.

    Di Minno, M N D; Di Minno, G; Di Capua, M; Cerbone, A M; Coppola, A

    2010-01-01

    In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

  14. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

    Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

    2013-09-01

    NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

  15. Cytogenetic study of Ascaris trypsin inhibitor in cultured human ...

    2009-04-01

    Apr 1, 2009 ... Although the physical and chemical properties of Ascaris trypsin inhibitors ... male of Ascaris suum according to the method of Pudles and. Rola (1967). ..... inhibitor isolated from Ascaris resulted in the appearance of dominant ...

  16. SGLT2 inhibitors: molecular design and potential differences in effect.

    Isaji, Masayuki

    2011-03-01

    The physiological and pathological handling of glucose via sodium-glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies. The potency and positioning of SGLT2 inhibitors as an antidiabetic drug are dependent on their characteristic profile, which induces selectivity, efficacy, pharmacokinetics, and safety. This profile decides which SGLT2 inhibitors can be expected for application of the theoretical concept of reducing renal glucose reabsorption for the treatment of diabetes. I review the structure and advancing profile of various SGLT2 inhibitors, comparing their similarities and differences, and discuss the expected SGLT2 inhibitors for an emerging category of antidiabetic drugs.

  17. Environmental life cycle analysis of potato sprout inhibitors

    Kerstholt, R.P.V.; Ree, C.M.; Moll, H.C.

    Potato sprout inhibitors are generally applied to suppress sprouting during winter storage. This study presents the compared environmental profiles of the two sprout inhibitors available on the Dutch market: A traditional chemical product with isopropyl-3-chlorophenylcarbamate (CIPC) and

  18. [Inhibitors of proteolytic enzymes under abiotic stresses in plants (review)].

    Mosolov, V V; Valueva, T A

    2011-01-01

    Data on the role of proteolytic enzyme inhibitors in plant adaptation to various unfavorable environmental abiotic factors--water deficiency, salinization of soil, extreme temperatures, etc.--and also probable functions of proteinases inhibitors in natural plant senescense are considered.

  19. Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.

    Rudolf K F Beran

    Full Text Available During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA and heat-shock protein 90 (HSP90 which have each been reported to inhibit replication of hepatitis C virus (HCV. By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino-17-demethoxygeldanamycin (17-AAG to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA, exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

  20. SGLT2 Inhibitors: Benefit/Risk Balance.

    Scheen, André J

    2016-10-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.

  1. Serine protease inhibitors of parasitic helminths.

    Molehin, Adebayo J; Gobert, Geoffrey N; McManus, Donald P

    2012-05-01

    Serine protease inhibitors (serpins) are a superfamily of structurally conserved proteins that inhibit serine proteases and play key physiological roles in numerous biological systems such as blood coagulation, complement activation and inflammation. A number of serpins have now been identified in parasitic helminths with putative involvement in immune regulation and in parasite survival through interference with the host immune response. This review describes the serpins and smapins (small serine protease inhibitors) that have been identified in Ascaris spp., Brugia malayi, Ancylostoma caninum Onchocerca volvulus, Haemonchus contortus, Trichinella spiralis, Trichostrongylus vitrinus, Anisakis simplex, Trichuris suis, Schistosoma spp., Clonorchis sinensis, Paragonimus westermani and Echinococcus spp. and discusses their possible biological functions, including roles in host-parasite interplay and their evolutionary relationships.

  2. Secreted and Transmembrane Wnt Inhibitors and Activators

    Cruciat, Cristina-Maria; Niehrs, Christof

    2013-01-01

    Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand–receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-β and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease. PMID:23085770

  3. Raltegravir: first in class HIV integrase inhibitor

    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  4. Small molecule inhibitors of anthrax edema factor.

    Jiao, Guan-Sheng; Kim, Seongjin; Moayeri, Mahtab; Thai, April; Cregar-Hernandez, Lynne; McKasson, Linda; O'Malley, Sean; Leppla, Stephen H; Johnson, Alan T

    2018-01-15

    Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5'-Fluorosulfonylbenzoyl 5'-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Novel nonpeptidic inhibitors of peptide deformylase.

    Jayasekera, M M; Kendall, A; Shammas, R; Dermyer, M; Tomala, M; Shapiro, M A; Holler, T P

    2000-09-15

    A novel series of nonpeptidic compounds structurally related to the known anticholesteremic thyropropic acid were found to inhibit Escherichia coli peptide deformylase (PDF), with IC50 values in the low-micromolar range. Kinetic analysis of [4-(4-hydroxyphenoxy)-3,5-diiodophenyl]acetic acid reveals competitive inhibition, with a Ki value of 0.66 +/- 0.007 microM. A structure-activity relationship study demonstrates that the carboxylate is required for activity, while the distal phenolic function can be methylated without significant effect. Either decreasing the number of iodine atoms on the molecule to one or increasing the number of iodine atoms to four results in the loss of an order of magnitude in potency. These compounds are the first nonpeptidic inhibitors disclosed and represent a template from which better inhibitors might be designed.

  6. Potent peptidic fusion inhibitors of influenza virus

    Kadam, Rameshwar U.; Juraszek, Jarek; Brandenburg, Boerries; Buyck, Christophe; Schepens, Wim B. G.; Kesteleyn, Bart; Stoops, Bart; Vreeken, Rob J.; Vermond, Jan; Goutier, Wouter; Tang, Chan; Vogels, Ronald; Friesen, Robert H. E.; Goudsmit, Jaap; van Dongen, Maria J. P.; Wilson, Ian A.

    2017-09-28

    Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.

  7. mTOR Inhibition and Tuberous Sclerosis Prevention

    J Gordon Millichap

    2013-09-01

    Full Text Available Investigators at Children's Memorial Health Institute, Warsaw, Poland, report monozygotic twin sisters with tuberous sclerosis complex (TSC, one treated with the mTOR inhibitor everolimus since age 4 years.

  8. Corrosion protection with eco-friendly inhibitors

    Shahid, Muhammad

    2011-12-01

    Corrosion occurs as a result of the interaction of a metal with its environment. The extent of corrosion depends on the type of metal, the existing conditions in the environment and the type of aggressive ions present in the medium. For example, CO3-2 and NO-3 produce an insoluble deposit on the surface of iron, resulting in the isolation of metal and consequent decrease of corrosion. On the other hand, halide ions are adsorbed selectively on the metal surface and prevent formation of the oxide phase on the metal surface, resulting in continuous corrosion. Iron, aluminum and their alloys are widely used, both domestically and industrially. Linear alkylbenzene and linear alkylbenzene sulfonate are commonly used as detergents. They have also been found together in waste water. It is claimed that these chemicals act as inhibitors for stainless steel and aluminum. Release of toxic gases as a result of corrosion in pipelines may lead in certain cases to air pollution and possible health hazards. Therefore, there are two ways to look at the relationship between corrosion and pollution: (i) corrosion of metals and alloys due to environmental pollution and (ii) environmental pollution as a result of corrosion protection. This paper encompasses the two scenarios and possible remedies for various cases, using 'green' inhibitors obtained either from plant extracts or from pharmaceutical compounds. In the present study, the effect of piperacillin sodium as a corrosion inhibitor for mild steel was investigated using a weight-loss method as well as a three-electrode dc electrochemical technique. It was found that the corrosion rate decreased as the concentration of the inhibitor increased up to 9×10-4 M 93% efficiency was exhibited at this concentration.

  9. Acrosin inhibitor detecting along the boar epididymis

    Maňásková-Postlerová, Pavla; Cozlová, Nina; Dorosh, Andriy; Šulc, Miroslav; Guyonet, B.; Jonáková, Věra

    2016-01-01

    Roč. 82, Jan 2016 (2016), s. 733-739 ISSN 0141-8130 R&D Projects: GA ČR(CZ) GAP503/12/1834; GA MŠk(CZ) ED1.1.00/02.0109; GA ČR GA14-05547S Institutional support: RVO:86652036 ; RVO:61388971 Keywords : Acrosin inhibitor * Boar epididymis * Spermatozoa Subject RIV: CE - Biochemistry Impact factor: 3.671, year: 2016

  10. Cyclooxygenase-2 inhibitors and knee prosthesis surgery

    Meunier, Andreas

    2008-01-01

    Adverse effects of cyclooxygenase (COX) inhibitors on bone healing have previously been demonstrated in diaphyseal fracture models in animals. In spite of that, they are widely used as postoperative analgesics in orthopaedic surgery. After joint replacement, a bone repair process starts at the interface between bone and cement. If this process is disturbed, the prosthesis may never become rigidly fixed to the bone, leading to migration and with time loosening. This thesis investigates the eff...

  11. Aurora kinase inhibitors: Progress towards the clinic

    Kollareddy, M.; Zheleva, D.; Dzubak, P.; Brahmkshatriya, Pathik; Lepšík, Martin; Hajduch, M.

    2012-01-01

    Roč. 30, č. 6 (2012), s. 2411-2432 ISSN 0167-6997 Grant - others:GA ČR(CZ) GA301/08/1649; GA ČR(CZ) GD303/09/H048 Program:GA; GD Institutional research plan: CEZ:AV0Z40550506 Keywords : Aurora kinases * cancer * inhibitors Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.498, year: 2012

  12. GSK-3 inhibitors induce chromosome instability

    Staples Oliver D

    2007-08-01

    Full Text Available Abstract Background Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.

  13. FAITH - Fast Assembly Inhibitor Test for HIV

    Hadravová, Romana; Rumlová, Michaela; Ruml, T.

    2015-01-01

    Roč. 486, Dec (2015), s. 78-87 ISSN 0042-6822 R&D Projects: GA ČR(CZ) GA14-15326S; GA MŠk LO1302; GA MŠk(CZ) LO1304 Institutional support: RVO:61388963 Keywords : retrovirus * HIV * assembly * assay * inhibitor Subject RIV: EE - Microbiology, Virology Impact factor: 3.200, year: 2015 http://www.sciencedirect.com/science/article/pii/S0042682215003864

  14. Monoamine oxidase inhibitors from Gentiana lutea.

    Haraguchi, Hiroyuki; Tanaka, Yasumasa; Kabbash, Amal; Fujioka, Toshihiro; Ishizu, Takashi; Yagi, Akira

    2004-08-01

    Three monoamine oxidase (MAO) inhibitors were isolated from Gentiana lutea. Their structures were elucidated to be 3-3''linked-(2'-hydroxy-4-O-isoprenylchalcone)-(2'''-hydroxy-4''-O-isoprenyldihydrochalcone) (1), 2-methoxy-3-(1,1'-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one and 5-hydroxyflavanone. These compounds, and the hydrolysis product of 1, displayed competitive inhibitory properties against MAO-B which was more effective than MAO-A.

  15. Trial Watch: Proteasomal inhibitors for anticancer therapy.

    Obrist, Florine; Manic, Gwenola; Kroemer, Guido; Vitale, Ilio; Galluzzi, Lorenzo

    2015-01-01

    The so-called "ubiquitin-proteasome system" (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients.

  16. Adverse Effects of COX-2 Inhibitors

    Jagdish N. Sharma

    2005-01-01

    Full Text Available Cyclooxygenase-2 selective inhibitors (COXIBs were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs. Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2 (PGH2 and other prostaglandin (PG metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2 from arachidonate, PGH2 is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2 (TXA2. These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2in vitro, the ultimate prostanoids they produce in vivo may be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF, promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.

  17. Rust Inhibitor And Fungicide For Cooling Systems

    Adams, James F.; Greer, D. Clay

    1988-01-01

    Mixture of benzotriazole, benzoic acid, and fungicide prevents growth of rust and fungus. Water-based cooling mixture made from readily available materials prevents formation of metallic oxides and growth of fungi in metallic pipes. Coolant remains clear and does not develop thick sludge tending to collect in low points in cooling systems with many commercial rust inhibitors. Coolant compatible with iron, copper, aluminum, and stainless steel. Cannot be used with cadmium or cadmium-plated pipes.

  18. Luminometric method for screening retroviral protease inhibitors

    Horáková, D.; Rumlová, Michaela; Pichová, Iva; Ruml, Tomáš

    2005-01-01

    Roč. 345, č. 1 (2005), s. 96-101 ISSN 0003-2697 R&D Projects: GA AV ČR(CZ) IAA4055304; GA MŠk(CZ) 1M0508; GA MŠk(CZ) 1M0520 Institutional research plan: CEZ:AV0Z40550506 Keywords : retroviral protease * inhibitors * luminescent assay Subject RIV: CE - Biochemistry Impact factor: 2.670, year: 2005

  19. Serine proteinases and their inhibitors in fertilization

    Jonáková, Věra

    2000-01-01

    Roč. 3, 3,4 (2000), s. 23 [ Proteolytic enzymes and their inhibitors in physiology and pathogenesis. 14.09.2000, Plzen] R&D Projects: GA ČR GV524/96/K162; GA ČR GA303/99/0357; GA MŠk VS96141 Grant - others:GA UK(CZ) 12/1998 Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  20. Modelling of potentially promising SARS protease inhibitors

    Plewczynski, Dariusz; Hoffmann, Marcin; Grotthuss, Marcin von; Knizewski, Lukasz; Rychewski, Leszek; Eitner, Krystian; Ginalski, Krzysztof

    2007-01-01

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation

  1. Inhibitors of polyamine metabolism: review article.

    Wallace, H M; Fraser, A V

    2004-07-01

    The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases. The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer. The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

  2. Recent advances in botulinum neurotoxin inhibitor development.

    Kiris, Erkan; Burnett, James C; Kane, Christopher D; Bavari, Sina

    2014-01-01

    Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn(2+) metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair.

  3. A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.

    Kenneth W Yip

    Full Text Available Uroporphyrinogen decarboxylase (UROD catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16, was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM, but did not affect porphobilinogen deaminase (at 62.5 µM, thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1. This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.

  4. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

  5. Modelling of potentially promising SARS protease inhibitors

    Plewczynski, Dariusz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Hoffmann, Marcin [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Grotthuss, Marcin von [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Knizewski, Lukasz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Rychewski, Leszek [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Eitner, Krystian [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Ginalski, Krzysztof [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland)

    2007-07-18

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation.

  6. Structure-Based Search for New Inhibitors of Cholinesterases

    Barbara Malawska

    2013-03-01

    Full Text Available Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC50 values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.

  7. ELISA analysis of soybean trypsin inhibitors in processed foods.

    Brandon, D L; Bates, A H; Friedman, M

    1991-01-01

    Soybean proteins are widely used in human foods in a variety of forms, including infant formulas, flour, protein concentrates, protein isolates, soy sauces, textured soy fibers, and tofu. The presence of inhibitors of digestive enzymes in soy proteins impairs the nutritional quality and possibly the safety of soybeans and other legumes. Processing, based on the use of heat or fractionation of protein isolates, does not completely inactivate or remove these inhibitors, so that residual amounts of inhibitors are consumed by animals and humans. New monoclonal antibody-based immunoassays can measure low levels of the soybean Kunitz trypsin inhibitor (KTI) and the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI) and the Bowman-Birk foods. The enzyme-linked immunosorbent assay (ELISA) was used to measure the inhibitor content of soy concentrates, isolates, and flours, both heated and unheated; a commercial soy infant formula; KTI and BBI with rearranged disulfide bonds; browning products derived from heat-treatment of KTI with glucose and starch; and KTI exposed to high pH. The results indicate that even low inhibitor isolates contain significant amounts of specific inhibitors. Thus, infants on soy formula consume about 10 mg of KTI plus BBI per day. The immunoassays complement the established enzymatic assays of trypsin and chymotrypsin inhibitors, and have advantages in (a) measuring low levels of inhibitors in processed foods; and (b) differentiating between the Kunitz and Bowman-Birk inhibitors. The significance of our findings for food safety are discussed.

  8. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

    Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

    2011-02-10

    Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

  9. Pathophysiological significance and therapeutic applications of snake venom protease inhibitors.

    Thakur, Rupamoni; Mukherjee, Ashis K

    2017-06-01

    Protease inhibitors are important constituents of snake venom and play important roles in the pathophysiology of snakebite. Recently, research on snake venom protease inhibitors has provided valuable information to decipher the molecular details of various biological processes and offer insight for the development of some therapeutically important molecules from snake venom. The process of blood coagulation and fibrinolysis, in addition to affecting platelet function, are well known as the major targets of several snake venom protease inhibitors. This review summarizes the structure-functional aspects of snake venom protease inhibitors that have been described to date. Because diverse biological functions have been demonstrated by protease inhibitors, a comparative overview of their pharmacological and pathophysiological properties is also highlighted. In addition, since most snake venom protease inhibitors are non-toxic on their own, this review evaluates the different roles of individual protease inhibitors that could lead to the identification of drug candidates and diagnostic molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Evaluation of Encapsulated Inhibitor for Autonomous Corrosion Protection

    Johnsey, M. N.; Li, W.; Buhrow, J. W.; Calle, L. M.; Pearman, B. P.; Zhang, X.

    2015-01-01

    This work concerns the development of smart coating technologies based on microencapsulation for the autonomous control of corrosion. Microencapsulation allows the incorporation of corrosion inhibitors into coating which provides protection through corrosion-controlled release of these inhibitors.One critical aspect of a corrosion protective smart coating is the selection of corrosion inhibitor for encapsulation and comparison of the inhibitor function before and after encapsulation. For this purpose, a systematic approach is being used to evaluate free and encapsulated corrosion inhibitors by salt immersion. Visual, optical microscope, and Scanning Electron Microscope (with low-angle backscatter electron detector) are used to evaluate these inhibitors. It has been found that the combination of different characterization tools provide an effective method for evaluation of early stage localized corrosion and the effectiveness of corrosion inhibitors.

  11. The "SWOT" of BRAF inhibition in melanoma: RAF inhibitors, MEK inhibitors or both?

    Nissan, Moriah H; Solit, David B

    2011-12-01

    Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.

  12. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  13. CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR.

    Circelli, Luisa; Sciammarella, Concetta; Guadagno, Elia; Tafuto, Salvatore; del Basso de Caro, Marialaura; Botti, Giovanni; Pezzullo, Luciano; Aria, Massimo; Ramundo, Valeria; Tatangelo, Fabiana; Losito, Nunzia Simona; Ieranò, Caterina; D'Alterio, Crescenzo; Izzo, Francesco; Ciliberto, Gennaro; Colao, Annamaria; Faggiano, Antongiulio; Scala, Stefania

    2016-04-05

    To evaluate the possible crosstalk between C-X-C chemokine receptor 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12)/C-X-C chemokine receptor 7 (CXCR7) axis with the mammalian target of rapamycin (mTOR) pathway in neuroendocrine tumors (NETs). Sixty-one human NETs were included into the study. CXCR4/CXCL12/CXCR7 axis and mTOR pathway were assessed by qRT-PCR and immunohistochemistry (IHC). The effect of mTOR inhibitor, RAD001, was evaluated on CXCR4 pathway through proliferation and p-Erk and p-AKT induction. CXCR4/CXCL12/CXCR7 axis and p-mTOR were found to be active and correlated with grading, Ki67 index and tumor stage. mTOR pathway activation significantly correlated with poor prognosis. In human NET cells, CXCL12 induced mTOR signalling while AMD3100 (CXCR4-antagonist) impaired it. The mTOR-antagonist, RAD001, impaired the CXCL12-dependent induction of CXCR4 downstream effectors. Combination of AMD3100 and RAD001 potentiate cell growth inhibition. CXCR4/CXCL12/CXCR7 axis is active in NETs and signals on mTOR. CXCR4 might be considered a prognostic factor in NETs. Combined treatment with AMD3100 and RAD001 may provide clinical benefits in NET patients with drug-resistant.

  14. Sifuvirtide, a potent HIV fusion inhibitor peptide

    Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua; Pang, Wei; Tam, Siu-Cheung; Tien, Po; Zheng, Yong-Tang

    2009-01-01

    Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC 50 ), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC 50 ) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1 IIIB were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.

  15. [Cholinesterase inhibitors for treating dementia. Review].

    Kremer, Janus

    2010-01-01

    Alzheimer's disease is the most common form of dementia seen in the clinical practice. The principal risk factor is aging. There is not currently any available curative medication. However, there a family of drugs call the cholinesterase inhibitors (donepezile, galantamine and rivastigmine) the enhances cholinergic activity in the CNS. Also, memantine is available is a NMDA receptor modulator. A new transdermal way of administration is available now for rivastigmine. The rivastigmines patches are now a rational alternative focusing in getting more tolerance, better blood levels of the drug and compliance to treatment in Alzheimer's disease patients.

  16. Serine proteinases and their inhibitors in fertilization

    Jonáková, Věra; Jelínková-Slavíčková, Petra

    2004-01-01

    Roč. 8, 3,4 (2004), s. 108-110 ISSN 1211-8869. [Central European Conference on Human Tumor Markers /5./. Praha, 01.10.2004-03.10.2004] R&D Projects: GA ČR GA303/02/0433; GA ČR GP303/02/P069; GA ČR GP303/04/P070; GA MZd NJ7463 Institutional research plan: CEZ:AV0Z5052915 Keywords : serine proteinase * proteinase inhibitors * fertilization Subject RIV: CE - Biochemistry

  17. A New Urease Inhibitor from Viola betonicifolia

    Naveed Muhammad

    2014-10-01

    Full Text Available Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.

  18. Tetomilast: new promise for phosphodiesterase-4 inhibitors?

    Bickston, Stephen J; Snider, Kenneth R; Kappus, Matthew R

    2012-12-01

    Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

  19. Potential mechanisms of resistance to microtubule inhibitors.

    Kavallaris, Maria; Annereau, Jean-Philippe; Barret, Jean-Marc

    2008-06-01

    Antimitotic drugs targeting the microtubules, such as the taxanes and vinca alkaloids, are widely used in the treatment of neoplastic diseases. Development of drug resistance over time, however, limits the efficacy of these agents and poses a clinical challenge to long-term improvement of patient outcomes. Understanding the mechanism(s) of drug resistance becomes paramount to allowing for alternative, if not improved, therapeutic options that might circumvent this challenge. Vinflunine, a novel microtubule inhibitor, has shown superior preclinical antitumor activity, and displays a different pattern of resistance, compared with other agents in the vinca alkaloid class.

  20. Larvicides and acetylcholinesterase inhibitors from Kalanchoe species

    Trevisan, Maria Teresa Salles; Bezerra, Maria Zeneide Barbosa; Santiago, Gilvandete Maria Pinheiro; Feitosa, Chistiane Mendes; Verpoorte, Robert; Gorlaeus Laboratories, Leiden; Braz Filho, Raimundo

    2006-01-01

    Acetylcholine esterase inhibitors are successfully used to treat the symptoms of Alzheimer's disease. Extracts of three Kalanchoe species (K. brasiliensis, K. pinnata and K. gastonis-bornieri) showed acetylcholine esterase inhibitory effects and a toxic effect on Aedes aegypti larvae. Here we describe the bioassay guided fractionation of extracts of the most active extracts (K. brasiliensis) which resulted in the isolation of an active mixture of three flavonoids: 8-methoxyquercetin, 3,7-di-O-rhamnopyranoside and 8-methoxykaempferol-3,7-di-O-rhamnopyranoside. On TLC these flavonoids showed an acetylcholine esterase inhibitory effect. (author)

  1. Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

    Kazi Abdus Salam

    2013-01-01

    Full Text Available Currently, hepatitis C virus (HCV infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin. The new therapy has significantly improved sustained virologic response (SVR; however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

  2. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience.

    Ciccarese, Mariangela; Fabi, Alessandra; Moscetti, Luca; Cazzaniga, Maria Elena; Petrucelli, Luciana; Forcignanò, Rosachiara; Lupo, Laura Isabella; De Matteis, Elisabetta; Chiuri, Vincenzo Emanuele; Cairo, Giuseppe; Febbraro, Antonio; Giordano, Guido; Giampaglia, Marianna; Bilancia, Domenico; La Verde, Nicla; Maiello, Evaristo; Morritti, Maria; Giotta, Francesco; Lorusso, Vito; Latorre, Agnese; Scavelli, Claudio; Romito, Sante; Cusmai, Antonio; Palmiotti, Gennaro; Surico, Giammarco

    2017-06-01

    This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

  3. HTCC: Broad Range Inhibitor of Coronavirus Entry.

    Aleksandra Milewska

    Full Text Available To date, six human coronaviruses have been known, all of which are associated with respiratory infections in humans. With the exception of the highly pathogenic SARS and MERS coronaviruses, human coronaviruses (HCoV-NL63, HCoV-OC43, HCoV-229E, and HCoV-HKU1 circulate worldwide and typically cause the common cold. In most cases, infection with these viruses does not lead to severe disease, although acute infections in infants, the elderly, and immunocompromised patients may progress to severe disease requiring hospitalization. Importantly, no drugs against human coronaviruses exist, and only supportive therapy is available. Previously, we proposed the cationically modified chitosan, N-(2-hydroxypropyl-3-trimethylammonium chitosan chloride (HTCC, and its hydrophobically-modified derivative (HM-HTCC as potent inhibitors of the coronavirus HCoV-NL63. Here, we show that HTCC inhibits interaction of a virus with its receptor and thus blocks the entry. Further, we demonstrate that HTCC polymers with different degrees of substitution act as effective inhibitors of all low-pathogenic human coronaviruses.

  4. Lonafarnib is a potential inhibitor for neovascularization.

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  5. Proton Pump Inhibitors and Risk of Rhabdomyolysis.

    Duncan, Scott J; Howden, Colin W

    2017-01-01

    Proton pump inhibitors (PPIs) have been associated with a variety of adverse events, although the level of evidence for many of these is weak at best. Recently, one national regulatory authority has mandated a change to the labeling of one PPI based on reports of possible associated rhabdomyolysis. Thus, in this review we summarize the available evidence linking PPI use with rhabdomyolysis. The level of evidence is insufficient to establish a causal relationship and is largely based on sporadic case reports. In general, patients with suspected PPI-associated rhabdomyolysis have not been re-challenged with a PPI after recovery. The mechanism whereby PPIs might have been associated with rhabdomyolysis is unclear but possibly related to interaction with concomitantly administered drugs such as HMG-CoA reductase inhibitors (statins). For patients with rhabdomyolysis, a careful search must be made for possible etiological factors. In patients who recover from an episode of possible PPI-related rhabdomyolysis but do not have a genuine requirement for PPI treatment, the PPI should not be re-introduced. For those with a definite indication for ongoing PPI treatment, the PPI can be re-introduced but should preferably not be administered with a statin.

  6. Polyphenol Compound as a Transcription Factor Inhibitor

    Seyeon Park

    2015-10-01

    Full Text Available A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1, c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and β-catenin/T cell factor (Tcf.

  7. Polyphenol Compound as a Transcription Factor Inhibitor.

    Park, Seyeon

    2015-10-30

    A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

  8. PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

    Stephanie Schneider

    2017-05-01

    Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

  9. Synthesis of Novel Chalcones as Acetylcholinesterase Inhibitors

    Thanh-Dao Tran

    2016-07-01

    Full Text Available A new series of benzylaminochalcone derivatives with different substituents on ring B were synthesized and evaluated as inhibitors of acetylcholinesterase. The study is aimed at identification of novel benzylaminochalcones capable of blocking acetylcholinesterase activity for further development of an approach to Alzheimer’s disease treatment. These compounds were produced in moderate to good yields via Claisen-Schmidt condensation and subjected to an in vitro acetylcholinesterase inhibition assay, using Ellman’s method. The in silico docking procedure was also employed to identify molecular interactions between the chalcone compounds and the enzyme. Compounds with ring B bearing pyridin-4-yl, 4-nitrophenyl, 4-chlorophenyl and 3,4-dimethoxyphenyl moieties were discovered to exhibit significant inhibitory activities against acetylcholinesterase, with IC50 values ranging from 23 to 39 µM. The molecular modeling studies are consistent with the hypothesis that benzylaminochalcones could exert their effects as dual-binding-site acetylcholinesterase inhibitors, which might simultaneously enhance cholinergic neurotransmission and inhibit β-amyloid aggregation through binding to both catalytic and peripheral sites of the enzyme. These derivatives could be further developed to provide novel leads for the discovery of new anti-Alzheimer drugs in the future.

  10. Replication and Inhibitors of Enteroviruses and Parechoviruses

    Lonneke van der Linden

    2015-08-01

    Full Text Available The Enterovirus (EV and Parechovirus genera of the picornavirus family include many important human pathogens, including poliovirus, rhinovirus, EV-A71, EV-D68, and human parechoviruses (HPeV. They cause a wide variety of diseases, ranging from a simple common cold to life-threatening diseases such as encephalitis and myocarditis. At the moment, no antiviral therapy is available against these viruses and it is not feasible to develop vaccines against all EVs and HPeVs due to the great number of serotypes. Therefore, a lot of effort is being invested in the development of antiviral drugs. Both viral proteins and host proteins essential for virus replication can be used as targets for virus inhibitors. As such, a good understanding of the complex process of virus replication is pivotal in the design of antiviral strategies goes hand in hand with a good understanding of the complex process of virus replication. In this review, we will give an overview of the current state of knowledge of EV and HPeV replication and how this can be inhibited by small-molecule inhibitors.

  11. Flavonoids as Inhibitors of Human Butyrylcholinesterase Variants

    Maja Katalinić

    2014-01-01

    Full Text Available The inhibition of butyrylcholinesterase (BChE, EC 3.1.1.8 appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels, such as Alzheimer’s disease. However, BCHE gene polymorphism should not be neglected in research since it could have an effect on the expected outcome. Several well-known cholinergic drugs (e.g. galantamine, huperzine and rivastigmine originating from plants, or synthesised as derivatives of plant compounds, have shown that herbs could serve as a source of novel target-directed compounds. We focused our research on flavonoids, biologically active polyphenolic compounds found in many plants and plant-derived products, as BChE inhibitors. All of the tested flavonoids: galangin, quercetin, fisetin and luteolin reversibly inhibited usual, atypical, and fluoride-resistant variants of human BChE. The inhibition potency increased in the following order, identically for all three BChE variants: luteolininhibitor dissociation constants (Ki ranged from 10 to 170 mmol/L. We showed that no significant change in the inhibition potency of selected flavonoids exists in view of BChE polymorphism. Our results suggested that flavonoids could assist the further development of new BChE-targeted drugs for treating symptoms of neurodegenerative diseases and dementia.

  12. Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors.

    Braun, Alexandra C; Gutmann, Marcus; Ebert, Regina; Jakob, Franz; Gieseler, Henning; Lühmann, Tessa; Meinel, Lorenz

    2017-01-01

    The inhibition of myostatin - a member of the transforming growth factor (TGF-β) family - drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to provide self-regulated MI concentration gradients within tissues of need. A protease cleavable linker (PCL) - responding to MMP upregulation - is attached to the MI and site-specifically immobilized on microparticle surfaces. The PCL disintegrated in a matrix metalloproteinase (MMP) 1, 8, and particularly MMP-9 concentration dependent manner, with MMP-9 being an effective surrogate biomarker correlating with the activity of myositis. The bioactivity of particle-surface bound as well as released MI was confirmed by luciferase suppression in stably transfected HEK293 cells responding to myostatin induced SMAD phosphorylation. We developed a MMP-responsive DDS for MI delivery responding to inflammatory flare of a diseased muscle matching the kinetics of MMP-9 upregulation, with MMP-9 kinetics matching (patho-) physiological myostatin levels. ᅟ: Graphical Abstract Schematic illustration of the matrix metalloproteinase responsive delivery system responding to inflammatory flares of muscle disease. The protease cleavable linker readily disintegrates upon entry into the diseased tissue, therby releasing the mystatin inhibitor.

  13. Nontoxic corrosion inhibitors for N80 steel in hydrochloric acid

    M. Yadav; Debasis Behera; Usha Sharma

    2016-01-01

    The purpose of this paper is to evaluate the protective ability of 1-(2-aminoethyl)-2-oleylimidazoline (AEOI) and 1-(2-oleylamidoethyl)-2-oleylimidazoline (OAEOI) as corrosion inhibitors for N80 steel in 15% hydrochloric acid, which may find application as eco-friendly corrosion inhibitors in acidizing processes in petroleum industry. Different concentrations of synthesized inhibitors AEOI and OAEOI were added to the test solution (15% HCl) and the corrosion inhibition of N80 steel in hydroch...

  14. Aromatase inhibitors in men: effects and therapeutic options

    de Jong Frank H

    2011-06-01

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

  15. Inhibitors of Fatty Acid Synthase for Prostate Cancer. Revision

    2013-05-01

    acetyl- cholinesterase inhibitors have been developed, many with femtomolar binding affinities (7). This body of literature also confirms that the...AD_________________ Award Number: W81XWH-09-1-0204 TITLE: Inhibitors of Fatty Acid Synthase for...May 2013 2. REPORT TYPE Revised Final 3. DATES COVERED 01 May 2009-30 Apr 2013 4. TITLE AND SUBTITLE Inhibitors of Fatty Acid Synthase for

  16. Inhibitors of Fatty Acid Synthase for Prostate Cancer

    2012-05-01

    compounds. For example, numerous classes of acetyl- cholinesterase inhibitors have been developed, m any with fe mtomolar binding affinities (7). This...AD_________________ Award Number: W81XWH-09-1-0204 TITLE: Inhibitors of Fatty Acid Synthase for...CONTRACT NUMBER Inhibitors of Fatty Acid Synthase for Prostate Cancer 5b. GRANT NUMBER W81XWH-09-1-0204 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR

  17. Natural compounds as corrosion inhibitors for highly cycled systems

    Quraishi, M.A.; Farooqi, I.H.; Saini, P.A. [Corrosion Research Lab., Aligarh (India)

    1999-11-01

    Strict environmental legislations have led to the development of green inhibitors in recent years. In continuation of the authors` research work on development of green inhibitors, they have investigated the aqueous extracts of three plants namely: Azadirachta indica, Punica Granatum and Momordica charantia as corrosion inhibitors for mild steel in 3% NaCl using weight loss and electrochemical methods. All the investigated compounds exhibited excellent corrosion inhibition properties comparable to that of HEDP. Azadirachta showed better scale inhibition effect than HEDP.

  18. Invertase proteinaceous inhibitor of Cyphomandra betacea Sendt fruits.

    Ordóñez, R M; Isla, M I; Vattuone, M A; Sampietro, A R

    2000-01-01

    This work describes a new invertase proteinaceous inhibitor from Cyphomandra betacea Sendt. (tomate de arbol) fruits. The proteinaceous inhibitor was isolated and purified from a cell wall preparation. The pH stability, kinetics of the inhibition of the C. betacea invertase, inhibition of several higher plant invertases and lectin nature of the inhibitor were studied. The inhibitor structure involves a single polypeptide (Mr = 19000), as shown by gel filtration and SDS-PAGE determinations. N-terminal aminoacid sequence was determined. The properties and some structural features of the inhibitor are compared with the proteinaceous inhibitors from several plant species (Beta vulgaris L., Ipomoea batatas L. and Lycopersicon esculentum Mill.). All these inhibitors share lectinic properties, some common epitopes, some aminoacid sequences and a certain lack of specificity towards invertases of different species, genera and even plant family. In consequence, the inhibitors appear to belong to the same lectin family. It is now known that some lectins are part of the defence mechanism of higher plants against fungi and bacteria and this is a probable role of the proteinaceous inhibitors.

  19. Predicting DPP-IV inhibitors with machine learning approaches

    Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

    2017-04-01

    Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

  20. Experimental and theoretical studies of benzoxazines corrosion inhibitors

    Abdulhadi Kadhim

    Full Text Available 2-Methyl-4H-benzo[d][1,3]oxazin-4-one (BZ1 and 3-amino-2-methylquinazolin-4(3H-one (BZ2 were evaluated for their corrosion inhibition properties on mild steel (MS in hydrochloric acid solution by weight loss technique and scanning electron microscopy. Results show the inhibition efficiency values depend on the amount of nitrogen in the inhibitor, the inhibitor concentration and the inhibitor molecular weight with maximum inhibition efficiency of 89% and 65% for BZ2 and BZ1 at highest concentration of the compounds. Keywords: Methylquinazoline, Benzoxazines, Corrosion, Inhibitors

  1. Cysteine peptidases and their inhibitors in breast and genital cancer.

    Magdalena Milan

    2010-11-01

    Full Text Available Cysteine proteinases and their inhibitors probably play the main role in carcinogenesis and metastasis. The metastasis process need external proteolytic activities that pass several barriers which are membranous structures of the connective tissue which includes, the basement membrane of blood vessels. Activities of the proteinases are regulated by endogenous inhibitors and activators. The imbalance between cysteine proteinases and cystatins seems to be associated with an increase in metastatic potential in some tumors. It has also been reported that proteinase inhibitors, specific antibodies for these enzymes and inhibition of the urokinase receptor may prevent cancer cell invasion. Some proteinase inhibitor could serve as agents for cancer treatment.

  2. Insights into the molecular evolution of peptidase inhibitors in arthropods.

    Alonso, Joaquin; Martinez, Manuel

    2017-01-01

    Peptidase inhibitors are key proteins involved in the control of peptidases. In arthropods, peptidase inhibitors modulate the activity of peptidases involved in endogenous physiological processes and peptidases of the organisms with which they interact. Exploring available arthropod genomic sequences is a powerful way to obtain the repertoire of peptidase inhibitors in every arthropod species and to understand the evolutionary mechanisms involved in the diversification of this kind of proteins. A genomic comparative analysis of peptidase inhibitors in species belonging to different arthropod taxonomic groups was performed. The results point out: i) species or clade-specific presence is shown for several families of peptidase inhibitors; ii) multidomain peptidase inhibitors are commonly found in many peptidase inhibitor families; iii) several families have a wide range of members in different arthropod species; iv) several peptidase inhibitor families show species-specific (or clade-specific) gene family expansions; v) functional divergence may be assumed for particular clades; vi) passive expansions may be used by natural selection to fix adaptations. In conclusion, conservation and divergence of duplicated genes and the potential recruitment as peptidase inhibitors of proteins from other families are the main mechanisms used by arthropods to fix diversity. This diversity would be associated to the control of target peptidases and, as consequence, to adapt to specific environments.

  3. The safety of proton pump inhibitors in pregnancy

    Nielsen, Gunnar Lauge; Sørensen, Henrik Toft; Thulstrup, Ane Marie

    1999-01-01

    AIM: To assess the safety of proton pump inhibitors during pregnancy. METHODS: Fifty-one pregnant women exposed to proton pump inhibitors around the time of conception or during pregnancy were compared with 13 327 controls without exposure to any prescribed drug in a population-based study based...... birth weight or number of preterm deliveries in pregnancies exposed to proton pump inhibitors. However, further monitoring is warranted in order to establish or rule out a potential association between the use of proton pump inhibitors and increased risk of either cardiac malformations or preterm birth....

  4. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Shohei Sakuda

    2014-03-01

    Full Text Available Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control.

  5. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-01-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  6. Inga laurina trypsin inhibitor (ILTI) obstructs Spodoptera frugiperda trypsins expressed during adaptive mechanisms against plant protease inhibitors.

    Machado, Suzy Wider; de Oliveira, Caio Fernando Ramalho; Zério, Neide Graciano; Parra, José Roberto Postali; Macedo, Maria Lígia Rodrigues

    2017-08-01

    Plant protease inhibitors (PIs) are elements of a common plant defense mechanism induced in response to herbivores. The fall armyworm, Spodoptera frugiperda, a highly polyphagous lepidopteran pest, responds to various PIs in its diet by expressing genes encoding trypsins. This raises the question of whether the PI-induced trypsins are also inhibited by other PIs, which we posed as the hypothesis that Inga laurina trypsin inhibitor (ILTI) inhibits PI-induced trypsins in S. frugiperda. In the process of testing our hypothesis, we compared its properties with those of selected PIs, soybean Kunitz trypsin inhibitor (SKTI), Inga vera trypsin inhibitor (IVTI), Adenanthera pavonina trypsin inhibitor (ApTI), and Entada acaciifolia trypsin inhibitor (EATI). We report that ILTI is more effective in inhibiting the induced S. frugiperda trypsins than SKTI and the other PIs, which supports our hypothesis. ILTI may be more appropriate than SKTI for studies regarding adaptive mechanisms to dietary PIs. © 2017 Wiley Periodicals, Inc.

  7. Identification of fermentation inhibitors in wood hydrolyzates and removal of inhibitors by ion exchange and liquid-liquid extraction

    Luo, Caidian

    1998-12-01

    Common methods employed in the ethanol production from biomass consist of chemical or enzymatic degradation of biomass into sugars and then fermentation of sugars into ethanol or other chemicals. However, some degradation products severely inhibit the fermentation processes and substantially reduce the efficiency of ethanol production. How to remove inhibitors from the reaction product mixture and increase the production efficiency are critical in the commercialization of any processes of energy from biomass. The present study has investigated anion exchange and liquid-liquid extraction as potential methods for inhibitor removal. An analytical method has been developed to identify the fermentation inhibitors in a hydrolyzate. The majority of inhibitors present in hybrid poplar hydrolyzate have positively been identified. Ion exchange with weak basic Dowex-MWA-1 resin has been proved to be an effective mean to remove fermentation inhibitors from hybrid poplar hydrolyzate and significantly increase the fermentation productivity. Extraction with n-butanol might be a preferred way to remove inhibitors from wood hydrolyzates and improve the fermentability of sugars in the hydrolyzates. n-Butanol also removes some glucose, mannose and xylose from the hydrolyzate. Inhibitor identification reveals that lignin and sugar degradation compounds including both aromatic and aliphatic aldehydes and carboxylic acids formed in hydrolysis, plus fatty acids and other components from wood extractives are major fermentation inhibitors in Sacchromyces cerevisiae fermentation. There are 35 components identified as fermentation inhibitors. Among them, 4-hydroxy benzoic acid, 3,4-dihydroxy benzoic acid, syringic acid, syringaldehyde, and ferulic acid are among the most abundant aromatic inhibitors in hybrid poplar hydrolyzate. The conversion of aldehyde groups into carboxylic acid groups in the nitric acid catalyzed hydrolysis reduces the toxicity of the hydrolyzate. A wide spectrum of

  8. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays.

    Marlien Pieters

    Full Text Available Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g, platelet-containing (352 g and platelet-rich plasma (200 g were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation. Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly

  9. Proton pump inhibitors inhibit pancreatic secretion

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition...

  10. Neuromuscular complications of immune checkpoint inhibitor therapy.

    Kolb, Noah A; Trevino, Christopher R; Waheed, Waqar; Sobhani, Fatemeh; Landry, Kara K; Thomas, Alissa A; Hehir, Mike

    2018-01-17

    Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  11. Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

    Di Luigi, Luigi; Sansone, Massimiliano; Sansone, Andrea; Ceci, Roberta; Duranti, Guglielmo; Borrione, Paolo; Crescioli, Clara; Sgrò, Paolo; Sabatini, Stefania

    Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

  12. Developing BACE-1 inhibitors for FXS

    Cara J Westmark

    2013-05-01

    Full Text Available Fragile X syndrome (FXS is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 (mGluR5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression (LTD. Two of the overexpressed proteins are amyloid-beta protein precursor (APP and its metabolite amyloid-beta (Aβ, which have been well-studied in Alzheimer’s disease (AD. Here we discus the possibility that pharmaceuticals under study for the modulation of these proteins in AD might be viable therapeutic strategies for FXS. Specifically, a recently identified acetyltransferase (ATase inhibitor that reduces the levels and activity of β-site APP cleaving enzyme (BACE-1 has strong potential to attenuate BACE-1 activity and maintain homeostatic levels APP catabolites in FXS.

  13. Coumarins as cholinesterase inhibitors: A review.

    de Souza, Luana G; Rennã, Magdalena N; Figueroa-Villar, Jose D

    2016-07-25

    The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    Mona Mehta

    2012-01-01

    Full Text Available Acetylcholinesterase (AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

  15. Endogenous Natural Complement Inhibitor Regulates Cardiac Development

    Mortensen, Simon A; Skov, Louise L; Kjaer-Sorensen, Kasper

    2017-01-01

    mechanisms during fetal development and adult homeostasis. In this article, we describe the function of an endogenous complement inhibitor, mannan-binding lectin (MBL)-associated protein (MAp)44, in regulating the composition of a serine protease-pattern recognition receptor complex, MBL-associated serine...... of MAp44 caused impaired cardiogenesis, lowered heart rate, and decreased cardiac output. These defects were associated with aberrant neural crest cell behavior. We found that MAp44 competed with MASP-3 for pattern recognition molecule interaction, and knockdown of endogenous MAp44 expression could...... be rescued by overexpression of wild-type MAp44. Our observations provide evidence that immune molecules are centrally involved in the orchestration of cardiac tissue development....

  16. Histone deacetylase inhibitors in multiple myeloma

    Sarah Deleu

    2009-06-01

    Full Text Available Novel drugs such as bortezomib and high dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow micro-environment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (preclinical trials.

  17. Molecular modeling of auxin transport inhibitors

    Gardner, G.; Black-Schaefer, C.; Bures, M.G.

    1990-01-01

    Molecular modeling techniques have been used to study the chemical and steric properties of auxin transport inhibitors. These bind to a specific site on the plant plasma membrane characterized by its affinity for N-1-naphthylphthalamic acid (NPA). A three-dimensional model was derived from critical features of ligands for the NPA receptor, and a suggested binding conformation is proposed. This model, along with three-dimensional structural searching techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the search criteria, 77 representative molecules were evaluated for their ability to compete for [ 3 H]NPA binding to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, from chemical classes not included in the original compound set, also inhibited polar auxin transport through corn coleoptile sections

  18. Carbocyclic Carbohydrate Mimics as Potential Glycosidase Inhibitors

    Fanefjord, Mette; Lundt, Inge

    It has been proven that aminocyclopentanols having the aminogroup adjacent to a carbon sidechain could be potential anomer-selective glycosidase inhibitors [1]. A successful pathway for synthesising mimics to L-carbohydrates 2, by introducing nitrogen to the C6 position in compound 1, has been...... developed in our group. A similar strategy has been used for synthesising mimics of D-carbohydrates. The α,β-unsaturated lactone 3 was cyclised to compound 4 which was further transformed into 5. The nitrogen functionality in compound 7 is introduced by an Overman rearrangement of 6 and the hydroxyl...... functionalities was introduced by either epoxidation or dihydroxylation of 7. Finally, reduction of the lactone ring led to the sugar mimics 8. The synthesis of several isomers of 8 will be presented. [1] a) Kleban, M. ; Hilgers, P. ; Greul, J.N. ; Kugler, R.D. ; Li, J. ; Picasso, S. ; Vogel, P. ; Jäger, V. Chem...

  19. Use of proteasome inhibitors in anticancer therapy

    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.

  20. Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors.

    Jayakumar, Jayanthi; Anishetty, Sharmila

    2014-05-01

    Chemotherapeutic resistance due to over expression of Inhibitor of Apoptosis Proteins (IAPs) XIAP, survivin and livin has been observed in various cancers. In the current study, Molecular Dynamics (MD) simulations were carried out for all three IAPs and a common ligand binding scaffold was identified. Further, a novel sequence based motif specific to these IAPs was designed. SMAC is an endogenous inhibitor of IAPs. Screening of ChemBank for compounds similar to lead SMAC-non-peptidomimetics yielded a cemadotin related compound NCIMech_000654. Cemadotin is a derivative of natural anti-tumor peptide dolastatin-15; hence these compounds were docked against all three IAPs. Based on our analysis, we propose that NCIMech_000654/dolastatin-15/cemadotin derivatives may be investigated for their potential in inhibiting XIAP, survivin and livin. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Effect of biocides and anionic homopolymeric inhibitors on the ...

    This paper describes the effect of biocides and of the anionic homopolymeric inhibitors on the precipitation behavior of calcium fluoride (CaF2).The efficiency of inhibitors in the presence and absence of biocides was calculated using the half-life (t1/2) approach, where 50% of the concentration has been precipitated.

  2. High throughput in vivo protease inhibitor selection platform

    2017-01-01

    The invention relates to a recombinant microbial cell comprising a selection platform for screening for a protease inhibitor, wherein the platform comprises transgenes encoding a protease having selective peptide bond cleavage activity at a recognition site amino acid sequence; and transgenes...... platform for screening for a protease inhibitor....

  3. Regulation of collagenase inhibitor production in chondrosarcoma chondrocytes

    Harper, J.; Harper, E.

    1987-01-01

    Swarm rat chondrosarcoma chondrocytes produce an inhibitor of collagenase. This inhibitor is similar to those isolated from normal cartilage tissues. These cells will synthesize proteins in the absence of serum. Since serum contains inhibitors of collagenase, it is necessary to culture cells without serum in order to obtain accurate measurements of enzyme and inhibitor levels. They examined the effect of insulin on inhibitor secretion by cultures of Swarm rat chondrosarcoma chondrocytes. They observed a 2.5 to 3.5 fold stimulation of inhibitory activity in the presence of as little as 10 ng/ml insulin as compared to controls in serum free Dulbecco's modified Eagle's medium supplemented with 4.5 g/l glucose. The units of inhibitor were determined over a 7 day culture period. Medium was harvested daily and assayed for collagenase activity and for inhibition of a known collagenase from rabbit skin or human skin, using the 14 C-glycine peptide release assay. The amount of inhibitor obtained from days 2 through 7 were: 1.4 unit (control), 3.8 units (10 ng/ml insulin), 5.2 units (1 μg/ml insulin). The addition of 1 mM dibutyryl cyclic AMP to these chondrocytes in the presence of 1 μg/ml insulin caused a decrease in the level of inhibitor, suggesting that a dephosphorylation event may be necessary for this stimulation by insulin to occur

  4. Nontoxic corrosion inhibitors for N80 steel in hydrochloric acid

    M. Yadav

    2016-11-01

    Full Text Available The purpose of this paper is to evaluate the protective ability of 1-(2-aminoethyl-2-oleylimidazoline (AEOI and 1-(2-oleylamidoethyl-2-oleylimidazoline (OAEOI as corrosion inhibitors for N80 steel in 15% hydrochloric acid, which may find application as eco-friendly corrosion inhibitors in acidizing processes in petroleum industry. Different concentrations of synthesized inhibitors AEOI and OAEOI were added to the test solution (15% HCl and the corrosion inhibition of N80 steel in hydrochloric acid medium containing inhibitors was tested by weight loss, potentiodynamic polarization and AC impedance measurements. Influence of temperature (298–323 K on the inhibition behavior was studied. Surface studies were performed by using FTIR spectra and SEM. Both the inhibitors, AEOI and OAEOI at 150 ppm concentration show maximum efficiency 90.26% and 96.23%, respectively at 298 K in 15% HCl solution. Both the inhibitors act as mixed corrosion inhibitors. The adsorption of the corrosion inhibitors at the surface of N80 steel is the root cause of corrosion inhibition.

  5. Protein C Inhibitor-A Novel Antimicrobial Agent

    Malmström, E.; Mörgelin, M.; Malmsten, M.; Johansson, L.; Norrby-Teglund, A.; Shannon, O.; Schmidtchen, A.; Meijers, J.C.M.; Herwald, H.

    2009-01-01

    Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which

  6. A simple radiometric in vitro assay for acetylcholinesterase inhibitors

    Guilarte, T.R.; Burns, H.D.; Dannals, R.F.; Wagner, H.N. Jr.

    1983-01-01

    A radiometric method for screening acetylcholinesterase inhibitors has been described. The method is based on the production of [ 14 C]carbon dioxide from the hydrolysis of acetylcholine. The inhibitory concentration at 50% (IC50) values for several known acetylcholinesterase inhibitors were in agreement with literature values. The new radiometric method is simple, inexpensive, and has the potential for automation

  7. Replacement inhibitors for tank farm cooling coil systems

    Hsu, T.C.

    1995-01-01

    Sodium chromate has been an effective corrosion inhibitor for the cooling coil systems in Savannah River Site (SRS) waste tanks for over 40 years. Due to their age and operating history, cooling coils occasionally fail allowing chromate water to leak into the environment. When the leaks spill 10 lbs. or more of sodium chromate over a 24-hr period, the leak incidents are classified as Unusual Occurrences (UO) per CERCLA (Comprehensive Environmental Response, Compensation and Liability Act). The cost of reporting and cleaning up chromate spills prompted High Level Waste Engineering (HLWE) to initiate a study to investigate alternative tank cooling water inhibitor systems and the associated cost of replacement. Several inhibitor systems were investigated as potential alternatives to sodium chromate. All would have a lesser regulatory impact, if a spill occurred. However, the conversion cost is estimated to be $8.5 million over a period of 8 to 12 months to convert all 5 cooling systems. Although each of the alternative inhibitors examined is effective in preventing corrosion, there is no inhibitor identified that is as effective as chromate. Assuming 3 major leaks a year (the average over the past several years), the cost of maintaining the existing inhibitor was estimated at $0.5 million per year. Since there is no economic or regulatory incentive to replace the sodium chromate with an alternate inhibitor, HLWE recommends that sodium chromate continue to be used as the inhibitor for the waste tank cooling systems

  8. Detecting and treating breast cancer resistance to EGFR inhibitors

    Moonlee, Sun-Young; Bissell, Mina J.; Furuta, Saori; Meier, Roland; Kenny, Paraic A.

    2016-04-05

    The application describes therapeutic compositions and methods for treating cancer. For example, therapeutic compositions and methods related to inhibition of FAM83A (family with sequence similarity 83) are provided. The application also describes methods for diagnosing cancer resistance to EGFR inhibitors. For example, a method of diagnosing cancer resistance to EGFR inhibitors by detecting increased FAM83A levels is described.

  9. Phytochemicals as Green Corrosion Inhibitors in Various Corrosive ...

    There is an intensive effort underway to develop new plant origin corrosion inhibitors for metal subjected to various environmental conditions. These efforts have been motivated by the desire to replace toxic inhibitors used for mitigation of corrosion of various metals and alloys in aqueous solutions. Plants represent a class ...

  10. Novel guanidine-based inhibitors of inosine monophosphate dehydrogenase.

    Iwanowicz, Edwin J; Watterson, Scott H; Liu, Chunjian; Gu, Henry H; Mitt, Toomas; Leftheris, Katerina; Barrish, Joel C; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Hollenbaugh, Diane L

    2002-10-21

    A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.

  11. DNA-linked Inhibitor Antibody Assay (DIANA) for sensitive and selective enzyme detection and inhibitor screening

    Navrátil, Václav; Schimer, Jiří; Tykvart, Jan; Knedlík, Tomáš; Vik, V.; Majer, Pavel; Konvalinka, Jan; Šácha, Pavel

    2017-01-01

    Roč. 45, č. 2 (2017), č. článku e10. ISSN 0305-1048 R&D Projects: GA MŠk LO1302 Institutional support: RVO:61388963 Keywords : quantitative PCR * enzyme detection * inhibitor screening Subject RIV: CE - Biochemistry OBOR OECD: Biochemical research methods Impact factor: 10.162, year: 2016 https:// academic .oup.com/nar/article-lookup/doi/10.1093/nar/gkw853

  12. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.

    Secrest, Matthew H; Udell, Jacob A; Filion, Kristian B

    2017-04-01

    In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    Ramadan, Ahmed M Ali; Eissa, Hala F.; El-Domyati, Fotouh M.; Saleh, Osama Mesilhy; Ibrahim, Nasser E.; Salama, M. I.; Mahfouz, Magdy M.; Bahieldin, Ahmed M.

    2011-01-01

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  14. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    Ramadan, Ahmed M Ali

    2011-06-26

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  15. Classification of Breast Cancer Resistant Protein (BCRP) Inhibitors and Non-Inhibitors Using Machine Learning Approaches.

    Belekar, Vilas; Lingineni, Karthik; Garg, Prabha

    2015-01-01

    The breast cancer resistant protein (BCRP) is an important transporter and its inhibitors play an important role in cancer treatment by improving the oral bioavailability as well as blood brain barrier (BBB) permeability of anticancer drugs. In this work, a computational model was developed to predict the compounds as BCRP inhibitors or non-inhibitors. Various machine learning approaches like, support vector machine (SVM), k-nearest neighbor (k-NN) and artificial neural network (ANN) were used to develop the models. The Matthews correlation coefficients (MCC) of developed models using ANN, k-NN and SVM are 0.67, 0.71 and 0.77, and prediction accuracies are 85.2%, 88.3% and 90.8% respectively. The developed models were tested with a test set of 99 compounds and further validated with external set of 98 compounds. Distribution plot analysis and various machine learning models were also developed based on druglikeness descriptors. Applicability domain is used to check the prediction reliability of the new molecules.

  16. Aggregation of trypsin and trypsin inhibitor by Al cation.

    Chanphai, P; Kreplak, L; Tajmir-Riahi, H A

    2017-04-01

    Al cation may trigger protein structural changes such as aggregation and fibrillation, causing neurodegenerative diseases. We report the effect of Al cation on the solution structures of trypsin (try) and trypsin inhibitor (tryi), using thermodynamic analysis, UV-Visible, Fourier transform infrared (FTIR) spectroscopic methods and atomic force microscopy (AFM). Thermodynamic parameters showed Al-protein bindings occur via H-bonding and van der Waals contacts for trypsin and trypsin inhibitor. AFM showed that Al cations are able to force trypsin into larger or more robust aggregates than trypsin inhibitor, with trypsin 5±1 SE (n=52) proteins per aggregate and for trypsin inhibitor 8.3±0.7 SE (n=118). Thioflavin T test showed no major protein fibrillation in the presence of Al cation. Al complexation induced more alterations of trypsin inhibitor conformation than trypsin. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Recent Natural Corrosion Inhibitors for Mild Steel: An Overview

    Marko Chigondo

    2016-01-01

    Full Text Available Traditionally, reduction of corrosion has been managed by various methods including cathodic protection, process control, reduction of the metal impurity content, and application of surface treatment techniques, as well as incorporation of suitable alloys. However, the use of corrosion inhibitors has proven to be the easiest and cheapest method for corrosion protection and prevention in acidic media. These inhibitors slow down the corrosion rate and thus prevent monetary losses due to metallic corrosion on industrial vessels, equipment, or surfaces. Inorganic and organic inhibitors are toxic and costly and thus recent focus has been turned to develop environmentally benign methods for corrosion retardation. Many researchers have recently focused on corrosion prevention methods using green inhibitors for mild steel in acidic solutions to mimic industrial processes. This paper provides an overview of types of corrosion, corrosion process, and mainly recent work done on the application of natural plant extracts as corrosion inhibitors for mild steel.

  18. Polyaspartic acid as a green corrosion inhibitor for carbon steel

    Cui, R. [Department of Chemistry, Hebei Normal University, Shijiazhuang 050016 (China); Department of Chemistry and Materials Engineering, Changshu Institute of Technology, Changshu 215500 (China); Gu, N.; Li, C. [Department of Chemistry, Hebei Normal University, Shijiazhuang 050016 (China)

    2011-04-15

    The inhibitor effect of the environmentally friendly corrosion inhibitor polyaspartic acid (PASP) on the corrosion of carbon steel in 0.5 M H{sub 2}SO{sub 4} was investigated by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). Polarization curve results clearly reveal the fact that PASP is a good anode-type inhibitor. EIS results confirm its corrosion inhibition ability. The inhibition efficiency increases with increasing PASP concentration, and the maximum inhibition efficiency was 80.33% at 10 C. SEM reveals that a protective film forms on the surface of the inhibited sample. The adsorption of this inhibitor is found to follow the Freundlich adsorption isotherm. A mechanism is proposed to explain the inhibitory action of the corrosion inhibitor. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  19. Peptide inhibitors of botulinum neurotoxin by mRNA display

    Yiadom, Kwabena P.A.B.; Muhie, Seid; Yang, David C.H.

    2005-01-01

    Botulinum neurotoxins (BoNTs) are extremely toxic. The metalloproteases associated with the toxins cleave proteins essential for neurotransmitter secretion. Inhibitors of the metalloprotease are currently sought to control the toxicity of BoNTs. Toward that goal, we produced a synthetic cDNA for the expression and purification of the metalloprotease of BoNT/A in Escherichia coli as a biotin-ubiquitin fusion protein, and constructed a combinatorial peptide library to screen for BoNT/A light chain inhibitors using mRNA display. A protease assay was developed using immobilized intact SNAP-25 as the substrate. The new peptide inhibitors showed a 10-fold increase in affinity to BoNT/A light chain than the parent peptide. Interestingly, the sequences of the new peptide inhibitors showed abundant hydrophobic residues but few hydrophilic residues. The results suggest that mRNA display may provide a general approach in developing peptide inhibitors of BoNTs

  20. Potent Inhibitors against Newcastle Disease Virus Hemagglutinin-Neuraminidase.

    Rota, Paola; La Rocca, Paolo; Piccoli, Marco; Montefiori, Marco; Cirillo, Federica; Olsen, Lars; Orioli, Marica; Allevi, Pietro; Anastasia, Luigi

    2018-02-06

    Neuraminidase activity is essential for the infection and propagation of paramyxoviruses, including human parainfluenza viruses (hPIVs) and the Newcastle disease virus (NDV). Thus, many inhibitors have been developed based on the 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid inhibitor (DANA) backbone. Along this line, herein we report a series of neuraminidase inhibitors, having C4 (p-toluenesulfonamido and azido substituents) and C5 (N-perfluorinated chains) modifications to the DANA backbone, resulting in compounds with 5- to 15-fold greater potency than the currently most active compound, the N-trifluoroacetyl derivative of DANA (FANA), toward the NDV hemagglutinin-neuraminidase (NDV-HN). Remarkably, these inhibitors were found to be essentially inactive against the human sialidase NEU3, which is present on the outer layer of the cell membrane and is highly affected by the current NDV inhibitor FANA. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Potential non-oncological applications of histone deacetylase inhibitors.

    Ververis, Katherine; Karagiannis, Tom C

    2011-01-01

    Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

  2. Organization of the gene coding for human protein C inhibitor (plasminogen activator inhibitor-3). Assignment of the gene to chromosome 14

    Meijers, J. C.; Chung, D. W.

    1991-01-01

    Protein C inhibitor (plasminogen activator inhibitor-3) is a plasma glycoprotein and a member of the serine proteinase inhibitor superfamily. In the present study, the human gene for protein C inhibitor was isolated and characterized from three independent phage that contained overlapping inserts

  3. Classification of Cytochrome P450 1A2 Inhibitors and Non-Inhibitors by Machine Learning Techniques

    Vasanthanathan, Poongavanam; Taboureau, Olivier; Oostenbrink, Chris

    2009-01-01

    of CYP1A2 inhibitors and non-inhibitors. Training and test sets consisted of about 400 and 7000 compounds, respectively. Various machine learning techniques, like binary QSAR, support vector machine (SVM), random forest, kappa nearest neighbors (kNN), and decision tree methods were used to develop...

  4. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays

    M. Pieters (Marlien); S.A. Barnard (Sunelle A.); D.T. Loots (Du Toit); D.C. Rijken (Dingeman)

    2017-01-01

    textabstractDue to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable) on various plasminogen activator inhibitor-1 and plasminogen

  5. Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection

    Borges, Álvaro H; Lundh, Andreas; Tendal, Britta

    2016-01-01

    BACKGROUND: Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS: ...

  6. Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

    Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

    2002-11-04

    A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

  7. Additives as corrosion inhibitors in reinforced concrete

    Venegas, Ricardo; Vera, Rosa; Carvajal, Ana Maria; Villarroel, Maria; Vera, Enrique; Ortiz, Cesar

    2008-01-01

    This work studies the behavior of two additives as inhibitors of corrosion in reinforced concrete. The presence of Microsilica, a physical inhibitor, in the mixture decreases pore size in structures and improves compression. Calcium Nitrite, a chemical inhibitor, is an oxidizing agent and allows a more homogenous film to form over the steel that becomes more resistant to attacks from aggressive ions like anion chloride and others. Three pairs of concrete test pieces were used without additives and with additives with a/c ration of 0.55. The samples were exposed to an accelerated attack of chlorides, submerging them in a 4.27 M solution of NaCl for 24 hours and then drying them at room temperature for another 24 hours, completing a cycle every 48 hours. The tests were carried out at 1 cycle and 5 cycles of partial moistening and drying. The steel corrosion was evaluated with corrosion potential measurements. Conductivity, pH, chlorides and sulfate profiles were defined depending on the depth of the concrete. The composition of the corrosion products was determined using X-ray diffraction and the morphology of the film by scanning electron microscopy. The results show that for 1 test cycle, the corrosion potential of the steel in the sample with calcium nitrite was -54mV, which was a higher value than that measured in the sample with microsilica (-217.3mV) and without an additive (-159.1mV), corroborating its inhibitory power. The content of the free chlorides in the sample with micros ice allows greater capillary suction by adding high amounts of chloride to the structure (2.6% on the outside up to 2.20% near the steel); while the test pieces with calcium nitrite and without an additive had concentrations lower than 2% in all the evaluated points. After five cycles of exposing the samples to the saline solution the behavior is inverted. The measures of conductivity agreed with the previous results. Meanwhile, the pH of the solutions obtained from the powder from the

  8. Urinary trypsin inhibitor - an experimental and clinical study

    Berling, B.M.

    1991-01-01

    The urinary trypsin inhibitor (UTI) is an acid stable proteinase inhibitor present in blood and urine. It was purified from urine using affinity chromatography, ion exchange chromatography and gel filtration. Two forms of UTI were present in urine, A and B. A radioimmunoassay for measurement of UTI in urine and plasma was performed. The normal level of UTI in plasma and serum was about 2 mg/l. The normal excretion in urine was about 8 mg per 24 hours. The plasma and urine levels of UTI were studied in patients with acute pancreatitis and in patients undergoing cholecystectomy. Uremic patients had a marked increase of UTI in plasma compatible with decreased glomerular filtration. In samples from healthy persons as well as from patients only inhibitor A was found. Inhibitor B has recently been renamed bikunin because of its two Kunitz-type inhibiting domains. Inhibitor A might be called tetrakunin. Radioactively labeled UTI (inhibitor A) was injected intravenously in three male volunteers. The plasma half-life of 125 I UTI was 2 hours. Free biologically active inhibitor was found in the urine during the first four hours after injection. The organ distribution of intravenously injected 125 I UTI was studied in rats. Fifteen minutes after injection the major part of the radioactivity was found in the kidneys, suggesting that the kidneys are the primary site of UTI metabolism. Using immunohistochemical techniques UTI was found in the proximal tubules of the normal human kidney further indicating the tubular reabsorption and methabolisms of UTI

  9. A novel class of small molecule inhibitors of HDAC6.

    Inks, Elizabeth S; Josey, Benjamin J; Jesinkey, Sean R; Chou, C James

    2012-02-17

    Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified in vitro. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor's selective toxicity against leukemia.

  10. A novel method for screening the glutathione transferase inhibitors

    Węgrzyn Grzegorz

    2009-03-01

    Full Text Available Abstract Background Glutathione transferases (GSTs belong to the family of Phase II detoxification enzymes. GSTs catalyze the conjugation of glutathione to different endogenous and exogenous electrophilic compounds. Over-expression of GSTs was demonstrated in a number of different human cancer cells. It has been found that the resistance to many anticancer chemotherapeutics is directly correlated with the over-expression of GSTs. Therefore, it appears to be important to find new GST inhibitors to prevent the resistance of cells to anticancer drugs. In order to search for glutathione transferase (GST inhibitors, a novel method was designed. Results Our results showed that two fragments of GST, named F1 peptide (GYWKIKGLV and F2 peptide (KWRNKKFELGLEFPNL, can significantly inhibit the GST activity. When these two fragments were compared with several known potent GST inhibitors, the order of inhibition efficiency (measured in reactions with 2,4-dinitrochlorobenzene (CDNB and glutathione as substrates was determined as follows: tannic acid > cibacron blue > F2 peptide > hematin > F1 peptide > ethacrynic acid. Moreover, the F1 peptide appeared to be a noncompetitive inhibitor of the GST-catalyzed reaction, while the F2 peptide was determined as a competitive inhibitor of this reaction. Conclusion It appears that the F2 peptide can be used as a new potent specific GST inhibitor. It is proposed that the novel method, described in this report, might be useful for screening the inhibitors of not only GST but also other enzymes.

  11. Indanones as high-potency reversible inhibitors of monoamine oxidase.

    Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

    2015-05-01

    Recent reports document that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is an appropriate scaffold for the design of high-potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between α-tetralone and 1-indanone, the present study involved synthesis of 34 1-indanone and related indane derivatives as potential inhibitors of recombinant human MAO-A and MAO-B. The results show that C6-substituted indanones are particularly potent and selective MAO-B inhibitors, with IC50 values ranging from 0.001 to 0.030 μM. C5-Substituted indanone and indane derivatives are comparatively weaker MAO-B inhibitors. Although the 1-indanone and indane derivatives are selective inhibitors of the MAO-B isoform, a number of homologues are also potent MAO-A inhibitors, with three homologues possessing IC50 values 1-indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1-indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Synthesis of tritium labeled renin inhibitor ditekiren

    Hsi, R.S.P.; Stolle, W.T.; Bundy, G.L.

    1994-01-01

    In the search for a radioactive form of the peptidomimetic renin inhibitor, ditekiren, with a metabolically suitable radiolabel for conducting drug disposition studies, we prepared [ 3 H]ditekiren with tritium labels in the N-methyl-histidine moiety and in the leu-val alcohol transition-state insert. [His- 3 H]ditekiren was obtained by first introducing two iodine substituents into the N-methyl-histidine moiety of the parent drug, followed by catalytic hydrodehalogenation with tritium gas. Administration of this labeled drug to monkeys, however, resulted in prolonged retention of radioactivity in the test animals, even though little or no tritiated water was detected in urine. The results, together with similar earlier findings after administration of [ 3 H]ditekiren labeled in the proline moiety of the drug, led us to synthesize [ 3 H]ditekiren labeled in the ''unnatural'' leu-val alcohol (LVA) portion of the molecule. The tritium label in [LVA- 3 H]ditekiren was found to be metabolically suitable for conducting drug disposition studies, with no liability for tritiated water production or prolonged retention of radioactivity in tissues of test animals. (author)

  13. Aromatase inhibitors in stimulated IVF cycles

    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

  14. Immunomodulatory effects of histone deacetylase inhibitors.

    Licciardi, P V; Ververis, K; Tang, M L; El-Osta, A; Karagiannis, T C

    2013-05-01

    Histone deacetylase inhibitors (HDACi) have emerged as a new generation of anticancer therapeutics. The classical broad-spectrum HDACi typically alter the cell cycle distribution and induce cell death, apoptosis and differentiation in malignant and transformed cells. This provides the basis for the clinical potential of HDACi in cancer therapy. Currently two compounds, suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza™) and depsipeptide (Romidepsin, Istodax™) have been approved for by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Apart from clinical application in oncology, HDACi have also been investigated as potential therapeutics for various pathologies including those of the central nervous system (such as Huntington's disease and multiple sclerosis), cardiac conditions (particularly hypertrophy), arthritis and malaria. Further, evidence is accumulating for potent immunomodulatory effects of classical HDACi which is the focus of this review. We review the antiinflammatory effects of HDACi and in particular findings implicating regulation of the innate and adaptive immune systems by HDAC enzymes. The recent findings highlighting the immunomodulatory function of HDAC11 which relates to balancing immune activation versus tolerance are also discussed.

  15. Inhibitors of Ras-SOS Interactions.

    Lu, Shaoyong; Jang, Hyunbum; Zhang, Jian; Nussinov, Ruth

    2016-04-19

    Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Potential Expanded Indications for Neprilysin Inhibitors

    Riddell, Elizabeth; Vader, Justin M.

    2017-01-01

    Purpose of review The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease. Recent findings Randomized trial data are lacking for use of sacubitril/valsartan in acute heart failure and advanced heart failure. Mechanistic data from animal studies suggest a role for neprilysin inhibition in the treatment of post-myocardial infarction systolic dysfunction and heart failure with preserved ejection fraction. Beyond the cardiovascular system, renal and neurological function may be impacted by neprilysin inhibition. Forthcoming randomized trials will address the clinical impact of sacubitril/valsartan on these conditions. Summary Neprolysin inhibition with sacubitril/valsartan offers a new therapeutic strategy with a broad range of potential therapeutic actions. In PARADIGM-HF, the combination of neprolysin and RAAS inhibition was proven to be superior to enalapril for patients with stable NYHA class II–III heart failure and reduced left ventricular ejection fraction. Preliminary data suggests it may also have a role in other cardiovascular and non-cardiovascular disease. Several ongoing and planned studies will determine the extent of its benefit for these other indications. PMID:28281174

  17. Enzymes and Inhibitors in Neonicotinoid Insecticide Metabolism

    Shi, Xueyan; Dick, Ryan A.; Ford, Kevin A.; Casida, John E.

    2009-01-01

    Neonicotinoid insecticide metabolism involves considerable substrate specificity and regioselectivity of the relevant CYP450, aldehyde oxidase, and phase II enzymes. Human CYP450 recombinant enzymes carry out the following conversions: CYP3A4, 2C19 and 2B6 for thiamethoxam (TMX) to clothianidin (CLO); 3A4, 2C19 and 2A6 for CLO to desmethyl-CLO; 2C19 for TMX to desmethyl-TMX. Human liver aldehyde oxidase reduces the nitro substituent of CLO to nitroso much more rapidly than that of TMX. Imidacloprid (IMI), CLO and several of their metabolites do not give detectable N-glucuronides but 5-hydroxy-IMI, 4,5-diol-IMI and 4-hydroxy-thiacloprid are converted to O-glucuronides in vitro with mouse liver microsomes and UDP-glucuronic acid or in vivo in mice. Mouse liver cytosol with S-adenosylmethionine converts desmethyl-CLO to CLO but not desmethyl-TMX to TMX. Two organophosphorus CYP450 inhibitors partially block IMI, thiacloprid and CLO metabolism in vivo in mice, elevating the brain and liver levels of the parent compounds while reducing amounts of the hydroxylated metabolites. PMID:19391582

  18. ADPRT inhibitors and hyperthermia as radiosensitizers

    Jonsson, G.G.

    1985-01-01

    Hyperthermia given in combination with gamma radiation has given considerable improvement in the therapeutic results for treatment of malignant tumors. The mechanism behind the hyperthermia effect is probably operative at the tissue level as well as at the molecular level. The metabolism of NAD + in relation to the activity of the chromosomal enzyme ADP-ribosyl transferase (ADPRT) has been studied as a possible molecular mechanism for this effect. The ADPRT activity was measured after radiosensitization with both hyperthermia and nicotinamide, which is a potent inhibitor of ADPRT. The results indicate that hyperthermia can improve the effect of radiotherapy by reducing the supply of NAD + , which is a co-substrate for ADPRT, while nicotinamide functions as a radiosensitizing agent by direct inhibition of the enzyme. The hypothesis is discussed in the thesis where inhibition of ADPRT might increase the radiosensitivity because the radiation-induced DNA damage can not be repaired with normal efficiency. The function of nicotinamide as a radiosensitizer was verified by studies on C3H mice with transplanted spontaneous mammary tumors. Because nicotinamide is not toxic, it seems quite attractive to test this vitamin as a radiosensitizing agent against human tumors. (251 refs.) (author)

  19. Efflux inhibitor suppresses Streptococcus mutans virulence properties.

    Zeng, Huihui; Liu, Jia; Ling, Junqi

    2017-04-01

    It is well established that efflux pumps play important roles in bacterial pathogenicity and efflux inhibitors (EIs) have been proved to be effective in suppressing bacterial virulence properties. However, little is known regarding the EI of Streptococcus mutans, a well-known caries-inducing bacterium. In this study, we identified the EI of S. mutans through ethidium bromide efflux assay and investigated how EI affected S. mutans virulence regarding the cariogenicity and stress response. Results indicated that reserpine, the identified EI, suppressed acid tolerance, mutacin production and transformation efficiency of S. mutans, and modified biofilm architecture and extracellular polysaccharide distribution. Suppressed glycosyltransferase activity was also noted after reserpine exposure. The data from quantitative real-time-PCR demonstrated that reserpine significantly altered the expression profile of quorum-sensing and virulence-associated genes. These findings suggest that reserpine represents a promising adjunct anticariogenic agent in that it suppresses virulence properties of S. mutans. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. In silico development of new acetylcholinesterase inhibitors.

    Pascoini, A L; Federico, L B; Arêas, A L F; Verde, B A; Freitas, P G; Camps, I

    2018-04-19

    In this work, we made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors. AChE is associated with Alzheimer's disease (AD). It was found that the cholinergic pathways in the cerebral cortex are compromised in AD and the accompanying cholinergic deficiency contributes to the cognitive deterioration of AD patients. In the FBDD approach, fragments are docked into the active site of the protein. As fragments are molecular groups with a low number of atoms, it is possible to study their interaction with localized amino acids. Once the interactions are measured, the fragments are organized by affinity and then linked together to form new molecules with a high degree of interaction with the active site. In the other approach, we used the de novo design technique starting from reference drugs used in the AD treatment. These drugs were broken into fragments (seeds). In the growing strategy, fragments were added to each seed, growing new molecules. In the linking strategy, two or more separated seeds were linked with different fragments. Both strategies combined produced a library of more than 2 million compounds. This library was filtered using absorption, distribution, metabolism, and excretion properties. The resulting library with around six thousand compounds was filtered again. In this case, structures with Tanimoto coefficients >.85 were discarded. The final library with 1500 compounds was submitted to docking studies. As a result, 10 compounds with better interaction energy than the reference drugs were obtained.

  1. Reverse transcriptase inhibitors as potential colorectal microbicides.

    Herrera, Carolina; Cranage, Martin; McGowan, Ian; Anton, Peter; Shattock, Robin J

    2009-05-01

    We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.

  2. Natural sesquiterpen lactones as acetylcholinesterase inhibitors

    HOMA HAJIMEHDIPOOR

    2014-06-01

    Full Text Available Background and the purpose of the study: The amount of elder people who suffer from Alzheimer disease is continuously increasing every year. Cholinesterase inhibitors have shown to be effective in alleviating the symptoms of the disease, thus opening a field of research for these treatments. Herbal products, owning a reputation as effective agents in many biological studies are now drawing attention for inhibiting acetylcholinesterase, in other words, Alzheimer disease. In the present study, the ability of three sesquiterpene lactones from Inula oculus-christi and I. aucheriana to inhibit AChE has been evaluated through Ellman assay.Materials and Methods: Gaillardin and pulchellin C were obtained from I. oculus-christi and britannin from I. aucheriana by chromatographic methods. They were dissolved in methanol in concentration of 3 mg/mL and the AChEI activity of the compounds was determined by Ellman method using Acethylthiocholine iodide as the substrate and 5, 5′-dithiobis-2-nitrobenzoic acid as the reagent, in 96-well plates at 405 nm.Results: AChEI activity of the examined compounds was obtained as 67.0, 25.2 and 10.9% in concentration of 300 µg/L for gaillardin, britannin and pulchellin C, respectively.Conclusion: Among the three sesquiterpene lactones, gaillardin with 67% inhibition of AChE could be considered a good candidate for future Alzheimer studies.

  3. Suppression of Coronavirus Replication by Cyclophilin Inhibitors

    Takashi Sasaki

    2013-05-01

    Full Text Available Coronaviruses infect a variety of mammalian and avian species and cause serious diseases in humans, cats, mice, and birds in the form of severe acute respiratory syndrome (SARS, feline infectious peritonitis (FIP, mouse hepatitis, and avian infectious bronchitis, respectively. No effective vaccine or treatment has been developed for SARS-coronavirus or FIP virus, both of which cause lethal diseases. It has been reported that a cyclophilin inhibitor, cyclosporin A (CsA, could inhibit the replication of coronaviruses. CsA is a well-known immunosuppressive drug that binds to cellular cyclophilins to inhibit calcineurin, a calcium-calmodulin-activated serine/threonine-specific phosphatase. The inhibition of calcineurin blocks the translocation of nuclear factor of activated T cells from the cytosol into the nucleus, thus preventing the transcription of genes encoding cytokines such as interleukin-2. Cyclophilins are peptidyl-prolyl isomerases with physiological functions that have been described for many years to include chaperone and foldase activities. Also, many viruses require cyclophilins for replication; these include human immunodeficiency virus, vesicular stomatitis virus, and hepatitis C virus. However, the molecular mechanisms leading to the suppression of viral replication differ for different viruses. This review describes the suppressive effects of CsA on coronavirus replication.

  4. Clinically Applicable Inhibitors Impacting Genome Stability.

    Prakash, Anu; Garcia-Moreno, Juan F; Brown, James A L; Bourke, Emer

    2018-05-13

    Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.

  5. SGLT2 Inhibitors in Diabetes Mellitus Treatment.

    Rosas-Guzman, Juan; Rosas-Saucedo, Juan; Romero-Garcia, Alma R J

    2017-01-01

    Type 2 Diabetes Mellitus (T2DM) is a chronic illness with high prevalence in Mexico, Latin- America, and the world and is associated to high morbidity, disability, and mortality rate, especially in developing countries. T2DM physiopathology is very complex; insulin resistance in the muscle, liver, and adipose tissue, a reduction in the production of incretins (mainly GLP-1) in the intestine, increased glucagon synthesis, an insufficient response of insulin generation, and increased glucose reabsorption in the kidney lead all together to an hyperglycemic state, which has been closely associated with the development of micro and macrovascular complications. Sodium Glucose Linked Transporter 2 inhibitors (SGLT2i) are the most recent therapeutic class available for treating T2DM. SGLT2i central effect is a glycosuric action, and they can reverse the deleterious effect of tubular reabsorption of glucose in the diabetic patient resulting in greater hyperglycemia. Because their mechanism of action is completely different to current drugs, they can be considered as monotherapy or in combination with any other oral or parenteral medication, including different types of insulin or its analogues. This therapeutic synergy accomplishes a greater percentage of patients achieving glycemic control goals. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Interpreting clinical assays for histone deacetylase inhibitors

    Martinet, Nadine; Bertrand, Philippe

    2011-01-01

    As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When “imprinted” early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulation, epigenetic modifications participate in the malignant transformation of cells. Their reversible nature has led to the emergence of the promising field of epigenetic therapy. The efforts made to inhibit in particular the epigenetic enzyme family called histone deacetylases (HDACs) are described. HDAC inhibitors (HDACi) have been proposed as a viable clinical therapeutic approach for the treatment of leukemia and solid tumors, but also to a lesser degree for noncancerous diseases. Three epigenetic drugs are already arriving at the patient’s bedside, and more than 100 clinical assays for HDACi are registered on the National Cancer Institute website. They explore the eventual additive benefits of combined therapies. In the context of the pleiotropic effects of HDAC isoforms, more specific HDACi and more informative screening tests are being developed for the benefit of the patients

  7. A novel small molecule inhibitor of hepatitis C virus entry.

    Carl J Baldick

    Full Text Available Small molecule inhibitors of hepatitis C virus (HCV are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc, blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.

  8. Inhibitor development and mortality in non-severe hemophilia A.

    Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

    2015-07-01

    The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

  9. Janus Associated Kinases Inhibitors in the Pharmacological Thera

    Daniela Santos1

    2017-01-01

    Full Text Available Janus associated kinases inhibitors are a new strategy for the treatment of different clinical conditions like immunologic, inflammatory and oncology disorders. The aim of this study was to perform a review of all Janus associated kinases inhibitors available in national and international pharmaceutical market, their therapeutic indications and adverse effects, and the potential indications for investigation of those already available in the pharmaceutical market. It was also performed a review of the main new Janus associated kinases inhibitors that are still in clinical research. A literature review was conducted by consulting the summary of product characteristics of Janus associated kinases inhibitors available in the pharmaceutical market and a research in the bibliographic database PubMed using the terms «JAK inhibitors», «Janus associated kinases inhibitors» and «Janus kinases inhibitors». Ninety-five publications were included in the present review, published from January 2014 to January 2015. Drug databases of the European Medicines Agency and United States Food and Drug Administration were also consulted to search for Janus associated kinases inhibitors authorized in clinical practice. Currently, ruxolitinib and tofacitinib are available in the pharmaceutical market and oclatinib is approved as a veterinary medicinal product. Both drugs approved for human use have major adverse effects at hematological and immunological levels, which enhance the importance of the pharmacist’s role in the monitoring of patients involved in these treatments. However, several molecules are in pre-clinical and clinical studies trying to prove its potential in the treatment of several immunologic, inflammatory and oncology disorders. Thus, it is still necessary to deepen the knowledge in this area in order to overcome the risks of therapy with these agents. These risks weighed against the benefits of its clinical use have compromised the progress of

  10. New synthetic thrombin inhibitors: molecular design and experimental verification.

    Sinauridze, Elena I; Romanov, Alexey N; Gribkova, Irina V; Kondakova, Olga A; Surov, Stepan S; Gorbatenko, Aleksander S; Butylin, Andrey A; Monakov, Mikhail Yu; Bogolyubov, Alexey A; Kuznetsov, Yuryi V; Sulimov, Vladimir B; Ataullakhanov, Fazoyl I

    2011-01-01

    The development of new anticoagulants is an important goal for the improvement of thromboses treatments. The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. New compounds that are both effective direct thrombin inhibitors (the best K(I) was 50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications.

  11. Serial 5-Year Evaluation of Side Branches Jailed by Bioresorbable Vascular Scaffolds Using 3-Dimensional Optical Coherence Tomography: Insights From the ABSORB Cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions).

    Onuma, Yoshinobu; Grundeken, Maik J; Nakatani, Shimpei; Asano, Taku; Sotomi, Yohei; Foin, Nicolas; Ng, Jaryl; Okamura, Takayuki; Wykrzykowska, Joanna J; de Winter, Robbert J; van Geuns, Robert-Jan; Koolen, Jacques; Christiansen, Evald; Whitbourn, Robert; McClean, Dougal; Smits, Pieter; Windecker, Stephan; Ormiston, John A; Serruys, Patrick W

    2017-09-01

    The long-term fate of Absorb bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, CA) struts jailing side branch ostia has not been clarified. We therefore evaluate serially (post-procedure and at 6 months, 1, 2, 3, and 5 years) the appearance and fate of jailed Absorb bioresorbable vascular scaffold struts. We performed 3-dimensional optical coherence tomographic analysis of the ABSORB Cohort B trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) up to 5 years using a novel, validated cut-plane analysis method. We included 29 patients with a total of 85 side branch ostia. From the 12 ostia which could be assessed in true serial fashion, 7 showed a pattern of initial decrease in the ostial area free from struts, followed by an increase in strut-free ostial area toward the end of the 5 years of follow-up. In a repeated-measures analysis with time as fixed variable and ostial area free from struts as dependent variable, we showed a numeric decrease in the estimated ostial area free from struts from 0.75 mm 2 (baseline) to 0.68 mm 2 (first follow-up visit at 6 months or 1 year) and 0.63 mm 2 (second follow-up visit at 2 or 3 years). However, from the second visit to the 5-year follow-up visit, there was a statistically significant increase from 0.63 to 0.89 mm 2 ( P =0.001). Struts overlying an ostium divided the ostium into compartments, and the number of these compartments decreased over time. This study showed that in most cases, the side branch ostial area free from struts initially decreased. However, with full scaffold bioresorption, the ostial area free from scaffold increased between 2 to 3 years and 5 years in the vast majority of patients. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856856. © 2017 American Heart Association, Inc.

  12. High-throughput screening to identify inhibitors of lysine demethylases.

    Gale, Molly; Yan, Qin

    2015-01-01

    Lysine demethylases (KDMs) are epigenetic regulators whose dysfunction is implicated in the pathology of many human diseases including various types of cancer, inflammation and X-linked intellectual disability. Particular demethylases have been identified as promising therapeutic targets, and tremendous efforts are being devoted toward developing suitable small-molecule inhibitors for clinical and research use. Several High-throughput screening strategies have been developed to screen for small-molecule inhibitors of KDMs, each with advantages and disadvantages in terms of time, cost, effort, reliability and sensitivity. In this Special Report, we review and evaluate the High-throughput screening methods utilized for discovery of novel small-molecule KDM inhibitors.

  13. The 'retro-design' concept for novel kinase inhibitors.

    Müller, Gerhard; Sennhenn, Peter C; Woodcock, Timothy; Neumann, Lars

    2010-07-01

    Protein kinases are among the most attractive therapeutic targets for a broad range of diseases. This feature review highlights and classifies the main design principles employed to generate active and selective kinase inhibitors. In particular, emphasis is focused on a fragment-based lead-generation approach, which constitutes a novel design method for developing type II kinase inhibitors with distinct binding kinetic attributes. This 'retro-design' strategy relies on a customized fragment library, and contrasts the traditional approach used in the design of type II inhibitors.

  14. Acalabrutinib (ACP-196: a selective second-generation BTK inhibitor

    Jingjing Wu

    2016-03-01

    Full Text Available Abstract More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton’s tyrosine kinase (BTK inhibitor, ibrutinib, has been in clinical use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292 are being explored. Acalabrutinib (ACP-196 is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib.

  15. Structure based design of 11β-HSD1 inhibitors.

    Singh, Suresh; Tice, Colin

    2010-11-01

    Controlling elevated tissue-specific levels of cortisol may provide a novel therapeutic approach for treating metabolic syndrome. This concept has spurred large scale medicinal chemistry efforts in the pharmaceutical industry for the design of 11β-HSD1 inhibitors. High resolution X-ray crystal structures of inhibitors in complex with the enzyme have facilitated the structure-based design of diverse classes of molecules. A summary of binding modes, trends in structure-activity relationships, and the pharmacodynamic data of inhibitors from each class is presented.

  16. HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

    Vanangamudi, Murugesan; Poongavanam, Vasanthanathan; Namasivayam, Vigneshwaran

    2017-01-01

    BACKGROUND: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising......: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine...

  17. HIV protease drug resistance and its impact on inhibitor design.

    Ala, P J; Rodgers, J D; Chang, C H

    1999-07-01

    The primary cause of resistance to the currently available HIV protease inhibitors is the accumulation of multiple mutations in the viral protease. So far more than 20 substitutions have been observed in the active site, dimer interface, surface loops and flaps of the homodimer. While many mutations reduce the protease's affinity for inhibitors, others appear to enhance its catalytic efficiency. This high degree of genetic flexibility has made the protease an elusive drug target. The design of the next generation of HIV protease inhibitors will be discussed in light of the current structural information.

  18. Bicyclic peptide inhibitor of urokinase-type plasminogen activator

    Roodbeen, Renée; Jensen, Berit Paaske; Jiang, Longguang

    2013-01-01

    The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptide-based inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established...... investigated the solution structures of the bicyclic peptide by NMR spectroscopy to map possible conformations. An X-ray structure of the bicyclic-peptide-uPA complex confirmed an interaction similar to that for the previous upain-1/upain-2-uPA complexes. These physical studies of the peptide...

  19. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.

    Robertson, Lindsay; Kesteven, Patrick; McCaslin, James E

    2015-06-30

    Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations. We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). We included

  20. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

    Honma, Daisuke; Kanno, Osamu; Watanabe, Jun; Kinoshita, Junzo; Hirasawa, Makoto; Nosaka, Emi; Shiroishi, Machiko; Takizawa, Takeshi; Yasumatsu, Isao; Horiuchi, Takao; Nakao, Akira; Suzuki, Keisuke; Yamasaki, Tomonori; Nakajima, Katsuyoshi; Hayakawa, Miho; Yamazaki, Takanori; Yadav, Ajay Singh; Adachi, Nobuaki

    2017-10-01

    Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.