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Sample records for combined pegylated interferon

  1. Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts.

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    Tseng, Po-Lin; Chen, Te-Chuan; Chien, Yu-Shu; Hung, Chao-Hung; Yen, Yi-Hao; Chang, Kuo-Chin; Tsai, Ming-Chao; Lin, Ming-Tsung; Lee, Chien-Te; Shen, Chien-Heng; Hu, Tsung-Hui

    2013-10-01

    Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. 2 prospective observational cohort studies. From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. Peginterferon alfa-2b monotherapy, 1.0 μg/kg/wk, versus peginterferon alfa-2b, 1.0 μg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  2. Predicative factors for Pegylated interferon-α plus ribavirin ...

    African Journals Online (AJOL)

    Predicative factors for Pegylated interferon-α plus ribavirin combination therapy in Egyptian patients with chronic Hepatitis Cinfected with genotype 4. SM Massoud, MA Shemis, EA Drees, MA Taha, HA Omar, MA Saber ...

  3. Research progress in combination therapy with pegylated interferon and nucleos(tide analogues in treatment of chronic hepatitis B

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    YU Yiqi

    2015-09-01

    Full Text Available Current antiviral treatment strategy for chronic hepatitis B (CHB includes pegylated interferon (PEG-IFN and nucleos(tide analogues (NAs. Whether combination therapy with PEG-IFN and NAs improve therapeutic efficacy has become the key question regarding the antiviral therapy for CHB. This article reviews the recent progress in combination therapy for the management of CHB. The results indicate that the efficacy of simultaneous combination of PEG-IFN and NAs is not superior to that of PEG-IFN monotherapy in terms of HBeAg seroconversion and response after drug withdrawal. Sequential combination or switching therapy in PEG-IFN- or NAs-treated patients, as well as combination with immune cell therapy, is a promising treatment strategy.

  4. A phase-II study of combination of pegylated interferon alfa-2a and capecitabine in locally advanced or metastatic renal cell cancer.

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    Sunela, Kaisa Leea; Koskinen, Sanna; Kellokumpu-Lehtinen, Pirkko-Liisa

    2010-05-01

    Combination of capecitabine and interferon has shown activity in metastatic renal cell carcinoma. Pegylated interferons might have more clinical activity and fewer side effects. This study evaluated the efficacy, tolerability, and safety of the combination of capecitabine and pegylated interferon alfa-2a. In this open label, single institution, non-randomized phase-II first-line study, 26 patients were included. Capecitabine was administered 2,000 mg/m(2) daily for 14 days followed by 1 week rest. Pegylated interferon alfa-2a was given once as weekly injections with a fixed dose of 180 microg. Overall survival, progression-free survival, and response rates were evaluated; safety and tolerability were monitored. Response rate was 27, with 4% complete responses. Stable disease was achieved in 42%. The treatment discontinued in 4 (15%) patients before first response evaluation because of toxicity. The median progression-free survival was 7.5 months; the median overall survival was 17 months. Grades 3-4 toxicity was seen in 46% of patients, but in 93% of cycles no serious toxicity was experienced. Dose reductions had to be done, but in 81% of cycles intensity of 70% or more was possible. Quality of life was better in cycle five than in the base line. The combination had moderate, but manageable toxicity. In the future studies, lower dose for capecitabine is recommended. The combination was active and the response rates seen here were in line with phase-II studies on former combinations of non-pegylated interferons. One complete remission was achieved.

  5. Combination therapy with pegylated interferon plus ribavirin in the treatment of hepatitis C virus-related thrombocytopenia

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    Karakan, Tarkan; Cindoruk, Mehmet; Degertekin, Bulent; Dogan, Ibrahim; Sancak, Alper; Dumlu, Sukru; Gorgul, Ahmet; Unal, Selahattin

    2005-01-01

    Background: Isolated thrombocytopenia is a common manifestation of hepatitis C virus (HCV) infection. There is no established treatment modality for this condition. The efficacy of standard interferon (IFN) monotherapy has been reported in some studies. The major disadvantage of this treatment is the high rate of recurrence due to viral breakthrough during the first 12 weeks of treatment. Pegylated IFNs are now the standard regimen for chronic hepatic disease due to HCV infection. However, due to a lack of evidence, pegylated IFNs are not widely used for HCV-related isolated thrombocytopenia. Objective: The aim of this report was to present the case of a male patientwith severe symptomatic thrombocytopenia due to HCV infection. Methods: Thrombocytopenia was treated with pegylated IFN plus ribavirin. Results: Although standard IFN monotherapy failed to achieve virologic and hematologic improvement, therapy with pegylated IFN alfa-2a plus ribavirin was associated with both virologic and hematologic improvement without any significant adverse effects. Conclusions: Pegylated IFN plus ribavirin was effective in this patient for thetreatment of HCV-related thrombocytopenia. However, further research is needed to define the response rate in different patient populations. PMID:24764593

  6. Incidence of neutropenia and infections during combination treatment of chronic hepatitis C with pegylated interferon alfa-2a or alfa-2b plus ribavirin.

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    Antonini, M G; Babudieri, S; Maida, I; Baiguera, C; Zanini, B; Fenu, L; Dettori, G; Manno, D; Mura, M S; Carosi, G; Puoti, M

    2008-06-01

    Combination therapy with pegylated interferon (peginterferon) plus ribavirin is associated with several side effects, including neutropenia and infection. To evaluate the incidence of neutropenia and infection between all consecutive patients with hepatitis C who were treated in two centers with peginterferon-alfa-2a and peginterferon-alfa-2b, in combination with ribavirin and actively monitored for occurrence of any infection. A total of 319 consecutive patients with chronic hepatitis C received once-weekly peginterferon alfa-2b at a weight-adjusted dose (n=162) or peginterferon alfa-2a at a flat dose (n=157), plus ribavirin. Neutropenia was observed in 53 patients overall (17%). There were 73 infections in 73 subjects (23% of the treated population); 4/73 required hospitalization. Infections included respiratory infections (n=23), cellulitis (n=17), dental abscesses (n=13), gastroenteric infections (n=2), and other types of infections (n=18). The incidence of all infections was significantly associated with age, especially over 60 years (pinterferon. During the treatment with pegylated interferons and ribavirin, we did not find a correlation between neutropenia and infections. This result provides a support for the notion that current guidelines for pegylated interferons dose reduction in the treatment of chronic hepatitis C for hematologic toxicity could be overly strict.

  7. [Short-term curative effect of ribavirin combination therapy with pegylated interferon alfa-2a vs. interferon alfa-2a in patients with chronic hepatitis C].

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    Wang, Meng; Zheng, Weiyang; Zhang, Hongyu; Li, Zhiqin; Jiang, Dong; Liu, Yanhong; Zhou, Rong; Li, Xiao-Gang; Zhang, Yingying; Zhang, Zhen; Wu, Shuhuan; Zhang, Yi; Li, Jiansheng

    2014-04-01

    To perform a retrospective cohort study in order to determine the differences in short-term curative effect of ribavirin in combination with interferon alfa (IFNa)-2a vs. pegylated (Peg)-IFNa-2a in patients with chronic hepatitis C (CHC). One-hundred-and-eighty-eight treatment of the CHC patients who were administered combination therapy of ribavirin with IFNa from 2010 to 2012. One-hundred-and-thirty-three of the patients received the therapy with IFNa-2a and the remaining 55 received Peg-IFNa-2a. Hepatitis C virus (HCV) load and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured at treatment weeks 4, 12, 24, and 48. Adverse reactions were recorded. Differences between the groups were assessed by statistical analysis. The patients in the Peg-IFNa-2a group and the IFNa-2a group showed no significant difference in sex distribution, age, smoking habits, or drinking habits at baseline (all P more than 0.05). Both antiviral therapies significantly reduced the HCV load and levels of ALT and AST (baseline levels vs. all treatment weeks examined, P less than 0.05); however, the reduction in the HCV load at week 4 was significantly more robust with the Peg-IFNa-2a therapy (2.96 ± 0.66) log10 IU/ ml vs. (3.47 ± 1.42)1og10 IU/ml; F =4.14, P=0.04). The Peg-IFNa-2a group also showed a significant higher rate of rapid virological response (RVR) than the IFNa-2a group (72.72% vs .57.14%; x²=4.37, P=0.04), but there were no statistically significant differences found between the two groups for early virological response rate (EVR), endpoint antiviral treatment virologic response rate (ETR), biochemical response rate, or rate of adverse reactions (all P more than 0.05). Ribavirin in combination with Peg-IFNa-2a produces a better RVR than in combination with IFNa-2a .Yet, the EVR, ETR, biochemical response rate, and rate of adverse reactions is similar for the two forms of IFNa-2a. Further studies are required to determine the potential

  8. The effect of pegylated interferon-alpha2b and ribavirin combination therapy for chronic hepatitis C infection in elderly patients

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    Nishikawa Hiroki

    2012-03-01

    Full Text Available Abstract Background The clearance of hepatitis C virus infection by interferon therapy significantly reduces the incidence of hepatocellular carcinoma and death in elderly chronic hepatitis patients. However, there are few reports concerning the efficacy and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in elderly patients. The aims of the present study were to examine the effect and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in 427 patients with chronic hepatitis C infection. We compared the rates of sustained virological response--defined as the absence of detectable hepatitis C virus in serum 24 weeks after the treatment ended--and the treatment discontinuation rate between 319 younger patients aged Results There was no significant difference in the sustained virological response rate between younger patients and elderly patients according to their hepatitis C virus genotype (41.5% (100/241 and 40.7% (35/86 for genotype 1; P = 0.899, 89.7% (70/78 and 86.4% (19/22 for genotype 2; P = 0.703, respectively. There was also no significant difference in the treatment discontinuation rate between the two age groups (10.3% (33/319 and 13.9% (15/108, respectively; P = 0.378. There were no serious adverse events requiring hospitalization. The factors contributing significantly to a sustained virological response in elderly patients were gender, hepatitis C virus genotype, platelet count, and the presence of a rapid or early virological response (undetectable hepatitis C virus in serum at weeks 4 or 12 of treatment, respectively. However, upon multivariate analysis, the presence of an early virological response was the only significant factor (odds ratio: 0.115, 95% confidence interval: 0.040- 0.330, P Conclusions The efficacy and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in elderly patients are not always inferior to those in younger patients. Obtaining an early

  9. Thyrotoxicosis with pegylated interferon alfa-2b.

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    Lowndes, Sarah A; Asher, Ruth; Middleton, Mark R

    2010-11-01

    Despite adequate surgery, a diagnosis of stage III melanoma carries a high risk of relapse, and hence mortality. Interferon alfa is the only treatment that has currently been shown to alter the natural history of the disease, delaying relapse-free survival, particularly in patients with micrometastatic disease. There is also recent evidence of a prognostic advantage conferred by the development of autoimmune conditions in patients receiving adjuvant interferon therapy. We present the case of a 27-year-old woman with stage IIIa melanoma who was entered into the European Organisation for the Research and Treatment of Cancer 18991 trial of 5-year adjuvant treatment with pegylated interferon (peginterferon) alfa-2b. The patient developed thyrotoxicosis 3 months after commencing treatment, which required treatment with propylthiouracil. The degree of thyrotoxicosis corresponded closely to the dose of peginterferon alfa-2b given. However, in this patient, the hyperthyroidism resolved spontaneously after 4 years when peginterferon treatment was still ongoing. Seven years following the initial diagnosis, the patient has not had disease relapse. Hyperthyroidism is less common than hypothyroidism as a consequence of interferon therapy, and this case is atypical in that it resolved spontaneously during interferon therapy but is in accordance with the recent evidence of a positive association between interferon-associated autoimmunity and prognosis.

  10. Synergistic Effects of Jerusalem Artichoke in Combination with Pegylated Interferon Alfa-2a and Ribavirin Against Hepatic Fibrosis in Rats.

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    Abdel-Hamid, Nabil Mohie; Wahid, Ahmed; Nazmy, Maiiada Hassan; Eisa, Marwa Abdel-Moniem

    2016-01-01

    Complementary and alternative medicine has been highly appreciated as a supportive regimen for classical treatment strategies. Here we offer a nutrition-based adjuvant therapy for liver fibrosis, a major risk factor for cirrhosis and hepatocellular carcinoma. To evaluate the possible hepatoprotective effects of Jerusalem artichoke tubers (JAT) in combination with interferon and ribavirin. Twelve groups of rats were administered JAT, interferon and ribavirin either separately or in combination from day one of CCL4 administration until the end of the study. Animals were killed after 8 weeks of CCL4- induced hepatotoxicity. Hepatocytes from rats treated with triple combination of interferon, ribavirin, and JAT showed more less normal architecture compared to CCL4- treated rats. We also detected significantly higher hepatic protein expression levels of p53, BAX and transforming growth factor-β (TGF-β) in the CCl4- intoxicated group compared to normal controls, as evidenced by immunohistochemical staining and western blotting analyses. Addition of JAT as a supportive regimen improved response to ribavirin and interferon and effectively participated in retaining normal histopathological and biochemical criteria and significantly lowered protein expression of p53, BAX, and TGF-β. We suggest that addition of JAT as a supportive regimen to interferon and ribavirin effectively potentiates their anti-fibrotic effects.

  11. Efficacy of combined antiviral therapy with pegylated interferon α-2a and ribavirin for chronic hepatitis C infection in intravenous drug users

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    Ružić Maja

    2010-01-01

    Full Text Available Introduction. Hepatitis C Virus infection represents not just a medical, but also a socio-economic problem. It is estimated that among 170 million infected, 60% belongs to the category of intravenous drug users (IDUs. Objective. The aim of this paper was to compare the response to the combined therapy of pegylated interferon alfa 2a and ribavirin, in the group of patients with HCV infection who were intravenous drug users (IDUs and in patients who were identified in the other way of transmission of HCV. Also to identify the influence of the therapy on diseases of addiction, during the course of HCV infection and on the effects of the combined therapy of pegylated interferon alfa 2a and ribavirin. Methods. We conducted a retrospective-prospective study, on 60 patients, treated with combined antiviral therapy-pegylated interferon alfa 2a and ribavirin. 30 patients were from the group of IDUs, and 30 patients from other epidemiological groups. Results. There were significant differences between the age of the patients (30.2±7.1 vs. 39.3±11.2 years; p=0.002, but no significant difference in the duration of the HCV infection between the two groups of patients (8.9±7.4 vs. 13.1±7.0 years; p>0.05. A large number of the patients in the group of IDUs had a problem with the abstinence of the drug abuse. In this group, there was the influence of alcohol (30% and other substances with potential hepatotoxicity: marihuana (23.3% and psycho-active drugs (73.6%. Staging of the liver fibrosis was not influenced by those two parameters and was similar in both groups (p>0.05. The genotype 3a was dominant in intravenous drug users (50.0% and genotype 1b in the control group of the patients (76.6%. In both groups, SVR was achieved at a higher percentage (86% vs. 70.00%; p>0.05, but among the intravenous drug users the relapses of HCV infection were at a lower percentage (3.3% vs. 20.0%; p=0.044. Side effects were noticed in solitary cases in both of the examined

  12. [Pegylation and interferons in multiple sclerosis

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    Diego Centonze

    2016-07-01

    Full Text Available Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs. [Article in Italian

  13. Prediction of effect of pegylated interferon alpha-2b plus ribavirin combination therapy in patients with chronic hepatitis C infection.

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    Tetsuro Takayama

    Full Text Available Treatment with pegylated interferon alpha-2b (PEGIFN plus ribavirin (RBV is standard therapy for patients with chronic hepatitis C. Although the effectiveness, patients with high titres of group Ib hepatitis C virus (HCV respond poorly compared to other genotypes. At present, we cannot predict the effect in an individual. Previous studies have used traditional statistical analysis by assuming a linear relationship between clinical features, but most phenomena in the clinical situation are not linearly related. The aim of this study is to predict the effect of PEG IFN plus RBV therapy on an individual patient level using an artificial neural network system (ANN. 156 patients with HCV group 1b from multiple centres were treated with PEGIFN (1.5 µg/kg plus RBV (400-1000 mg for 48 weeks. Data on the patients' demographics, laboratory tests, PEGIFN, and RBV doses, early viral responses (EVR, and sustained viral responses were collected. Clinical data were randomly divided into training data set and validation data set and analyzed using multiple logistic regression analysis (MLRs and ANN to predict individual outcomes. The sensitivities of predictive expression were 0.45 for the MLRs models and 0.82 for the ANNs and specificities were 0.55 for the MLR and 0.88 for the ANN. Non-linear relation analysis showed that EVR, serum creatinine, initial dose of Ribavirin, gender and age were important predictive factors, suggesting non-linearly related to outcome. In conclusion, ANN was more accurate than MLRs in predicting the outcome of PEGIFN plus RBV therapy in patients with group 1b HCV.

  14. Osteopontin as a marker for response to pegylated interferon Alpha ...

    African Journals Online (AJOL)

    Osteopontin as a marker for response to pegylated interferon Alpha-2b treatment in Chronic HCV Saudi patients. Yousri Mostafa Hussein, Ayman Alhazmi, Saad Alzahrani, Ahmad El-Askary, Abdulrahman Alghamdy, Eman Bayomy, Assmaa Selim, Mohammed Alghamdy ...

  15. Pegylated interferon alpha-2a combined with ribavirin for chronic hepatitis C: a clinical analysis of 160 patients of Uygur nationality or Han nationality

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    LIN Wei

    2015-11-01

    Full Text Available ObjectiveTo investigate the influencing factors for achieving sustained virological response (SVR to pegylated interferon alpha-2a combined with ribavirin in Uygur and Han patients with chronic hepatitis C, and to provide a reference for predicting the treatment of chronic hepatitis C in Uygur and Han patients. MethodsA retrospective analysis was performed on the clinical data of 160 patients (80 cases of Uygur nationality and 80 cases of Han nationality with chronic hepatitis C who received pegylated interferon alpha-2a combined with ribavirin in the Infectious Disease Hospital in Hetian from January 2012 to March 2014. All patients were followed up for 24 weeks after 48 weeks of treatment. The two groups were compared in terms of the ratios of rapid virological response (RVR, early virological response (EVR, end treated virus response (ETVR, SVR, and no response (NR. The factors which might influence achieving SVR to interferon therapy in the two groups were subjected to univariate analysis and multivariate analysis (conditional logistic regression. For normally distributed continuous data, the comparison was made by t test, and Wilcoxon rank-sum test was made for abnormally distributed continuous data. The comparison of categorical data was made by chi-square test. And univariate analysis and multivariate analysis (conditional logistic regression were carried out. ResultsThere were no significant differences in the rates of RVR (48.8% vs 60.0%, P>0.05, EVR (53.8% vs 63.8%, P>0.05, ETVR (72.5% vs 78.7%, P>0.05, SVR (63.8% vs 72.5%, P>0.05, and NR (27.5% vs 213%, P>0.05 between Uygur group and Han group. The univariate analysis showed that age and age>40 years were the influencing factors for all patients′ SVR (P<0.05. Age>40 years and HCV RNA level>1×106 copies/ml were the influencing factors for Uygur patients′ SVR (P<0.05. Male sex, age, and age>50 years were the influencing factors for Han patients′ SVR (P

  16. Pegylated Interferon (Alone or With Ribavirin for Chronic Hepatitis C in Haemodialysis Population

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    Mario Espinosa

    2015-05-01

    Full Text Available Background/Aims: Hepatitis C virus infection remains prevalent among patients undergoing long-term haemodialysis and has a detrimental impact on survival in this population. Antiviral therapy for chronic hepatitis C in haemodialysis patients is still a challenge to clinicians. The aim of the current study is to evaluate the efficacy and safety of therapy with pegylated interferon, alone or combined with ribavirin, for chronic hepatitis C among patients undergoing long-term hemodialysis. Methods: We conducted a retrospective, multicenter cohort trial with monotherapy (pegylated interferon (n=21 or combined antiviral therapy (pegylated interferon plus ribavirin (n=5 for chronic hepatitis C in patients undergoing long-term haemodialysis. Results: Sustained virological response was obtained in eleven (42% patients. Seven (26.9% patients interrupted prematurely the antiviral treatment due to serious side-effects, the most frequent cause of treatment withdrawal being hematological (n=3. HCV RNA load was lower in responder than non-responder patients, 5.44 (3.45; 6.36 vs. 5.86 (4.61; 6.46 log10 copies/mL, even if the difference was not significant (P=0.099. Blood transfusion requirement was greater in patients on combined antiviral therapy than those on pegylated interferon alone, 100% (5/5 vs. 0% (0/21, P=0.0001. No difference in sustained viral response occurred between patients on combined antiviral therapy and those on pegylated interferon monotherapy [40% (2/5 vs. 42.8% (9/21, P=0.90]. Conclusions: Results from this study showed that pegylated interferon alone or with ribavirin is unsatisfactory in terms of efficacy and safety. Prospective trials based on interferon-free regimens (i.e., sofosbuvir plus ribavirin or sofosbuvir plus daclatasvir are under way in patients with hepatitis C receiving long-term hemodialysis.

  17. Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study.

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    Suda, Goki; Ito, Jun; Nagasaka, Atsushi; Yamamoto, Yoshiya; Furuya, Ken; Okamoto, Munenori; Terashita, Katsumi; Kobayashi, Tomoe; Tsunematsu, Izumi; Yoshida, Junichi; Meguro, Takashi; Ohara, Masatsugu; Kawagishi, Naoki; Kimura, Megumi; Umemura, Machiko; Izumi, Takaaki; Tsukuda, Yoko; Nakai, Masato; Sho, Takuya; Natsuizaka, Mitsuteru; Morikawa, Kenichi; Ogawa, Koji; Sakamoto, Naoya

    2017-07-19

    The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients. © 2017 The Japan Society of Hepatology.

  18. Pegylated interferon-alfa plus ribavirin therapies for chronic hepatitis C

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    T Kanda

    2011-03-01

    Full Text Available Until HCV NS3/4A protease inhibitors become available at the end of 2011, the combination pegylated-interferon (PEG-IFN-alfa and ribavirin (RBV will remain the standard treatment for chronic hepatitis C patients. In some hepatitis C virus-infected patients, PEG-IFN plus RBV treatment against HCV should continue to be used because of side effects of new drugs such as anemia. Our Japanese experiences should provide new information for the treatment of chronic hepatitis C. Keywords: Direct-acting antiviral agents (DAA, HCV, pegylated interferon, ribavirin, standard of care (SOC .

  19. Induction pegylated interferon alfa-2b in combination with ribavirin in patients with genotypes 1 and 4 chronic hepatitis C: a prospective, randomized, multicenter, open-label study.

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    Brady, Daniel E; Torres, Dawn M; An, Jong W; Ward, John A; Lawitz, Eric; Harrison, Stephen A

    2010-01-01

    Standard of care (SOC) treatment for chronic hepatitis C (CHC) involves weekly pegylated (PEG) interferon plus weight-based ribavirin with resultant sustained virologic response (SVR) rates at or near 50% for genotypes 1 and 4 virus. Induction therapy with higher doses of PEG interferon may improve first-phase viral kinetics and thus improve the overall SVR in genotypes 1 and 4 patients. This multicenter, randomized, open-label trial enrolled treatment-naive genotypes 1- and 4-infected CHC patients to either initial induction therapy versus SOC. The induction group received PEG interferon alfa-2b 3.0 mcg/kg/wk for 12 weeks followed by PEG interferon alfa-2b 1.5 mcg/kg/wk for 36 weeks and 13 +/- 2 mg/kg ribavirin daily for 48 weeks. SOC patients received PEG interferon alfa-2b 1.5 mcg/kg weekly for 48 weeks and 13 +/- 2 mg/kg ribavirin daily for 48 weeks. The primary end point was SVR. There were 610 patients enrolled throughout the United States. Complete early virologic response was 62.6% versus 57.7% in induction versus SOC (NS). Overall SVR was 32% in induction versus 29% in SOC group (NS). Dose reduction of either PEG interferon (24.1% vs 23.8%) or ribavirin (26.8% vs 25.1%) was similar between the 2 groups. There was a trend toward a significant difference when comparing the SVR in induction therapy in patients weighing more than 85 kg versus those receiving SOC (38% vs 28%; P = .08). Induction therapy does not enhance complete early virologic response or SVR rates in a predominantly genotype 1 CHC population compared with SOC therapy. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  20. The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients

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    Hee Jae Jung

    2014-03-01

    Full Text Available Background/AimsLipid profile and insulin resistance (IR are associated with hepatitis C virus (HCV and may predict the chronic hepatitis C (CHC treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment.MethodsIn total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA of IR (HOMA-IR, and HOMA of β cells (HOMA-β were evaluated before interferon plus ribavirin therapy (BTx, at the end of treatment (DTx, and 24 weeks after the end of treatment (ATx.ResultsA sustained virologic response (SVR was achieved by 81% of all patients (49/60, 60% (n=36 of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24. Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0±11.2 years, mean±SD; non-SVR, 56.6±9.9 years; P2.5, HOMA-IR was significantly changed at DTx in the SVR group.ConclusionsLDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5.

  1. Hashimoto encephalopathy with pegylated interferon alfa-2b and ribavirin.

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    Deutsch, Melanie; Koskinas, John; Tzannos, Konstatinos; Vassilopoulos, Dimitrios; Mailis, Antonis; Tolis, George; Hadziyannis, Stephanos

    2005-10-01

    To report an instance of Hashimoto encephalopathy probably resulting from pegylated interferon alfa-2b and ribavirin. A 36-year-old woman with a 10-year history of autoimmune thyroiditis presented with symptoms and signs consistent with Hashimoto encephalopathy during therapy with pegylated interferon alfa-2b and ribavirin for chronic hepatitis C. Hashimoto encephalopathy is a rare autoimmune condition that occurs in patients with Hashimoto thyroiditis and high titers of antithyroid antibodies. It is characterized by a variety of nonspecific neuropsychiatric symptoms, increased cerebrospinal fluid protein level, and abnormal brain imaging and electroencephalogram. Prompt response to corticosteroids is observed in most cases. As of August 29, 2005, this is the first report of such an association. An objective causality assessment revealed that the Hashimoto encephalopathy was probably caused by the patient's medications. Hashimoto encephalopathy may rarely be triggered by interferon alfa therapy in susceptible patients.

  2. Effect of pegylated interferon α-2a combined with thymosin α1 on quality of life in patients with chronic hepatitis B

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    LU Jianguo

    2013-12-01

    Full Text Available ObjectiveTo investigate the effect of pegylated interferon α-2a (PEG-IFN α-2a combined with thymosin α1 (Tα1 on the quality of life (QOL in patients with chronic hepatitis B (CHB. MethodsA total of 148 patients with CHB who were admitted to our department from October 2008 to October 2012 were selected and randomly divided into observation group (n=74 and control group (n=74. The control group was treated with PEG-IFN α-2a, while the observation group was treated with PEG-IFN α-2a plus Tα1. The hepatitis B virus (HBV DNA load, QOL, Chronic Liver Disease Questionnaire scores, and adverse reactions were compared between the two groups at months 3, 6, and 12 of treatment. Comparisons between groups were made by independent-samples t test; comparisons between variables before and after treatment were made by paired t test; categorical data were analyzed by chi-square test. ResultsCompared with the control group, the observation group had significantly higher decrease in HBV DNA load and virological response rate at months 3 (t=2.281, P=0.02; χ2=3.950, P=0.04, 6 (t=3.237, P=0.00;χ2=4.022, P=0.04, and 12 (t=3.197, P=0.00; χ2=4.028, P=0.04, significantly higher overall QOL, physiological, social relation, fatigue, and anxiety scores at month 6 (t=2.039-3.472, P<0.05, and significantly higher overall QOL, general health status, physiological, psychological, social relation, fatigue, systemic symptom, activity, anxiety, and environment scores at month 12 (t=2.020-3.201, P<0.05. ConclusionPEG-IFN α-2a combined with Tα1 can improve immunity and antiviral ability and promote HBV clearance in the treatment of CHB, thus leading to the improvement in patients’ QOL. This therapy holds promise for clinical application.

  3. Long-term pegylated interferon-α and its potential in the treatment of melanoma

    Directory of Open Access Journals (Sweden)

    Reinhard Dummer

    2009-04-01

    Full Text Available Reinhard Dummer, Joanna ManganaDepartment of Dermatology, University Hospital, Zürich, SwitzerlandAbstract: Conventional interferons including interferon-α (IFN-α are cytokines used for years in the treatment of solid tumors and hematological malignancies. Their half-life is short. Pegylated forms of IFN-α present an improved pharmacokinetic profile that rendered them the preferred IFNs in hepatitis therapy. In the last decade, pegylated interferons (PegIFNs have been investigated in melanoma patients. We review the scientific published literature on biology, pharmacokinetics, side effects and clinical applications of PegIFN-α in the treatment of stage III and IV melanoma. In the adjuvant setting, PegIFNα-2b has significant prolonged distant metastases free survival in patients with microscopic nodal involvement (stage TxN1aM0 and therefore is a promising treatment option in this patient population. In the palliative setting, monotherapy with PegIFNα-2α can induce complete remissions in a minority of stage IV melanoma patients. The combination of monochemotherapy is feasible and may result in lasting complete remissions. Ongoing research must focus on the identification of patients who mostly benefit, so that unnecessary toxicity would be avoided. Combining PegIFNs and chemotherapy or targeted agents deserves further exploration.Keywords: interferons, pegylated interferon-α, melanoma

  4. [PROGNOSTIC VALUE OF THE COMBINATION OF BLOOD GROUP SPECIFICITY AND INTERLEUKIN 28B GENE POLYMORPHISM FOR ESTIMATION OF EFFICIENCY OF THERAPY WITH THE USE OF PEGYLATED INTERFERON α-2 AND RIBAVARIN IN PATIENTS WITH CHRONIC GENOTYPE 1 HEPATITIS C].

    Science.gov (United States)

    Ogurtsov, P P; Kukhareva, E I

    2016-01-01

    To estimate the prognostic value of the combination of blood group specificity and interleukin 28B gene polymorphism for the achievement of sustained virologic response (SVR) to antiviral therapy (AVT) with the use of pegylated interferon α-2 and ribavarin in patients with chronic genotype 1 hepatitis C (CHC-1). The secondary aim was to evaluate the influence of these genetic factors on the progress of hepatic fibrosis in case of failure of the above treatment. A total of 146 patients with CHC-1 were examined. We studied the RNA genotype of hepatitis C virus, blood group specificity, IL-28B gene polymorphism, and severity of hepatic fibrosis (puncture biopsies). Dynamics of hepatic fibrosis was followed up in 40 patients who failed to develop the virologic response. 20 control patients did not receive AVT. The multifactor significance criterion was used to identify the initial factor that produced the highest effect on SVR. SVR was observed in 56.8% of the patients. Its efficiency was most significantly influenced by. the combination of blood group specificity and interleukin 28B gene polymorphism (p = 0.000024). Combination of blood group (0)1 with C/C or T/T IL-28B genotypes, A(II) with C/T or T/T and B(III) with T/G was associated with SVR in 100, 88.2, and 94.4% cases respectively. It was absent in patients with blood group A(II) in combination with double-nucleotide substitution in rs8099917 of the IL-28B gene (TG and GG genotypes); these patients suffered progressive fibrosis. SVR occurred in 83.8% of the patients with blood group B(III). The knowledge of blood group in patients with CHC-1 and IL-28B gene polymorphism treated with the use of pegylated interferon α-2 and ribavarin allows to predict SVR with a probability of 100% in case of blood group 0(1) and C/C or T/T genotypes, 88.2% in case of blood group A(II) and single-nucleotide C>Tsubstitution in rs8099917 locus of the IL-28B gene, 94.4% in case of blood group B(II) and single-nucleotide T

  5. Pegylated interferon alfa and ribavirin for children with chronic hepatitis C.

    Science.gov (United States)

    Rosen, Irit; Kori, Michal; Eshach Adiv, Orly; Yerushalmi, Baruch; Zion, Nataly; Shaoul, Ron

    2013-02-21

    To study current treatment options for pediatric hepatitis C infection and their associated success rates. We retrospectively reviewed charts of thirty children who had been treated with combination therapy of pegylated interferon alfa plus ribavirin for chronic hepatitis C infection. Patients had been treated with ribavirin (15 mg/kg per day) and either pegylated interferon alfa 2a (180 mg/m(2) once weekly) or pegylated interferon alfa 2b (1.5 mg/kg once weekly). Patients' follow-up included subjective assessment of complaints, physical examination including weight and height, as well as laboratory evaluations for viral load [before treatment, at 12 wk, and 6 mo following treatment completion, as determined by sustained viral response (SVR)], complete blood count, liver enzymes, alkaline phosphatase, bilirubin, renal function tests, and thyroid function tests. For patients not achieving a two log decrease in viral load at treatment week 12, treatment was discontinued and the patient was considered a treatment non-responder. Thirty children aged 3-18 years were included in the study. Twenty patients (11 males, 9 females) received pegylated interferon alfa 2b and ten patients (6 males, 4 females) received pegylated interferon alfa 2a. Twenty-three patients were infected with genotype 1, six patients were infected with genotype 3, and one patient was infected with genotype 2. Twenty patients (67%) achieved SVR. Treatment success rates were 90% with pegylated interferon alfa 2a vs 55% with pegylated interferon alfa 2b. Although a trend was noted for improved outcomes in the group receiving pegylated interferon alfa 2a, there were no statistically significant outcome differences between the two treatment groups (P = 0.1). Treatment success was 56.5% for patients infected with genotype 1 virus, compared to 100% for patients infected with other genotypes (P = 0.064). There was no difference in treatment response between males and females. A cut-off age of twelve years

  6. Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C

    DEFF Research Database (Denmark)

    Manns, Michael P; Gane, Edward; Rodriguez-Torres, Maribel

    2012-01-01

    Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this...

  7. Natural Killer Cell Characteristics in Patients With Chronic Hepatitis B Virus (HBV) Infection Are Associated With HBV Surface Antigen Clearance After Combination Treatment With Pegylated Interferon Alfa-2a and Adefovir.

    Science.gov (United States)

    Stelma, Femke; de Niet, Annikki; Tempelmans Plat-Sinnige, Marjan J; Jansen, Louis; Takkenberg, R Bart; Reesink, Hendrik W; Kootstra, Neeltje A; van Leeuwen, Ester M M

    2015-10-01

    The role of natural killer (NK) cells in the process of hepatitis B virus (HBV) surface antigen (HBsAg) clearance and whether their phenotype is related to treatment outcome in patients with chronic hepatitis B are currently unknown. Patients with chronic hepatitis B (HBV DNA load, >17 000 IU/mL) were treated with pegylated interferon alfa-2a and adefovir for 48 weeks. NK cell phenotype and function were analyzed in 7 responders (defined as individuals with HBsAg clearance by week 72; 3 HBV e antigen [HBeAg]-positive and 4 HBeAg-negative), 7 matched nonresponders, and 7 healthy controls. Subsequently, 34 baseline samples from HBeAg-positive patients with chronic hepatitis B were analyzed. During treatment, the percentage and absolute number of CD56(bright) NK cells increased significantly, whereas the percentage and absolute number of CD56(dim) NK cells decreased. At baseline, responders had a significantly lower expression of chemokine receptor CX3CR1 on CD56(bright) NK cells and inhibitory receptor NKG2A on CD56(dim) NK cells, compared with nonresponders. In addition, responders had higher CD56(bright) TRAIL expression and interferon γ production at end of treatment. These baseline differences were not found in HBeAg-positive patients who had HBeAg seroconversion without HBsAg clearance. Combination therapy significantly influences NK cell phenotype and function. Differences between patients with chronic hepatitis B with HBsAg clearance and nonresponders suggest that NK cells play a role in the clearance of HBsAg during interferon-based combination therapy. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid

    Directory of Open Access Journals (Sweden)

    Mao Qing

    2012-07-01

    Full Text Available Abstract Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys treatment. One patient progressed into acute-on-chronic liver failure (ACLF at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre-ACLF at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.

  9. Acute inflammatory demyelinating polyneuropathy after treatment with pegylated interferon alfa-2a in a patient with chronic hepatitis C virus infection: a case report

    Directory of Open Access Journals (Sweden)

    Lahbabi Mounia

    2012-09-01

    Full Text Available Abstract Introduction The combination of polyethylene glycol (PEGylated interferon (pegylated interferon and ribavirin has been shown to be an effective treatment for chronic hepatitis C virus. In general, common side effects related to this combination therapy are mild and are well tolerated. However, peripheral neuropathy including demyelinating polyneuropathy related to PEG-interferon α2a (pegylated interferon alfa-2a is extremely rare. In the literature, only one case of acute inflammatory demyelinating polyneuropathy related to PEG-interferon α2a has been published previously. Case presentation To the best of our knowledge we present only the second case of acute inflammatory demyelinating polyneuropathy related to PEG-interferon α2a, occurring in a 63-year-old Caucasian man. He developed tingling, numbness, and weakness of his upper and lower extremities with acute neurological deficits after five weeks of a combination therapy with PEG-interferon α2a and ribavirin for chronic hepatitis C virus infection. His clinical course, neurological findings, and his electromyogram results were all consistent with acute inflammatory demyelinating polyneuropathy. Our patient recovered completely after interferon was stopped and symptomatic treatment and a further electromyogram showed a disappearance of neuropathy. Four weeks later, PEG-interferon α2a was reintroduced with a gradually increasing dose without any reappearance of neurological symptoms allowing hepatitis C seroconversion. Conclusions Recognition of this rare yet possible presentation is important for early and accurate diagnosis and treatment. This case report also suggests that the reintroduction of PEGylated interferon in patients who had presented with acute inflammatory demyelinating polyneuropathy related to interferon α may be safe, but this must be confirmed by further studies.

  10. Can pegylated interferon improve the outcome of polycythemia vera patients?

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    Elena Crisà

    2017-01-01

    Full Text Available Abstract Pegylated interferon (peg-IFN was proven by phase II trials to be effective in polycythemia vera (PV; however, it is not clear whether it could improve patient outcome compared to hydroxyurea (HU. Here, we present an observational study on 65 PV patients aged 65 years or younger, who received either peg-IFN (30 or HU (35 according to the physician choice. Median follow-up was 75 months. The two cohorts were comparable for patient and disease characteristics. Eighty-seven percent of the patients treated with peg-INF responded, with a CR rate of 70% as compared to 100 and 49% with HU, respectively. Discontinuation rate was similar in the two groups (20% in peg-IFN vs 17% in HU. JAK2 allele burden was monitored in peg-INF arm only, and a reduction was observed in 88% of the patients. No thrombotic events were observed during peg-IFN treatment compared to three on HU. Disease progression to myelofibrosis or acute myeloid leukemia occurred to a patient only in peg-INF, compared to three in HU. Overall, three second malignancies were observed during the study, two in patients who received HU only, and one in a patient largely treated HU who received also peg-IFN for 3 months. Overall survival was significantly better for peg-IFN patients compared to HU, p = 0.027. Our study, albeit limited by small patient and event number and lack of randomization, confirms the efficacy of peg-INF in PV and shows a significant survival advantage for peg-INF-treated patients. Waiting for confirming data from the ongoing phase III trials, our study can support peg-INF as a first-line treatment option for PV, at least for younger patients.

  11. Management of chronic hepatitis C patients who have relapsed or not responded to pegylated interferon alfa plus ribavirin.

    Science.gov (United States)

    Dieterich, D T; Rizzetto, M; Manns, M P

    2009-12-01

    Development of therapeutic strategies for patients with chronic hepatitis C who experience virological breakthrough, relapse or nonresponse lag behind those for treatment-naïve patients. The probability of a previously treated patient responding to re-treatment depends on the nature of the previous regimen, the magnitude of the response to previous treatment and the patient's characteristics. Relapsers have higher sustained virological response rates than nonresponders when re-treated with pegylated interferon plus ribavirin. Re-treatment of nonresponders to pegylated interferon plus ribavirin with the standard 48-week regimen resulted in an approximate 6% sustained response rate in the EPIC-3 program. In the REPEAT trial, the sustained response rate was significantly higher in nonresponders to pegylated interferon alfa-2b (12 kD) plus ribavirin randomized to 72 weeks of peginterferon alfa-2a (40 kD) plus ribavirin, compared with a 48-week regimen (16%vs 8%, P = 0.0006). Based on available data, extended treatment is the best option for these individuals. Undetectable viral RNA at week 12 is an important criterion for re-treatment in the REPEAT and EPIC studies. Maintenance therapy with pegylated interferon is generally ineffective in nonresponders and cannot be recommended. Directly acting antivirals may increase response rates and the burden of adverse events when combined with the standard of care, but will not be available for some years. In conclusion, after careful evaluation of an individual's benefit-risk ratio, a 72-week regimen is the preferred strategy for optimizing sustained response rates in patients who have not responded to the standard of care, provided that viral RNA is undetectable at week 12 of re-treatment.

  12. Erythema annulare centrifugum-like eruption associated with pegylated interferon treatment for hepatitis C

    Directory of Open Access Journals (Sweden)

    Mark Naccarato

    2013-07-01

    Full Text Available Current standard of treatment for chronic hepatitis C virus infection requires the use of pegylated interferon plus ribavirin. Treatment with these two agents has been associated with numerous side effects, which frequently include dermatologic eruptions. We report a cutaneous eruption associated with interferon having clinical presentation of erythema annulare centrifugum. The eruption occurred within days of the first interferon injection and repeatedly flared following subsequent injections. Our patient was able to continue therapy without interruption, while managing the reaction with topical corticosteroid and oral antihistamine. We conclude that this is a benign cutaneous eruption associated with interferon which can be managed without dis- continuing treatment for hepatitis C.

  13. Pegylated interferon alfa for chronic hepatitis B: systematic review and meta-analysis.

    Science.gov (United States)

    Kim, V; Abreu, R M; Nakagawa, D M; Baldassare, R M; Carrilho, F J; Ono, S K

    2016-03-01

    Conventional interferon alfa and nucleos(t)ide analogues, such as lamivudine, are frequently used for chronic hepatitis B (CHB) treatment, but are associated with adverse effects and viral resistance. Here we performed a systematic review and meta-analysis evaluating all studies of pegylated interferon alfa (PEG-IFNα) treatment in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB. We searched electronic databases--PubMed, EMBASE, Cochrane Library and LILACS--for randomized controlled trials evaluating PEG-IFNα therapy between 1999 and September 2014. Virological response was the primary outcome. We identified 14 studies involving 2829 patients. Our analysis revealed that PEG-IFNα + lamivudine combination therapy produced better virological and biochemical responses than PEG-IFNα monotherapy in HBeAg-positive and HBeAg-negative patients at the end of treatment. PEG-IFNα + adefovir dipivoxil achieved better seroconversion rate than PEG-IFNα in HBeAg-positive patients at the end of treatment. The present findings demonstrated a beneficial response rate following PEG-IFNα combination therapy with nucelos(t)ides among HBeAg-positive and HBeAg-negative patients with CHB. Further trials are needed to investigate simultaneous and sequential therapy strategies. © 2015 The Authors Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.

  14. Successful treatment of chronic hepatitis B and D with pegylated-interferon plus entecavir

    Directory of Open Access Journals (Sweden)

    Guei-Ying Chen

    2015-11-01

    Full Text Available Interferon-based regimen has been used to treat hepatitis D virus (HDV super-infection on top of hepatitis B virus (HBV carriers; however, viral relapse is frequent after stopping therapy. Recently, quantitative hepatitis B surface antigen (qHBsAg was introduced to help the management of chronic hepatitis B (CHB. Little is known about its role in the treatment of HBV and HDV dual infection. Herein, we reported a 45-year-old male HBV carrier with HDV co-infection who received combination therapy of pegylated-interferon α-2a plus entecavir. The qHBsAg level was adopted as the treatment guidance and a consolidation therapy of 12 months was continued after HBsAg loss. The patient achieved HBsAg seroconversion with HDV RNA undetectable after 35 months of combination therapy and sustained therapeutic response 12 months post-therapy. Therefore, personalized response-guided therapy by using qHBsAg may be an option for the treatment for HBV and HDV dual infection.

  15. A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B.

    Science.gov (United States)

    Xie, Qing; Zhou, Huijuan; Bai, Xuefan; Wu, Shuhuan; Chen, Jian-Jie; Sheng, Jifang; Xie, Yao; Chen, Chengwei; Chan, Henry Lik-Yuen; Zhao, Mianzhi

    2014-12-15

    Treatment with pegylated interferon (peg-IFN) alfa-2a (40KD) results in hepatitis B "e" antigen (HBeAg) seroconversion 6 months after treatment in up to 36% of HBeAg-positive chronic hepatitis B patients. This study explored the efficacy of a novel combination of peg-IFN alfa-2a and entecavir (ETV), a potent nucleoside analogue. In total, 218 treatment-naive Chinese HBeAg-positive patients were randomized to peg-IFN alfa-2a (180 µg/week) for 48 weeks, either as monotherapy (n = 72), or with 24 weeks of ETV (0.5 mg/daily) added at week 13 (ETV add-on, n = 73), or pretreatment with a 24-week course of ETV, starting peg-IFN alfa-2a at week 21 (ETV pretreatment, n = 73). The primary endpoint was reduction in quantitative HBeAg from baseline to 24 weeks posttreatment. Significant reductions in HBeAg from baseline were achieved in all treatment groups 24 weeks posttreatment; reductions were comparable across treatment arms (shown as log10 Paul Ehrlich international units [PEIU]/mL): monotherapy: -1.4 (SD, 1.8); ETV add-on: -1.6 (SD, 1.8); ETV pretreatment: -1.3 (SD, 1.7). Rates of HBeAg seroconversion were similar across treatment groups posttreatment (monotherapy: 22 [31%]; ETV add-on: 18 [25%]; ETV pretreatment: 19 [26%]). Significantly greater reductions of hepatitis B virus DNA were achieved with ETV add-on while on treatment, but were not sustained posttreatment. Safety profiles were comparable between treatment groups; adverse events were experienced by 62 (86%) monotherapy, 65 (89%) ETV add-on, and 58 (81%) ETV pretreatment patients. Neither ETV add-on nor ETV pretreatment demonstrated superiority compared with 48 weeks of peg-IFN alfa-2a monotherapy. The optimal treatment strategy using nucleos(t)ide analogues and peg-IFN alfa-2a remains to be determined. Clinical Trials Registration. NCT00614471. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e

  16. Preparation and PEGylation of recombinant human interferon lambda3

    African Journals Online (AJOL)

    After ion exchange, molecular sieve and other column chromatography purification, the purity of the purified rhIFN-λ3 was as high as 90% and the purity of the mono-PEGylated rhIFN-λ3 after cation-exchange chromatography was as high as 86%. The 50% effective concentration (EC50) of rhIFN-λ3 in WISH cells against ...

  17. Treatment of eosinophilic otitis media with pegylated interferon-α 2a and 2b.

    Science.gov (United States)

    Neff, Brian A; Voss, Stephen G; Carlson, Matthew L; O'Brien, Erin K; Butterfield, Joseph H

    2017-05-01

    Eosinophilic otitis media (EOM) is a variant of chronic otitis media that is characterized by the development of thick mucoid middle ear effusion, adult onset bronchial asthma, sinonasal polyposis, and aspirin sensitivity. EOM is typically refractory to corticosteroid therapy and surgical intervention. Pegylated interferon (PEG-IFN) has effectively treated hypereosinophilic syndrome in clinical trials; however, the efficacy of this medication for EOM treatment remains undefined. Retrospective, case series, tertiary academic center. A retrospective chart review was performed on EOM patients from 2008-2014. A total of 32 patients met the clinical criteria for EOM according to established diagnostic guidelines. Outcomes of all patients with severe, refractory EOM who initiated PEG-IFN therapy are reported. Eight patients were treated with pegylated interferon-α 2a or 2b for refractory EOM. Half of the patients had significant side effects with interferon treatment. Three of these were able to continue at a reduced dosage without side effect reoccurrence, and one patient stopped the medication permanently. Four of eight (50%) patients had a complete clinical response with total resolution of otorrhea and normalization of middle ear mucosa, and were able to discontinue corticosteroid treatment. Two patients attempted to stop PEG-IFN therapy after prolonged symptom remission and had recurrent otorrhea. Both patients had symptom resolution after PEG-IFN reinitiation. These data demonstrate that pegylated interferon-α 2a and 2b therapy may benefit patients with severe, refractory EOM. Further larger studies with long-term follow-up are required to validate these early but promising results. 4. Laryngoscope, 127:1208-1216, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

  18. Pharmacokinetics comparison of two pegylated interferon alfa formulations in healthy volunteers.

    Science.gov (United States)

    Costa, Marisa Boff; Picon, Paulo Dornelles; Sander, Guilherme Becker; Cuni, Hugo Nodarse; Silva, Carmen Valenzuela; Meireles, Rolando Páez; Góes, Ana Carolina Magalhães Andrade; Batoreu, Nadia Maria; Maia, Maria de Lourdes de Sousa; Albuquerque, Elizabeth Maciel; Matos, Denise Cristina de Souza; Saura, Pedro Lopez

    2018-01-04

    Several countries have used pegylation technology to improve the pharmacokinetic properties of essential drugs. Recently, a novel interferon alfa-2b protein conjugated to four-branched 12 kDa polyethylene glycol molecules was developed jointly between Cuba and Brazil. The aim of this study was to compare the pharmacokinetic properties of BIP48 (pegylated interferon alfa-2b from Bio-Manguinhos/Fiocruz, Brazil) to those of PEGASYS® (commercially available pegylated interferon alfa-2a from Roche Pharmaceutical). This phase I, single-centre, randomized, double-blind crossover trial enrolled 31 healthy male volunteers aged 19 to 35 who were allocated to two stages, either side of a 5-week wash-out period, with each arm lasting 14 consecutive days after subcutaneous administration of 180 μg of one formulation or the other (study or comparator). The main outcome variable was serum pegylated interferon concentrations in 15 samples collected during the course of the study and tested using an enzyme immunoassay. There were no differences between formulations in terms of magnitude or absorption parameters. Analysis of time parameters revealed that BIP48 remained in the body significantly longer than PEGASYS® (T max : 73 vs. 54 h [p = 0.0010]; MRT: 133 vs. 115 h [p = 0.0324]; ke: 0.011 vs. 0.013 h(-1) [p = 0.0153]; t 1/2 : 192 vs. 108 h [p = 0.0218]). BIP48 showed the expected pharmacokinetic profile for a pegylated product with a branched molecular structure. Compared to PEGASYS®, the magnitude absorption was similar, but time parameters were consistent with slower elimination. Further studies should be conducted to evaluate the clinical implications of these findings. A phase II-III repeated-dose clinical trial is ongoing to study these findings in patients with chronic hepatitis C virus infection. This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 ). This trial was retrospectively registered in June 2013.

  19. Treatment of chronic hepatitis D patients with pegylated interferon: a real-world experience.

    Science.gov (United States)

    Abbas, Zaigham; Memon, Mohammad S; Mithani, Hammad; Jafri, Wasim; Hamid, Saeed

    2014-01-01

    Published experience of treating chronic hepatitis D patients with pegylated interferon (PEG-IFN)-α is limited. The aim of this study was to determine the efficacy of 48 weeks of treatment with PEG-IFN in naive patients outside the clinical trial setting, in the real world. Patients with chronic hepatitis D were treated with PEG-IFN. The primary end points were sustained clearance of HDV RNA and normal alanine aminotransferase (ALT) at 24 weeks post-treatment. The total number of patients treated with PEG-IFN was 104; 91 males, mean age ±SD 30.1 ±10.0 years (range 15-55). Cirrhosis was present in 41 patients. With an intention-to-treat analysis, end of treatment virological response (ETR) was achieved in 44 (42.3%), normalization of ALT in 38 (35%) and a combined response in 23 (22.1%) patients. Sustained virological response (SVR) at 24 weeks post-treatment was seen in 24 (23.1%) patients each for the virological and biochemical responses and in 13 (12.5%) as combined response. Both ETR and SVR were associated with a negative HDV RNA at 24 weeks of treatment (P=0.001 and P=0.000, respectively). Detectable HDV RNA at this point had a positive predictive value of 0.95 (range 0.85-0.99) for detectable RNA at 6 months post-treatment. End of treatment biological response, that is, normal ALT at the end of treatment was also a predictor of ETR and SVR (P=0.004 and P=0.041, respectively). Treatment with PEG-IFN for hepatitis D is of limited efficacy. Detectable HDV RNA at 24 weeks of treatment is a predictor for a failed SVR.

  20. Efficacy of pegylated interferon alfa-2a or alfa-2b in combination with ribavirin in the treatment of chronic hepatitis caused by hepatitis C virus genotype 1b.

    Science.gov (United States)

    Mach, Tomasz H; Cieśla, Andrzej; Warunek, Wioleta; Janas-Skulina, Urszula; Cibor, Dorota; Owczarek, Danuta; Ciećko-Michalska, Irena

    2011-12-01

    Treatment of chronic hepatitis C (CHC) with pegylated interferon (Peg-IFN) and ribavirin leads to sustained virological response (SVR) in approximately 50% of the patients. SVR depends on hepatitis C virus (HCV) and host factors, including IL28B genotypes. The aim of the study was to investigate the therapeutic efficacy of the difficult-to-treat HCV genotype 1b in patients from the south of Poland. A total of 260 adult patients with CHC and HCV genotype 1b were treated with Peg-IFN alfa-2a or Peg-IFN alfa-2b with ribavirin for 48 weeks. Efficacy was assessed at 12 weeks (early virological response - EVR), 48 weeks (end-of-treatment response - ETR), and at 6 months (SVR). HCV-RNA, alanine transaminase (ALT), and other biochemical parameters were measured in serum at baseline and at 12, 48, and 72 weeks of therapy. HCV-RNA levels were 3.72 ±1.17 × 106 IU/ml at baseline and decreased significantly at 12 weeks (0.02 ±0.17 × 106 IU/ml); there were no differences between the group treated with Peg-INF alfa-2a and the group treated with Peg-INF alfa-2b. ALT was 94.1 ±7.6 IU/l at baseline and decreased significantly at 12 weeks (42.5 ±3.1 IU/l). The overall EVR, ETR, and SVR were achieved by 63.9%, 77.7%, and 48.1% of the patients, respectively. Tolerance of therapy was similar in both groups. Efficacy of Peg-IFN alfa-2a with ribavirin is not significantly different from that of Peg-IFN alfa-2b with ribavirin, and SVR was achieved in 48.3% and 44.3% of the patients, respectively. Our study confirms that the efficacy of treatment of patients with HCV genotype 1b from the southern region of Poland is similar to that observed in the overall Polish population.

  1. The acute hepatic flare in a patient with chronic hepatitis C infection receiving pegylated interferon alpha 2b and ribavirin

    Directory of Open Access Journals (Sweden)

    Hayati Demiraslan

    2012-09-01

    Full Text Available The pegylated interferon alpha and ribavirin treatment is well established therapy for hepatitis C virus (HCV infection.During the treatment alanine aminotransferase (ALT flare may be observed rarely.A 51-year-old female receiving pegylated interferon and ribavirin therapy for HCV infection, complained nausea, vomitingin seventh week of the therapy, and her ALT level was detected over 20 times above the normal level. Hepatitis B surfaceantigen, anti-nuclear antibody, anti-mitochondrial antibody, anti-double stranded DNA antibody and anti-hepatitisA virus IgM antibody were negative, and thyroid stimulating hormone was normal. HCV RNA level was 424 IU/ml. PEGIFN and ribavirin therapy was interrupted for three weeks, after liver enzyme level was detected less than 100U/L, thetreatment was resumed. The patient was followed up for 2 months, ALT flare was not observed.In conclusion, we present a rare case with ALT flare, while receiving pegylated interferon and ribavirin therapy forchronic HCV infection. J Microbiol Infect Dis 2012; 2(3: 121-123Key words: Pegylated interferon, ribavirin, ALT flare, hepatitis C virus

  2. Raynaud's phenomenon and bilateral olecranon bursitis co-existing in a patient with chronic hepatitis B and D treated with pegylated interferon.

    Science.gov (United States)

    Arain, Shafique Rehman; Umer, Tahira Perveen

    2016-06-01

    Pegylated interferon remains the first line treatment for patients with hepatitis D virus and more than one year therapy may be necessary. Interferon a has the most extensive clinical application and is used for the treatment of chronic hepatitis B and D virus as well as HCV infections. The attachment of polyethylene glycol to interferon increases its half-life. Treatment with peg interferon is associated with many troublesome and occasionally with serious or even life-threatening side effects. In this case report, we have described a patient with chronic hepatitis B and D, who developed Raynaud's phenomenon, ischaemic digital necrosis and bilateral olecranon bursitis during Pegylated interferon therapy. The patient underwent a very extensive workup in order to determine the underlying cause of his digital ischaemia and olecranon bursitis, which was finally determined to be secondary to the use of Pegylated interferon.

  3. Hepatitis C Drugs: The End of the Pegylated Interferon Era and the Emergence of All-Oral, Interferon-Free Antiviral Regimens: A Concise Review

    Directory of Open Access Journals (Sweden)

    Alan Hoi Lun Yau

    2014-01-01

    Full Text Available Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV infection was a combination of pegylated interferon (PEGIFN and ribavirin (RBV. In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor-based regimens in combination with other direct-acting antiviral agent(s with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.

  4. Pegylated liposomal doxorubicin/carboplatin combination in ovarian cancer, progressing on single-agent pegylated liposomal doxorubicin

    OpenAIRE

    Grenader, Tal; Rosengarten, Ora; Isacson, Rut; Plotkin, Yevgeni; Gabizon, Alberto

    2012-01-01

    AIM: To assess the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) and carboplatin in patients with recurrent epithelial ovarian carcinoma (ROC), following disease progression on single agent PLD.

  5. PEGylated interferon beta-1a in the treatment of multiple sclerosis – an update

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    Reuss R

    2013-05-01

    Full Text Available Reinhard ReussDepartment of Neurology, BKH Bayreuth, Bayreuth, GermanyAbstract: Current standard immunomodulatory therapy with interferons (IFNs for relapsing–remitting multiple sclerosis (MS exhibits proven, but limited, efficacy and increased side effects due to the need of frequent application of the drug. Therefore, there is a need for more effective and tolerable drugs. Due to their small size, optimization of therapy with IFNs in MS by PEGylation is feasible. PEGylation of an IFN means that at least one molecule of polyethylene glycol (PEG is covalently added. This modification is a standard procedure to increase the stability, solubility, half-life, and efficacy of a drug, and is applied in several drugs and diseases. Currently, a therapy regimen applying PEG-IFN beta-1a in MS is being developed to achieve an optimized relationship between therapy-related side effects and pharmacokinetic/pharmacodynamic efficacy. Phase I studies demonstrated that subcutaneous PEG-IFN beta-1a at a dose of 125 µg every 2 or 4 weeks might be at least as efficient and safe as the current standard therapy with IFN beta-1a. A global Phase III clinical study is investigating the efficacy of PEG-IFN beta-1a in terms of reduction of the relapse rate in relapsing–remitting MS patients. The latest primary safety and efficacy analysis after 1 year has revealed a favorable risk–benefit profile with no significant difference between dosing regimens. Compared to placebo, the annualized relapse rate was reduced by about one-third and new or newly enlarging T2 brain lesions were reduced by about one-third when dosing every 4 weeks or by two-thirds when dosing every 2 weeks. This presents a significant effect of the dosing interval, favoring administration every 2 weeks. Chronic administration of PEGylated proteins mostly at toxic concentrations causes vacuolation of renal epithelium in animals, which – along with the issue of occurrence of anti-PEG antibodies

  6. Therapeutic effectiveness of biosimilar standard interferon versus pegylated interferon for chronic hepatitis C genotypes 2 or 3

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    Aline Gonzalez Vigani

    Full Text Available BACKGROUND: Pegylated interferon (Peg-IFN and standard interferon (IFN play a significant role in the treatment of hepatitis C virus (HCV infection. Biosimilar standard IFN is widely available in Brazil for the treatment of HCV infection genotypes 2 or 3, but its efficacy compared to Peg-IFN is unknown. OBJECTIVE: To compare the sustained virological response (SVR rates following treatment with biosimilar standard IFN plus ribavirin (RBV versus Peg-IFN plus RBV in patients with HCV genotypes 2 or 3 infection. METHODS: A retrospective cohort study was conducted in patients with HCV genotypes 2 or 3 infection treated with biosimilar standard IFN plus RBV or with Peg-IFN plus RBV. SVR rates of the two treatments were compared. RESULTS: From January 2005 to December 2010, 172 patients with a mean age of 44 +/- 9.3 years were included. There were eight (4.7% patients with HCV genotype 2 infections. One hundred fourteen (66.3% were treated with biosimilar standard IFN plus RBV, whist 58 (33.7% patients were treated with Peg-IFN plus RBV. Between the two groups, there were no significant differences regarding age, gender, glucose level, platelet count, hepatic necroinflammatory grade, and hepatic fibrosis stage. Overall, 59.3% (102/172 patients had SVR. In patients treated with Peg-IFN plus RBV, 79.3% (46/58 had SVR compared to 49.1% (56/114 among those treated with biosimilar standard IFN plus RBV (p = 0.0001. CONCLUSION: In patients with HCV genotypes 2 or 3 infection, a higher SVR was observed in patients receiving Peg-IFN plus RBV related to patients treated with biosimilar standard IFN plus RBV.

  7. Secondary bronchiolitis obliterans organizing pneumonia during treatment of chronic hepatitis C: role of pegylated interferon alfa-2a

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    Ronaldo Soares Martins

    2012-10-01

    Full Text Available The treatment of chronic hepatitis C has frequent side effects such as cytopenias and neuropsychiatric symptoms. However, pulmonary toxicity associated with interferon is rarely described. This paper describes the clinical case of a 67-year-old female patient with chronic hepatitis C who presented an acute onset of dry cough, dyspnoea, and fever 36 weeks after the use of pegylated interferon alfa-2a and ribavirin. The lung biopsy confirmed the diagnosis of a bronchiolitis obliterans organizing pneumonia (BOOP. Corticotherapy was initiated, with clinical and radiological improvement. This paper aims to advise physicians to this occasional, though severe, adverse event related to hepatitis C virus (HCV treatment.

  8. Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals

    OpenAIRE

    Alexopoulou, Alexandra; Karayiannis, Peter

    2015-01-01

    The development of protease inhibitors (PIs) such as telaprevir and boceprevir constitutes a milestone in chronic hepatitis C antiviral treatment since it has achieved sustained virological response (SVR) rates of up to 75% in na?ve and 29-88% in treatment-experienced patients with genotype 1 infection. Both require combination treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) as PI monotherapy results in resistant mutations. New direct acting antiviral agents (DAAs) have rec...

  9. Is physical activity possible and beneficial for patients with hepatitis C receiving pegylated interferon and ribavirin therapy?

    Science.gov (United States)

    Payen, J-L; Pillard, F; Mascarell, V; Rivière, D; Couzigou, P; Kharlov, N

    2009-01-01

    The great majority of patients with chronic viral hepatitis C are treated with pegylated interferon-ribavirin therapy. The aim of this study was to demonstrate that these patients were able to have some form of physical exercise, and that this activity can lead to an improvement in their quality-of-life. Twelve volunteer patients with hepatitis C, who were either sedentary or had become sedentary and who had been treated by combination therapy for the past few weeks, were recruited at hepatology clinics in the Midi-Pyrénées region of France early in 2006. All patients attended a sports medicine consultation for an initial evaluation: maximal aerobic power and maximal oxygen consumption tests, maximum heart rate (MHR), search for contraindications for participation in the proposed program of physical exercise. The patients were given a heart rate monitor so they could measure their heart rate during physical exercise and check that they exercised under safe conditions and remained within the so-called "endurance" zone. The patients came to a sports facility daily for 5 days for the exercise program. The activities were divided into four sessions each day: an individual physical exercise selected by the patient, team physical exercise, recreational physical exercise, lectures on the different types of hepatitis and their treatment, on nutrition and on sports medicine assessments. Data on hepatitis, results of the cardiorespiratory examination and personal history and record of past physical activity were collected for each patient. Quality-of-life (SF36) was assessed at enrollment in the study and one month after the training sessions. At the initial sports medicine consultation, all patients reached their MHR and were found capable of participating in the proposed physical exercise program. One enrolled patient was excluded from the analysis because of the presence of sinusitis on arrival. Seven men and four women, mean age of 46 years completed the full course of

  10. Pegylated interferon α enhances recovery of memory T cells in e antigen positive chronic hepatitis B patients.

    Science.gov (United States)

    Liu, Yong Zhe; Hou, Feng Qin; Ding, Peng; Ren, Yuan Yuan; Li, Shi Hong; Wang, Gui Qiang

    2012-11-16

    Interferons (IFNs) are a group of cytokines commonly used in the clinical treatment of chronic hepatitis B (CHB) patients. Their therapeutic effects are highly correlated with recovery of host antiviral immunity. Clearance of hepatitis B virus (HBV) is mediated partially by activated functional memory T cells. The aims of the present study were to investigate memory T cell status in patients with different outcomes following pegylated interferon-α (IFN-α) therapy and to identify new biomarkers for predicting antiviral immune responses. Peripheral blood cells were isolated from 23 CHB patients who were treated with pegylated IFN-α at week 0 (baseline) and week 24. Co-expression of programmed death-1 (PD-1) and CD244 in CD45RO positive T cells, as well as a subset of CD127 and CXCR4 positive memory T cells were assessed. In addition, perforin, granzyme B, and interferon-γ (IFN-γ) expressions were also analyzed by flow cytometric analysis after intracytoplasmic cytokine staining (ICCS). Peripheral blood mononuclear cells (PBMC) isolated at week 24 were re-challenged with exogenous HBV core antigen, and the percentage of IFN-γ expression, serum HBV DNA loads, and ALT (alanine aminotransferase) levels were evaluated. At week 24, PD-1 and CD244 expression in CD8 memory T cells were down-regulated (P memory T cells was up-regulated (P memory T cells after pegylated IFN-α treatment (P memory T cells than the non-responders did after HBV antigen re-stimulation in vitro. Pegylated IFN-α treatment enhanced recovery of memory T cells in CHB patients by down-regulating inhibitory receptors and up-regulating effector molecules. The expressions of CXCR4 and CD127 in CD8 memory T cell may be used as biomarkers for predicting the outcome of treatment.

  11. [24 weeks treatment with pegylated interferon alfa plus ribavirin may be possible in genotype 1 chronic hepatitis C patients with rapid virological response who have low pretreatment viremia].

    Science.gov (United States)

    Moon, Sung Soo; Kang, Hyoun Gu; Seo, Jeong Ah; Jung, Eun Uk; Lee, Sang Heon; Park, Sung Jae; Lee, Youn Jae; Seol, Sang Yong

    2010-07-01

    The standard treatment for chronic hepatitis C infected with hepatitis C virus (HCV) genotype 1 is a combination of pegylated interferon alfa and ribavirin over a 48 weeks period. It is unclear if 24 weeks treatment is possible for patients showing a rapid virological response (RVR) without compromising the sustained virological response (SVR) in Korea. Between June 2005 and September 2008, among patients chronically infected with the HCV genotype 1 who were treated with pegylated interferon alfa subcutaneously once weekly plus ribavirin based on body weight, 55 patients who had low pretreatment viral load (<600,000 IU/mL) and RVR were enrolled. A total of 55 patients were divided into 24 weeks treatment group (n=29) and the standard treatment group (n=26). The HCV RNA was quantitatively assessed before treatment, and after 12 weeks of treatment, and also qualitatively assessed after 4 weeks of treatment, at end of treatment (24 weeks), and 24 weeks after end of treatment. RVR was defined as undetectable HCV RNA at the 4 weeks of treatment. Among the 55 patients, SVR was achieved in 100% (29/29) of the patients in 24 weeks treatment and 96.2% (25/26) of the patients in the standard treatment (p=0.473). HCV genotype 1 infected patients with a low baseline HCV RNA concentration who become HCV RNA negative at week 4 may be treated for 24 weeks without compromising sustained virological response. However, an additional trial will be needed to optimize the treatment duration.

  12. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration.

    Science.gov (United States)

    Azzoni, Livio; Foulkes, Andrea S; Papasavvas, Emmanouil; Mexas, Angela M; Lynn, Kenneth M; Mounzer, Karam; Tebas, Pablo; Jacobson, Jeffrey M; Frank, Ian; Busch, Michael P; Deeks, Steven G; Carrington, Mary; O'Doherty, Una; Kostman, Jay; Montaner, Luis J

    2013-01-15

    Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication. A total of 23 HIV type 1 (HIV-1)-infected, virologically suppressed subjects receiving ART (CD4(+) T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg-interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, ≥ 400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed. At week 12 of Peg-interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication. NCT00594880.

  13. PEGylation of proteins in organic solution: a case study for interferon beta-1b.

    Science.gov (United States)

    Peng, Fei; Wang, Yinjue; Sun, Lijing; Liu, Yongdong; Hu, Tao; Zhang, Guifeng; Ma, Guanghui; Su, Zhiguo

    2012-09-19

    Conventional protein PEGylation is carried out in aqueous solution. However, some hydrophobic proteins seem to be stable in organic solution. In this study, a novel approach of PEGylating IFN-β-1b in an organic solution of 2-butanol (2-BuOH) was investigated. Compared with protein PEGylation in aqueous solution, the overall modification yields increased more than 37%, while the yield of mono-PEGylated products could be increased by 36%. Furthermore, the PEGylated IFN-β-1b, which was obtained in organic solution, demonstrated 18% more antiviral potency than those derived from aqueous solution. The PEGylation step could be directly connected to the previous protein separation step for process integration. Dynamic light scattering (DLS) and atomic force microscope (AFM) analysis revealed that IFN-β-1b formed aggregates both in water and in 2-BuOH solutions. However, the aggregates were much smaller and more homogeneous in 2-BuOH than those in aqueous solution, thereby providing larger solvent accessible protein surfaces, which resulted in a more productive PEGylation process. In addition, the results of circular dichroism (CD), fluorescence spectra, and peptide mapping suggested that the increased bioactivity came from the difference in PEGylation site distribution due to solution environment that induced conformational discrepancy. The results of this study show that PEGylation of IFN-β-1b in organic solution is a facile and efficient process, which might find applications for other hydrophobic proteins.

  14. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera.

    Science.gov (United States)

    Kiladjian, Jean-Jacques; Cassinat, Bruno; Chevret, Sylvie; Turlure, Pascal; Cambier, Nathalie; Roussel, Murielle; Bellucci, Sylvia; Grandchamp, Bernard; Chomienne, Christine; Fenaux, Pierre

    2008-10-15

    Interferon-alpha (IFN-alpha) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-alpha-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-alpha-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-alpha-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6(+) to 18(+) months, and persisted after pegylated IFN-alpha-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-alpha-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

  15. The impact of interleukin 28b gene polymorphism on the virological response to combined pegylated interferon and ribavirin therapy in chronic HCV genotype 4 infected egyptian patients using data mining analysis.

    Science.gov (United States)

    Khairy, Marwa; Fouad, Rabab; Mabrouk, Mahassen; El-Akel, Wafaa; Awad, Abu Bakr; Salama, Rabab; Elnegouly, Mayada; Shaker, Olfat

    2013-01-01

    Chronic HCV represents one of the common causes of chronic liver disease worldwide with Egypt having the highest prevalence, namely genotype 4. Interleukin IL-28B gene polymorphism has been shown to relate to HCV treatment response, mainly in genotype1. We aim to evaluate the predictive power of the rs12979860 IL28B SNP and its protein for treatment response in genotype 4 Egyptian patients by regression analysis and decision tree analysis. The study included 263 chronic HCV Egyptian patients receiving peg-interferon and ribavirin therapy. Patients were classified into 3 groups; non responders (83patients), relapsers (76patients) and sustained virological responders (104 patients). Serum IL 28 B was performed, DNA was extracted and analyzed by direct sequencing of the SNP rs 12979860 of IL28B gene. CT, CC and TT represented 56 %, 25 % and 19% of the patients, respectively. Absence of C allele (TT genotype) was significantly correlated with the early failure of response while CC was associated with sustained virological response. The decision tree showed that baseline alpha fetoprotein (AFP ≤ 2.68 ng/ml) was the variable of initial split (the strongest predictor of response) confirmed by regression analysis. Patients with TT genotype had the highest probability of failure of response. Absence of the C allele was significantly associated with failure of response. The presence of C allele was associated with a favorable outcome. AFP is a strong baseline predictor of HCV treatment response. A decision tree model is useful for predicting the probability of response to therapy.

  16. Lichen planus induced by pegylated interferon alfa-2a therapy in a patient monitored for delta hepatitis.

    Science.gov (United States)

    Kaya, Safak; Arslan, Eyup; Baysal, Birol; Baykara, Sule Nergiz; Uzun, Ozlem Ceren; Kaya, Sehmuz

    2015-01-01

    Interferons are used for treatment of chronic hepatitis B. They can induce or exacerbate some skin disorders, such as lichen planus. In this study, as we know, we presented the first case developing lichen planus while receiving interferon treatment due to delta hepatitis. A 31-year-old male patient presented to our outpatient clinic with HBsAg positivity. With his analyses, HBV DNA was negative, anti-delta total was positive, ALT was 72 U/L (upper limit 41 U/L), and platelet was 119 000/mm(3). He was therefore started on subcutaneous pegylated interferon alfa-2a therapy at 180 mcg/week for delta hepatitis. At month 4 of therapy, the patient developed diffuse eroded lace-like lesions in oral mucosa, white plaques on lips, and itchy papular lesions in the hands and feet. Lichen planus was considered by the dermatology clinic and topical treatment (mometasone furoate) was given. The lesions persisted at month 5 of therapy and biopsy samples were obtained from oral mucosal lesions and interferon dose was reduced to 135 mcg/week. Biopsy demonstrated nonkeratinized stratified squamous epithelium; epithelial acanthosis, spongiosis, and apoptotic bodies were observed in the epidermis and therefore lichen planus was considered. At month 6 of therapy, lesions did not improve and even progressed and interferon treatment was therefore discontinued.

  17. Kinetic of Virologic Response to Pegylated Interferon and Ribavirin in Children With Chronic Hepatitis C Predicts the Effect of Treatment.

    Science.gov (United States)

    Indolfi, Giuseppe; Nebbia, Gabriella; Cananzi, Mara; Maccabruni, Anna; Zaramella, Marco; D'Antiga, Lorenzo; Grisotto, Laura; Azzari, Chiara; Resti, Massimo

    2016-12-01

    Chronic hepatitis C is a global health problem. Although new, highly effective and safe direct-acting antivirals have been approved for adults, the only drugs currently registered for children are pegylated interferon and ribavirin. The timelines for the pediatric approval of the new treatment regimens are far off. Three phase II-III pediatric trials with direct-acting antivirals are recruiting, and the estimated dates of completion of these studies range between April 2018 and January 2023. The aim of this study was to evaluate the value of on-treatment virologic response (VR) as predictor of sustained virologic response (SVR) in a cohort of Italian children with chronic hepatitis C and to establish possible stopping rules. Sixty-four children were enrolled (January 2012 to December 2015). SVR rate was 79.7% (51/64). VR at weeks 2 to 12 were shown to be robust predictors for the attainment of SVR. The positive predictive values of VR at weeks 8 and 12 were 98% and 92.7%, respectively. The negative predictive values at the same treatment weeks were 92.9% and 100%, indicating that no child who did not achieve VR at week 12 obtained SVR and that the likelihood of achieving SVR if still positive at week 8 was very low. Our results suggest for the first time that VR at week 8 could be considered a reliable predictor of SVR. Monitoring viral kinetics is useful for predicting the success of pegylated interferon and ribavirin therapy in children.

  18. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.

    Science.gov (United States)

    Eggermont, Alexander M M; Suciu, Stefan; Santinami, Mario; Testori, Alessandro; Kruit, Wim H J; Marsden, Jeremy; Punt, Cornelis J A; Salès, François; Gore, Martin; Mackie, Rona; Kusic, Zvonko; Dummer, Reinhard; Hauschild, Axel; Musat, Elena; Spatz, Alain; Keilholz, Ulrich

    2008-07-12

    Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in

  19. Pegylated interferon monotherapy for hepatitis C virus infection in patients on hemodialysis: A single center study

    Directory of Open Access Journals (Sweden)

    S K Agarwal

    2016-01-01

    Full Text Available There is no published study from India on hepatitis C virus (HCV treatment in dialysis patients. Patients on dialysis with HCV infection treated with pegylated interferon (Peg-INF monotherapy were studied. All patients were subjected to HCV-polymerase chain reaction, viral load, genotype, and liver biopsy. Quantitative HCV-RNA was performed monthly. Patients with genotype 1 and 4 were given 12 month therapy while those with genotypes 2 and 3 were given 6 months therapy. Response was classified as per standard criteria of rapid virological response (RVR, early virological response (EVR, end of treatment response (ETR, and sustained virological response (SVR. A total of 85 patients were treated. Mean age was 35.2 ± 10.5 (range 15–67 years, and 77.6% were males. HCV genotypes were 1 in 40.9%, 2 in 12%, 3 in 36.1%, 4 in 3.6%, and others in 7.2%. Mean viral load was 106 copies/mL. Mean liver biopsy grade was 4 ± 1.7 and stage 0.8 ± 0.8. Mean time from diagnosis of HCV infection and the treatment start was 10.7 ± 14.3 months. One patient died of unrelated illness, one was lost to follow-up, and three could not sustain treatment due to cost. Forty-three of the 80 (54% patients had RVR while 49 (61% patients had EVR and ETR. There was no difference in term of RVR related to genotype. Fifty -four percentage had SVR. Mild flu-like symptoms were seen in all patients. Sixty-four (80% patients required increase in erythropoietin doses. Twenty-eight (35% patients developed leukopenia (three treatment-limiting and 16 (20% developed thrombocytopenia (one treatment-limiting. Five patients developed tuberculosis, five bacterial pneumonia, and one bacterial knee monoarthritis. None of the patients developed depression. Our study concludes that Peg-INF monotherapy resulted in 54% RVR and SVR in dialysis patients with HCV infection. Therapy was well-tolerated with minimal side effects. There was no effect of viral genotype on response to therapy.

  20. Low Efficacy of Pegylated Interferon plus Ribavirin plus Nitazoxanide for HCV Genotype 4 and HIV Coinfection.

    Directory of Open Access Journals (Sweden)

    Juan Macías

    Full Text Available Nitazoxanide (NTZ plus pegylated interferon and ribavirin (Peg-IFN/RBV improved the sustained virological response (SVR achieved with Peg-IFN/RBV in hepatitis C virus genotype 4 (HCV-4-monoinfected patients. There are no data currently on the efficacy of Peg-IFN/RBV plus NTZ for human immunodeficiency virus (HIV/HCV-4 coinfection. Therefore, the objectives of this clinical trial were to assess the efficacy and to evaluate the safety of Peg-IFN/RBV plus NTZ in HIV/HCV-4-coinfected patients.This was an open-label, single arm, multicenter phase II pilot clinical trial (NCT01529073 enrolling HIV-infected individuals with HCV-4 chronic infection, naïve to HCV therapy. Patients were treated with NTZ 500 mg bid for 4 weeks, followed by NTZ 500 mg bid plus Peg-IFN alpha-2b 1.5 μg/kg/week plus weight-adjusted RBV during 48 weeks. Analyses were done by intention-to-treat (ITT, missing = failure. A historical cohort of HIV/HCV-4-infected patients treated with Peg-IFN alpha-2b and RBV at the same area was used as control.Two (9.5% of 21 patients included in the trial compared with 5 (21.7% of 23 patients included in the historical cohort achieved SVR (SVR risk difference, -12.2%; 95% confidence interval, -33.2% to 8.8%; p = 0.416. Virological failure was due to lack of response in 13 (62% individuals recruited in the trial. Two (9.5% patients included in the trial and two (9.5% individuals from the historical cohort discontinued permanently due to adverse events.No increase in SVR was observed among HIV/HCV-4-coinfected patients receiving Peg-IFN/RBV plus NTZ compared with a historical cohort treated with Peg-IFN/RBV. Interruptions due to adverse events of Peg-IFN/RBV plus NTZ were similar to those of dual therapy.ClinicalTrials.gov NCT01529073.

  1. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma

    NARCIS (Netherlands)

    A.M.M. Eggermont (Alexander); S. Suciu (Stefan); A. Testori (Alessandro); M. Santinami (Mario); W.H.J. Kruit (Wim); J. Marsden (Jeremy); C.J.A. Punt (Cornelis); F. Salès (François); R. Dummer (Reinhard); C. Robert (Caroline); D. Schadendorf (Dirk); P. Patel (Poulam); G. de Schaetzen (Gaetan); A. Spatz (Alan); U. Keilholz (Ulrich)

    2012-01-01

    textabstractPurpose: Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. Patients and Methods: In all, 1,256 patients with resected stage III melanoma were randomly

  2. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response

    DEFF Research Database (Denmark)

    Dalgard, Olav; Bjøro, Kristian; Larsen, Helmer Ring

    2008-01-01

    treatment-naïve HCV RNA-positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon alpha-2b (1.5 microg/kg) subcutaneously weekly and ribavirin (800-1400 mg) orally daily...

  3. Pegylated-Interferon Alpha 2b and Ribavirin for Recurrent Hepatitis C after Liver Transplantation: From a Canadian Experience to Recommendations for Therapy

    Directory of Open Access Journals (Sweden)

    Mohamed Babatin

    2005-01-01

    Full Text Available BACKGROUND: Recurrent hepatitis C (HCV after liver transplantation (LT is often more aggressive and treatments tend to be less successful. Pegylated-interferon and ribavirin are the standard of care for the treatment of HCV; however, there is limited published experience of its use after LT.

  4. Efficacy and safety of pegylated interferon plus ribavirin therapy for chronic hepatitis C genotype 6: a meta-analysis.

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    Xiwei Wang

    Full Text Available BACKGROUND: Hepatitis C genotype 6 (HCV-6 is prevalent in Southeast Asia. Data on the efficacy of direct-acting antiviral agents in chronic HCV-6 patients is limited and pegylated interferon (Peg-IFN plus ribavirin (RBV combination therapy remains standard therapy for those patients. AIM: Meta-analysis was performed to assess the efficacy and safety of Peg-IFN plus RBV combination therapy for chronic HCV-6 patients. METHODS: Relevant studies were found by database search through Medline, Embase, Web of Science and The Cochrane Library. All published clinical trials assessing the efficacy of Peg-IFN plus RBV combination therapy for chronic HCV-6 patients were included. Sustained virological response rate (SVR was pooled. We performed additional meta-analyses to compare the SVR outcomes of 24 versus 48 weeks of treatment in four head-to-head trials. Another second meta-analysis was also conducted to compare the efficacy of combination Peg-IFN plus RBV therapy in HCV-6 versus HCV-1 patients. RESULTS: Thirteen studies met the inclusion criteria. The pooled SVR of all single arms was 75% (95% CI: 0.68-0.81. The SVR of 24 weeks treatment was significantly lower than that at 48 weeks, with a risk difference of -14% (95% CI: -0.25 to -0.02, p = 0.02. However, when restricted to the patients with rapid virological response (RVR, there was no significant effect on SVR between these two treatment groups, with a risk difference of -1% (95% CI: -0.1 to 0.07, p = 0.67. The SVR in HCV-6 patients was significantly higher than that in HCV-1 patients, with a relative risk of 1.35 (95% CI: 1.16-1.57, p<0.001. Side effects were common, but rarely caused treatment discontinuation. CONCLUSIONS: The results of this meta-analysis suggest that Peg-IFN plus RBV is effective and safe for HCV-6 patients. Shortening treatment seems to be feasible in HCV-6 patients with RVR when tolerance to treatment is poor. However, this decision should be made cautiously.

  5. De novo Cryoglobulinaemic Mononeuritis Multiplex during Treatment of Chronic Hepatitis C Infection: A Viral Effect or Induced by Pegylated Interferon Alpha

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    J.R. Potts

    2012-03-01

    Full Text Available Cryoglobulinaemic mononeuritis multiplex (MNM is an extrahepatic manifestation of chronic hepatitis C virus (HCV infection for which interferon-based antiviral therapy is currently the treatment of choice. Rarely MNM can be associated with HCV treatment though generally in the setting of pre-existing cryoglobulinaemia and detectable HCV viraemia. We report an unusual case of de novo MNM occurring late during the course of pegylated interferon and ribavirin therapy for chronic HCV infection, following a prolonged period of viral suppression. The patient had no evidence of cryoglobulinaemia prior to HCV treatment and undetectable HCV RNA levels at the time of presentation with MNM. The case raises the possibility that MNM could develop as an adverse immunomodulatory effect of pegylated interferon therapy.

  6. Acute pericarditis due to pegylated interferon alpha therapy for chronic HCV hepatitis - Case report

    Science.gov (United States)

    2011-01-01

    Background Cardio toxicity due to interferon therapy was reported only in small case series or case reports. The most frequent cardiac adverse effects related to interferon are arrhythmias and ischemic manifestations. The cardiomyopathy and pericarditis are rare but can be life threatening. The predisposing factors for interferon cardio toxicity were described only for ischemic manifestations and arrhythmias. Case presentation The authors report a case of pericarditis due to alpha interferon therapy for chronic hepatitis C, in a young woman without previous cardiac pathology. The clinical manifestations started during the 7-th month of interferon treatment. The cessation of interferon was necessary. After interferon discontinuation the patient recovered, with complete resolution of pericarditis. The patient scored 9 points on the Naranjo ADR probability scale, indicating a very probable association between pericarditis and interferon administration. Conclusion If a patient receiving interferon therapy complains of chest pain of sudden onset, a cardiac ultrasound should be performed in order to rule out pericarditis. We point out the possibility of an infrequent but severe adverse effect of interferon therapy. PMID:21453456

  7. Transient Hypothyroidism and Autoimmune Thyroiditis in Children with Chronic Hepatitis C Treated with Pegylated-Interferon-α-2b and Ribavirin.

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    Serranti, Daniele; Indolfi, Giuseppe; Nebbia, Gabriella; Cananzi, Mara; D'Antiga, Lorenzo; Ricci, Silvia; Stagi, Stefano; Azzari, Chiara; Resti, Massimo

    2017-09-22

    Autoimmune thyroid disease and thyroid dysfunction are common in adults receiving interferon-based treatment for chronic hepatitis C (CHC). Few data are available in children with CHC. This study is aimed to evaluate the appearance and timing of thyroid dysfunction and anti-thyroid autoimmunity in children with CHC treated with pegylated interferon-α-2b and ribavirin. 61 otherwise healthy children with CHC, 3-17 years of age, infected perinatally and treatment naïve, receiving therapy with pegylated interferon-α-2b and ribavirin and 183 age- and sex-matched controls were included in a multicenter, prospective, case-control study. Thyroid-stimulating hormone, free thyroxine, anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies were assessed before, during and 24 weeks after the end of treatment. From baseline to the end of treatment subclinical hypothyroidism and autoimmune thyroiditis were diagnosed in 17/61 (27.94%) and in 4/61 (6.6%) of the children treated, respectively, and in 5/183 (2.7%) and in none of the controls [p < 0.0001, relative risk (RR): 10.2, 95% confidence interval (CI): 3.9 to 26.5; p = 0.03, RR: 26.8, 95% CI: 1.5 to 489.1, respectively]. Twenty-four weeks after the end of treatment subclinical hypothyroidism persisted in only 4/61 (6.6%). Autoimmune thyroiditis persisted in 3/4 (75%) of the cases. Subclinical hypothyroidism is common in children with CHC receiving treatment with pegylated interferon-α-2b and ribavirin, but in most cases is transient. Autoimmune thyroiditis, which is less common, generally persists after treatment completion. Thyroid function should be carefully monitored in patients presenting with anti-thyroid autoantibodies and thyroid dysfunction during and after pegylated interferon-α based treatment.

  8. Retinopatia em paciente portador de hepatite C tratado com interferon peguilado e ribavirina: relato de caso Retinopathy in a patient with hepatitis C treated with pegylated interferon and ribavirin: case report

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    Marcos Pereira de Ávila

    2006-04-01

    Full Text Available O interferon é uma citocina imunomoduladora utilizada no tratamento de diversas doenças, incluindo infecções crônicas pelo vírus da hepatite C. O interferon peguilado é uma nova forma de interferon, desenvolvida para aumentar o tempo de meia-vida da droga. Uma série de efeitos adversos têm sido associados ao uso do interferon, dentre eles a toxicidade ocular com desenvolvimento de retinopatia. As lesões oculares típicas incluem exsudatos algodonosos e hemorragias retinianas no pólo posterior, particularmente em torno do disco óptico. Descrevemos o caso de paciente tratado com associação de interferon peguilado e ribavirina com diminuição da acuidade visual e quadro oftalmológico compatível com retinopatia associada ao interferon. Quatro semanas após a suspensão do interferon, houve melhora da acuidade visual e diminuição importante das alterações retinianas.Interferon is an immunomodulating cytokine used to treat patients with different diseases, such as hepatitis C chronic infection. Pegylated interferon is a new type of interferon, developed to increase the half-life of the drug. Many side effects have been related to its use, including ocular toxicity and retinopathy. The most reported ocular findings are cotton-wool spots and hemorrhages located at the posterior pole and surrounding optic nerve head. We describe one case of pegylated interferon-associated retinopathy with visual loss. The patient had visual acuity improvement four weeks after discontinuation of the medication and the ocular findings became much more subtle.

  9. Single-dose pharmacokinetics and safety of pegylated interferon-alpha2b in patients with chronic renal dysfunction.

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    Gupta, Samir K; Pittenger, Amy L; Swan, Suzanne K; Marbury, Thomas C; Tobillo, Emlyn; Batra, Vijay; Sack, Marshall; Glue, Paul; Jacobs, Sheila; Affrime, Melton

    2002-10-01

    This study evaluates the pharmacokinetics and safety of pegylated interferon-alpha2b (PEG-Intron) following a single-dose subcutaneous injection into subjects with normal renal function, subjects with chronic renal impairment, and patients on hemodialysis. In this open-label, single-dose, parallel group study, subjects were divided into five groups according to their degree of renal function: four groups as defined by measured creatinine clearance and a fifth hemodialysis dependent group. They received 1 microg/kg PEG-Intron subcutaneously after a 10-hour fast. Pharmacokinetic and safety assessments were performed up to 168 hours postdose. Hemodialysis patients had a second PEG-Intron dose 12 hours prior to a hemodialysis session. PEG-Intron pharmacokinetic parameters (AUCtf, Cmax, and t1/2) increased progressively as CL(CR) declined. All subjects reported at least one adverse event, which were typical of those reported after alpha-interferon administration (e.g., flu-like symptoms, headache). Single-dose PEG-Intron administration to volunteers with normal renal function and chronic renal impairment was safe and well tolerated. In patients with CL(CR) < 30 ml/min, AUCand Cmax values were increased 90% compared with controls, while half-life was increased by up to 40% over controls. Based on the relationship between PEG-Intron apparent clearance and CL(CR), renal clearance accountsfor less than half of its total clearance. Hemodialysis did not affect PEG-Intron apparent clearance.

  10. Short versus standard treatment with pegylated interferon alfa-2A plus ribavirin in patients with hepatitis C virus genotype 2 or 3: the cleo trial

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    Picardi Antonio

    2010-02-01

    Full Text Available Abstract Background In patients with chronic hepatitis C virus (HCV genotype 2 or 3, 24 weeks' treatment with pegylated interferon alfa (PEG-IFN-alpha and ribavirin induces a sustained virological response (SVR in almost 80% of cases. Evidence suggests that a similar response rate may be obtained with shorter treatment periods, especially in patients with a rapid virological response (RVR. The aim of this study was to compare the efficacy of 12 or 24 weeks of treatment in patients with chronic HCV genotype 2 or 3 and to identify patients suitable for 12 weeks treatment. Methods Two hundred and ten patients received PEG-IFN-alpha-2a (180 ug/week and ribavirin (800-1200 mg/day for 4 weeks. Patients with a RVR (HCV RNA not detectable were randomized (1:1 to either 12 (group A1 or 24 (group A2 weeks of combination therapy. Patients without a RVR continued with 24-weeks' combination therapy (group B. HCV RNA was monitored at weeks 4, 8, 12, and 24, and at week 24 post-treatment. Results At study end, end of treatment response (ETR was observed in 62 (86% patients of group A1 and in 55 (77% patients of group A2 (p Conclusion In HCV patients with genotype 2 or 3, 12-week combination therapy is as efficacious as 24-week therapy and several independent covariates were predictive of SVR. Trial registration Trial number ISRCTN29259563

  11. Unmasking of myasthenia gravis during pegylated Alfa 2 a interferon and ribavirin therapy for chronic hepatitis C.

    Science.gov (United States)

    Saleem, Ayesha

    2016-05-01

    Over last few decades, hepatitis C has emerged as a serious infection that has threatened the health and budgets of millions in the world. The objective of health professionals to treat it with recommended therapy of Alfa interferon and Ribavirin combination presents certain risks. One of the alarms is the ability of interferon to stimulate the production of autoantibodies in the body resulting in expression of autoimmune diseases in few who develop these antibodies. The case presented here is about unmasking of myasthenia gravis in a patient who received alfa interferon therapy for her chronic hepatitis C. Alfa interferon probably plays an important role in manifestation of the diseases in susceptible patients and all autoimmune diseases cannot be taken as mere side effects of the therapy. Clinicians need to be alert to pick up these diseases earlier so that the prompt management is possible.

  12. Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial.

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    Asmuth, David M; Murphy, Robert L; Rosenkranz, Susan L; Lertora, Juan J L; Kottilil, Shyam; Cramer, Yoninah; Chan, Ellen S; Schooley, Robert T; Rinaldo, Charles R; Thielman, Nathan; Li, Xiao-Dong; Wahl, Sharon M; Shore, Jessica; Janik, Jennifer; Lempicki, Richard A; Simpson, Yaa; Pollard, Richard B

    2010-06-01

    To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.

  13. Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy.

    Science.gov (United States)

    Marcellin, Patrick; Wursthorn, Karsten; Wedemeyer, Heiner; Chuang, Wan-Long; Lau, George; Avila, Claudio; Peng, Cheng-Yuan; Gane, Edward; Lim, Seng Gee; Fainboim, Hugo; Foster, Graham R; Safadi, Rifaat; Rizzetto, Mario; Manns, Michael; Bao, Weibin; Trylesinski, Aldo; Naoumov, Nikolai

    2015-01-01

    This study investigated the antiviral efficacy and safety of telbivudine in combination with pegylated interferon (PegIFN) alpha-2a in chronic hepatitis B (CHB) patients. This was a randomized, open-label, multicentre study, in treatment-naïve patients with HBeAg-positive CHB, comparing the efficacy and safety of telbivudine in combination with PegIFN alpha-2a with telbivudine monotherapy and PegIFN alpha-2a monotherapy. The study was terminated early due to increased rates of peripheral neuropathy in the combination-therapy group. Of the 159 patients randomized (from 300 planned) 50 were assigned to combination therapy, 55 to telbivudine, 54 to PegIFN, and 110 (18, 49, and 43, respectively) reached week 24. Peripheral neuropathy occurred in 7/50, 1/54, and 0/54 patients in the three groups of safety populations, respectively. No relationship between the occurrence of peripheral neuropathy and other variables (e.g., pharmacokinetic data, treatment efficacy, ALT levels, creatine kinase elevations) were observed. At week 24, undetectable HBV DNA (<300 copies/ml) was achieved by 71% (12/17), 35% (17/48), and 7% (3/42) of patients, with available data receiving combination therapy, telbivudine monotherapy and PegIFN monotherapy, respectively (p = 0.022 for combination therapy vs. telbivudine; p<0.0001 for combination therapy vs. PegIFN). Combination therapy carried an increased risk of peripheral neuropathy. Despite the rapid and profound reductions in HBV DNA levels, combination therapy with telbivudine and PegIFN should not be used. Copyright © 2014. Published by Elsevier B.V.

  14. Treatment of chronic hepatitis C in non-responsive patients with pegylated interferon associated with ribavirin and thalidomide: report of six cases of total remission Tratamento de hepatite C crônica em pacientes não respondedores, com a associação interferon peguilado, ribavirina e talidomida: Relato de seis casos

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    Marcos Montani Caseiro

    2006-04-01

    Full Text Available Hepatitis C virus (HCV infection is an important public health issue worldwide. It is estimated that over 170 million people are infected with the virus. The present study reports six cases in which patients did not respond to combination therapy with pegylated interferon and ribavirin. However, after the addition of thalidomide to the therapy, the patients presented negative RNA PCR. The use of thalidomide combined with pegylated interferon and ribavirin for the treatment of hepatitis C is described here for the first time in the related literature.A infecção pelo vírus da Hepatite C (HCV representa um importante problema de saúde pública no mundo, estima-se que mais de 170 milhões de pessoas estejam infectadas. Relatamos o encontro de 6 pacientes não respondedores à associação de Interferon Peguilado e Ribavirina que negativaram seu PCRRNA após a associação com talidomida. Trata-se do primeiro relato desta associação no tratamento da hepatite C encontrado na literatura.

  15. The influence of treatment with pegylated interferon-alfa and ribavirin on neutrophil function and death in patients with HIV/HCV coinfection.

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    Jablonowska, Elzbieta; Wojcik, Kamila; Nocun, Marek

    2012-04-01

    In patients with human immunodeficiency virus (HIV) as well as in patients with hepatitis C virus (HCV) infection the impairment of neutrophil activity is observed. We decided to analyze how treatment with pegylated interferon-alfa (Peg-IFN-alfa) and ribavirin affects neutrophil function in HIV/HCV coinfected patients. The study group consisted of 18 patients with HIV/HCV coinfection, on combination antiretroviral treatment (cART), aged between 27 and 42 y (mean 33.1±4.5 y). At the beginning of treatment with Peg-IFN-alfa and ribavirin all patients had an undetectable HIV viral load, and CD4 T-cell counts higher than 350 cells/μL. At two time points, before and after 12 wk of treatment with Peg-IFN-alfa and ribavirin, we examined intracellular levels of reactive oxygen species (ROS), and expression of selected adhesion molecules on whole blood neutrophils, along with apoptosis and necrosis of these cells. These analyses were done with flow cytometry. During anti-HCV therapy undetectable HIV levels were maintained in all patients. Treatment with PEG-IFN-alfa and ribavirin resulted in increases in the expression of CD11b and CD18, and decreases of CD16 and CD62L. However, only the change in CD62L expression was statistically significant (palfa and ribavirin treatment caused an activation of neutrophil function, yet it did not affect the suppression of HIV replication.

  16. A randomized, open-label, multicenter study evaluating the efficacy of peginterferon alfa-2a versus interferon alfa-2a, in combination with ribavirin, in naïve and relapsed chronic hepatitis C patients.

    Science.gov (United States)

    Nevens, F; Van Vlierberghe, H; D'Heygere, E; Delwaide, J; Adler, M; Henrion, J; Lenaerts, A; Hendlisz, A; Michielsen, P; Bastens, B; Brenard, R; Laureys, A

    2010-01-01

    A large multicenter trial to compare the efficacy of peginterferon alfa-2a with interferon alfa-2a, in combination with ribavirin, in chronic hepatitis C patients. Efficacy data for prior relapsers are reported because treatment recommendations for this patient population are not well defined. This study was a multicenter, prospective, randomized clinical trial. The primary efficacy endpoint was sustained virologic response in naive patients (n = 348) and relapsers (n = 95). Sustained virologic response rates were similar in naïve patients and relapsers, both for non-pegylated and pegylated interferon (respectively 27 and 26% and 54 and 43%). Pegylated interferon given for 48 weeks did not improved the relapse rate: 15.9 and 27.3% for non-pegylated and 16.7 and 30.4% for pegylated interferon, naïve vs relapsers respectively. Stepwise logistic regression analysis revealed a significant association between slow response (detectable HCV RNA at week 12 and undetectable at week 24) and relapse in patients with an end-of-treatment response (55% versus 13% respectively; p = 0.02; odds ratio = 6.07). This trial confirms the value of using peginterferon alfa-2a in both naïve and relapsed patients and provides support for a more tailored approach to treatment for relapsers and particulary for patients with a slow viral response.

  17. Effect of aging, glucose level, and HIV viral load on response to treatment with pegylated interferon plus ribavirin in HIV/HCV co-infected women.

    Science.gov (United States)

    Nasta, Paola; Maida, Ivana; Cattelan, Anna Maria; Pontali, Emanuele; Angeli, Elena; Giralda, Mariarosaria; Verucchi, Gabriella; Caputo, Antonietta; Iannacone, Claudio; Puoti, Massimo; Carosi, Giampiero

    2015-02-01

    This was a post-hoc analysis of the Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study, originally designed to document routine clinical and treatment data in HIV/HCV coinfected patients treated with pegylated interferon/ribavirin (PEG-IFN/RBV). The aim of this study was to define the impact of several variables, such as age, glucose metabolism, and HIV viral load, on PEG-IFN/RBV treatment outcomes, in HIV/HCV coinfected women. Female subjects from the OPERA database were retrospectively evaluated and factors associated with sustained virological response (SVR) were assessed and compared to the male population by logistic regression analysis. At baseline, clinical and demographic data were collected. Patients were then administered with PEG-IFN/RBV therapy for 48 weeks. After a 24-week follow-up period, SVR was evaluated. A total of 1523 patients were enrolled in 98 centers across Italy, 1284 of whom were IFN therapy naïve and were included in the post-hoc analysis. In the female group, factors associated with SVR were the presence of HCV genotype 2,3 (adjusted odds ratio [AOR]=6.87, pHIV-RNA (AOR=1.47, p=0.033) but not glucose level (AOR=1.0, p=0.95) predicted SVR. Findings from the present study demonstrate that several factors may be predictive of SVR when pegylated interferon plus ribavirin is used (i.e., age, gender, HIV viral load and HCV genotype) that need to be carefully considered prior to therapeutic intervention, since they may hinder successful therapy. Use of PEG-IFN/RBV with novel direct antiviral agents will likely be still maintained until less expensive and effective interferon-free strategies become available.

  18. Celiac disease onset after pegylated interferon and ribavirin treatment of chronic hepatitis C Doença celíaca após tratamento de hepatite C crônica com interferon peguilado e ribavirina

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    Elson V. Martins Jr.

    2004-06-01

    Full Text Available AIM: Report of a case of a woman patient who developed celiac disease after pegylated interferon alpha-2a and ribavirin use for chronic hepatitis C. PATIENT AND METHOD: A 34-year-old woman with chronic hepatitis C, genotype 3, receiving pegylated interferon alpha-2a and ribavirin for 6 months, developed progressive malaise and anemia 6 months after the end of treatment. RESULT: Additional investigation revealed duodenal villous atrophy and positivity for anti-endomysium and anti-gliadin antibodies. Celiac disease diagnosis was performed and symptoms and laboratory abnormalities improved after gluten-free diet. CONCLUSION: Celiac disease must be ruled out in patients with malabsorption complaints in or after interferon (or pegylated interferon therapy. Screening for celiac disease with detection of anti-endomysium antibodies would be done in susceptible patients.OBJETIVO: Relatar caso de doença celíaca ocorrendo após uso de interferon peguilado e ribavirina em paciente com hepatite C crônica. PACIENTE E MÉTODO: Mulher de 34 anos com hepatite C crônica, genótipo 3, tratada com interferon peguilado alfa-2a e ribavirina durante 6 meses, desenvolveu quadro de astenia e anemia após 6 meses do término do tratamento. RESULTADO: Investigação complementar revelou atrofia vilositária à biopsia duodenal e detecção de anticorpos anti-endomísio e anti-gliadina, realizando-se diagnóstico de doença celíaca. Dieta isenta de glúten foi instituída, observando-se boa resposta clínica e laboratorial. CONCLUSÃO: Doença celíaca deve ser afastada em pacientes com quadro de má absorção durante ou após uso de interferon (ou interferon peguilado. Rastreamento de doença celíaca através da realização de anticorpo anti-endomísio pode ser considerado em populações susceptíveis.

  19. ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C.

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    Sakamoto, Naoya; Tanaka, Yasuhito; Nakagawa, Mina; Yatsuhashi, Hiroshi; Nishiguchi, Shuhei; Enomoto, Nobuyuki; Azuma, Seishin; Nishimura-Sakurai, Yuki; Kakinuma, Sei; Nishida, Nao; Tokunaga, Katsushi; Honda, Masao; Ito, Kiyoaki; Mizokami, Masashi; Watanabe, Mamoru

    2010-11-01

    Host genetic variants leading to inosine triphosphatase (ITPA) deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in chronic hepatitis C patients receiving ribavirin. In this study, we evaluated the clinical significance of ITPA variants in Japanese hepatitis C patients who were treated with pegylated interferon plus ribavirin. In this multicenter retrospective cross-sectional study, 474 hepatitis C patients were enrolled who were treated with pegylated interferon plus ribavirin in four geographically different hospitals in Japan. Patients were grouped according to hemoglobin decline of more than 3 g/dL at week 4. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs6051702, rs1127354) were genotyped.  A functional SNP, rs1127354, within the ITPA exon was strongly associated with protection against anemia with only one (0.8%) in 129 patients with the ITPA minor variant A developing severe anemia (P=5.9×10(-20) ). For rs6051702, which had significant association in European-Americans, significant but weak association with severe hemoglobin reduction was found in Japanese (P= 0.009). In patients excluding genotype 1b and high viral load, those with the ITPA minor variant A achieved significantly higher sustained viral response rate than those with the major variant (CC) (96% vs 70%, respectively, P= 0.0066). ITPA SNP, rs1127354, is confirmed to be a useful predictor of ribavirin-induced anemia in Japanese patients. Patients with the ITPA minor variant A (~ 27%) have an advantage in pegylated interferon plus ribavirin-based therapies, due to expected adherence of ribavirin doses, resulting in a higher viral clearance rate. © 2010 The Japan Society of Hepatology.

  20. Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas.

    Science.gov (United States)

    Jakacki, Regina I; Dombi, Eva; Steinberg, Seth M; Goldman, Stewart; Kieran, Mark W; Ullrich, Nicole J; Pollack, Ian F; Goodwin, Anne; Manley, Peter E; Fangusaro, Jason; Allen, Rudy; Widemann, Brigitte C

    2017-02-01

    There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP). PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1‒related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (≥20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib. Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044). In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status.

  1. Durability of Response in Children Treated With Pegylated Interferon alfa [corrected] 2a ± Ribavirin for Chronic Hepatitis C.

    Science.gov (United States)

    Schwarz, Kathleen B; Molleston, Jean P; Jonas, Maureen M; Wen, Jessica; Murray, Karen F; Rosenthal, Philip; Gonzalez-Peralta, Regino P; Lobritto, Steven J; Mogul, Douglas; Pavlovic, Vedran; Warne, Charles; Wat, Cynthia; Thompson, Bruce

    2016-01-01

    No long-term data have been published on the durability of response following pegylated interferon (PegIFN) treatment in children with chronic hepatitis C. This prospective, multicenter, long-term follow-up (LTFU) study aimed to assess long-term durability of sustained virological response (SVR), long-term safety and tolerability, and the association between IL28B genotype and treatment response, in children previously treated with PegIFN alfa-2a ± ribavirin (RBV) in the PEDS-C trial. A total of 93 patients were assessed for enrollment, and 38 enrolled in the study. Patients attended 2 study visits: 5 (mean 5.6, range 4.1-6.6) and 6 (6.6, 5.1-7.7) years after treatment cessation. Standardized medical history, physical examination, and laboratory testing were performed at these visits. Reminder telephone calls were conducted at 4 and 8 months after the initial visit. The LTFU cohort was the representative of the original PEDS-C cohort because both baseline and treatment characteristics were comparable. Of the 38 participants, 21 achieved SVR (responders) during the PEDS-C trial and 17 had not (nonresponders). All 21 responders maintained undetectable hepatitis C virus RNA during the LTFU (4.4-7.0 years after achieving SVR) in contrast to the nonresponders who demonstrated persistent viremia. IL28B CC genotype was associated with SVR (67% vs 30% in non-CC, P = 0.028). Long-term durability of SVR is excellent following PegIFN alfa-2a treatment in children with chronic hepatitis C; SVR is higher in those with IL28B CC versus non-CC.

  2. Impact of pegylated interferon alfa-2a treatment on mental health during recent hepatitis C virus infection

    Science.gov (United States)

    Alavi, Maryam; Grebely, Jason; Matthews, Gail V.; Petoumenos, Kathy; Yeung, Barbara; Day, Carolyn; Lloyd, Andrew R.; Van Beek, Ingrid; Kaldor, John M.; Hellard, Margaret; Dore, Gregory J; Haber, Paul S.

    2011-01-01

    Background Pegylated interferon (PEG-IFN) treatment for hepatitis C virus (HCV) infection has neuropsychiatric side effects. Data on the impact of HCV treatment on mental health among injecting drug users (IDUs) are limited. We assessed mental health during treatment of recently acquired HCV, within a predominantly IDU population. Methods Participants with HCV received PEG-IFN α-2a (180µg/week) for 24 weeks; HCV/HIV received PEG-IFN with ribavirin. Depression was assessed using the Mini-International Neuropsychiatric Interview (MINI). Logistic regression was used to identify factors associated with depression at enrolment and during treatment. Also, the impact of depression prior to and during treatment on SVR was assessed. Results Of 163 participants, 111 received treatment (HCV, n=74; HCV/HIV, n=37), with 76% ever reporting IDU. At enrolment, 16% had depression (n=25). In adjusted analysis, depression at enrolment occurred less often in participants full-/part-time employed (AOR 0.23; 95% CI: 0.06, 0.82, P=0.023) and more often in recent IDUs (AOR 3.04; 95% CI: 1.19, 7.72, P=0.019). During treatment, 35% (n=31) developed new-onset depression. In adjusted analysis, poorer social functioning (higher score) was associated with new-onset depression (score ≤9 vs. score ≥17; OR 5.69; 95% CI: 1.61, 20.14, P=0.007). SVR was similar among participants with and without depression at enrolment (60% vs. 61%, P=0.951) and in those with and without new-onset depression (74% vs. 63%, P=0.293). Conclusions Although depression at enrolment and during treatment was common among participants with recent HCV, neither impacted SVR. Participants with poor social functioning may be most at risk of developing depression during HCV therapy. PMID:22142332

  3. Effect of pegylated interferon-α-2a treatment on mental health during recent hepatitis C virus infection.

    Science.gov (United States)

    Alavi, Maryam; Grebely, Jason; Matthews, Gail V; Petoumenos, Kathy; Yeung, Barbara; Day, Carolyn; Lloyd, Andrew R; Van Beek, Ingrid; Kaldor, John M; Hellard, Margaret; Dore, Gregory J; Haber, Paul S

    2012-05-01

    Pegylated interferon (PEG-IFN) treatment for hepatitis C virus (HCV) infection has neuropsychiatric side effects. Data on the effect of HCV treatment on mental health among injecting drug users (IDUs) are limited. We assessed mental health during treatment of recently acquired HCV, within a predominantly IDU population. Participants with HCV received PEG-IFN-α-2a (180 µg/week) for 24 weeks; HCV/HIV received PEG-IFN with ribavirin. Depression was assessed using the Mini-International Neuropsychiatric Interview (MINI). Logistic regression was used to identify factors associated with depression at enrolment and during treatment. Also, the effect of depression prior to and during treatment on sustained virological response (SVR) was assessed. Of 163 participants, 111 received treatment (HCV, n = 74; HCV/HIV, n = 37), with 76% ever reporting IDU. At enrolment, 16% had depression (n = 25). In adjusted analysis, depression at enrolment occurred less often in participants full-/part-time employed (adjusted odds ratio [AOR] 0.23; 95% confidence interval [CI]: 0.06, 0.82, P = 0.023) and more often in recent IDUs (AOR 3.04; 95% CI: 1.19, 7.72, P = 0.019). During treatment, 35% (n = 31) developed new-onset depression. In adjusted analysis, poorer social functioning (higher score) was associated with new-onset depression (score ≤ 9 vs score ≥ 17; OR 5.69; 95% CI: 1.61, 20.14, P = 0.007). SVR was similar among participants with and without depression at enrolment (60% vs 61%, P = 0.951) and in those with and without new-onset depression (74% vs 63%, P = 0.293). Although depression at enrolment and during treatment was common among participants with recent HCV, neither influenced SVR. Participants with poor social functioning may be most at risk of developing depression during HCV therapy. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  4. Extrahepatic manifestations of chronic hepatitis C and their influence on response to treatment with Pegylated interferon alfa-2a and ribavirin

    OpenAIRE

    Fabri Milotka; Ružić Maja; Lendak Dajana; Preveden Tomislav; Fabri Izabela; Petrić Vedrana

    2013-01-01

    Introduction. Thirty to 50% of patients with chronic hepatitis C (CHC) have one or more extrahepatic manifestations (EHMs) of hepatitis C virus (HCV) infection. Objective. The aim of this study was to evaluate the frequency of EHMs and to investigate the efficacy of pegylated interferon (Peg­IFN)­α­2a plus ribavirin therapy in patients with HCV­related EHMs. Methods. The study included 280 patients suffering from CHC and treated with Peg­IFN­α­2a and ribavirin. The patients were divided...

  5. Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3.

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    Nelson, David R; Benhamou, Yves; Chuang, Wan-Long; Lawitz, Eric J; Rodriguez-Torres, Maribel; Flisiak, Robert; Rasenack, Jens W F; Kryczka, Wiesław; Lee, Chuan-Mo; Bain, Vincent G; Pianko, Stephen; Patel, Keyur; Cronin, Patrick W; Pulkstenis, Erik; Subramanian, G Mani; McHutchison, John G

    2010-10-01

    A phase 3 active-controlled study was conducted to assess the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of recombinant human albumin and interferon alfa-2b, in patients with chronic hepatitis C virus (HCV) genotype 2/3. In all, 933 patients were randomized to open-label subcutaneous treatment with pegylated interferon-alfa-2a (Peg-IFNalfa-2a) 180 μg/wk, or albIFN 900 or 1200 μg every 2 weeks for 24 weeks, each administered with oral ribavirin 800 mg/day. The primary end point of the study was sustained virologic response (SVR) (HCV-RNA level, alfa-2b 900 μg every 2 weeks provides an alternative efficacious treatment option in patients with chronic HCV genotype 2 or 3. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  6. [Cognitive disturbances observed in chronic hepatitis C patients during pegylated interferon alpha and ribavirin therapy].

    Science.gov (United States)

    Pawełczyk, Tomasz; Pawełczyk, Agnieszka; Białkowska, Jolanta; Jabłkowski, Maciej; Strzelecki, Dominik; Dworniak, Daniela; Rabe-Jabłońska, Jolanta

    2008-01-01

    Chronic hepatitis C (CHC) patients treated with peg-interferon alpha and ribavirin (peg-IFNalpha/RBV) complain of irritability, attention and memory disturbances which may indicate cognitive impairment associated with treatment. Assessment of the probable connection between peg-IFNalpha/RBV treatment and the development of cognitive disturbances in CHC patients. 47 CHC patients were divided into two groups: experimental (n=26) and control (n=21). The experimental group patients were given peg-IFNalpha2a (n=18) or peg-IFNalpha2b (n=8) plus RBV in standard doses as recommended by the manufacturers. Control group patients did not receive the above treatment. Both groups underwent a neuropsychological examination consisting of R. Brickenkamp d2 test, Auditory Verbal Learning Test and Hooper Visual Organization Test at the beginning (t=0) and after 12 weeks of treatment or observation (t=1). The experimental group patients showed significant deterioration in all the measured cognitive functions in t=1 comparing to t=0. Cognitive decline was not seen in the control group. The observed cognitive performance changes could not be correlated sufficiently enough with the presence of organic affective disorders diagnosed according to ICD-10 criteria. The findings suggest that peg-IFNalpha/RBV therapy of CHC patients is connected with the deterioration in cognitive functioning including attention, auditory verbal memory and visuo-spatial skills. These changes may be the effect of peg-IFNalpha-induced neurotransmission abnormalities in the dorso-lateral prefrontal cortex, anterior cingulate cortex, hippocampus and parieto-orbital cortical regions and can impair patients' ability to drive a motor vehicle, operate machinery, or their engagement in hazardous activities requiring attention and coordination. Medical professionals should thoroughly inform patients about the possibility of cognitive decline associated with peg-IFNalpha/RBV therapy.

  7. PEGYLATED INTERFERON AND RIBAVIRIN FOR TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION: a single-liver transplant center experience in Brazil

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    José Huygens Parente GARCIA

    2015-09-01

    Full Text Available BackgroundTreatment of hepatitis C virus infection in post-transplantation patients is a challenge due to poor tolerance and low success rates.ObjectiveTo determine the response rate to pegylated interferon and ribavirin in post-liver transplant patients with hepatitis C recurrence.MethodsBetween 18 May 2002 and 18 December 2011, 601 patients underwent liver transplantation at our service (Hospital Universitário Walter Cantídio, University of Ceará, 176 (29.2% of whom were hepatitis C virus positive. Forty received antiviral therapy and were included in this cohort study. Twenty-eight (70% completed the treatment protocol, which consisted of pegylated interferon and ribavirin for 48 weeks.ResultsThe sustained virological response rate was 55% according to intention-to-treat analysis. Recipient age and exposure to antiviral drugs prior to liver transplantation were associated with sustained virological response in the multivariate analysis. Patients were followed for 57 months on the average. Survival at 1 and 5 years was 100% in responders, versus 100% and 78%, respectively, in non-responders.ConclusionSustained virological response rates were satisfactory in our series of liver transplantation patients, and decreased with increasing recipient age. Non-exposure to antiviral drugs prior to liver transplantation was positively associated with sustained virological response. The overall survival of responders and non-responders was similar.

  8. HBcrAg Identifies Patients Failing to Achieve HBeAg Seroconversion Treated with Pegylated Interferon Alfa-2b.

    Science.gov (United States)

    Ma, Hui; Yang, Rui-Feng; Li, Xiao-He; Jin, Qian; Wei, Lai

    2016-09-20

    We aimed to evaluate the usefulness of serum hepatitis B virus core-related antigens (HBcrAg) for predicting hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients treated with conventional interferon (IFN) alfa-2b or pegylated IFN. Fifty-eight patients were enrolled: 29 for the training group and 29 for the validating group. HBcrAg was measured at baseline, week 12, end of the treatment, and 12- and 24-week follow-ups. Sixteen patients in the training group were enrolled in the long-term follow-up (LTFU), during which time the dynamics of the HBcrAg was monitored. The serum HBcrAg level gradually declined during treatment among the HBeAg seroconversion patients of the training group (from baseline, week 12, end of the treatment, 12-week follow-up to 24-week follow-up were 110,245 kU/ml, 3760 kU/ml, 7410 kU/ml, 715 kU/ml, 200 kU/ml, respectively). HBcrAg <19,565 kU/ml at week 24, HBcrAg <34,225 kU/ml at 12-week follow-up, and HBcrAg decrease ≥0.565 log10kU/ml from the baseline to the end of treatment (EOT) had negative predictive values (NPVs) of 100% for HBeAg seroconversion at the end of follow-up, whereas the positive predictive values (PPVs) were 30.77%, 26.67%, and 25.00%, respectively. The patients with HBeAg seroconversion at the end of 24-week follow-up remained in seroconversion during the LTFU, during which time their serum HBcrAg levels steadily declined or even became undetectable, ranging from 0 to 2.1 kU/ml. Effective antiviral treatment can decrease HBcrAg levels in the serum. The NPVs of HBcrAg for predicting HBeAg seroconversion at 24-week follow-up was 100%, but the PPVs were not satisfactory (all <31%). The serum HBcrAg levels of the patients with HBeAg seroconversion at the end of the 24-week follow-up steadily declined or even became undetectable during the LTFU.

  9. The vitamin D receptor gene bAt (CCA) haplotype impairs the response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C patients.

    Science.gov (United States)

    Baur, Katharina; Mertens, Joachim C; Schmitt, Johannes; Iwata, Rika; Stieger, Bruno; Frei, Pascal; Seifert, Burkhardt; Bischoff Ferrari, Heike A; von Eckardstein, Arnold; Müllhaupt, Beat; Geier, Andreas

    2012-01-01

    Chronic hepatitis C infection is a major cause of end-stage liver disease. Therapy outcome is influenced by 25-OH vitamin D deficiency. To further address this observation, our study investigates the impact of the vitamin D receptor (NR1I1) haplotype and combined effects of plasma vitamin D levels in a well-described cohort of hepatitis C patients. A total of 155 chronic hepatitis C patients were recruited from the Swiss Hepatitis C Cohort Study for NR1I1 genotyping and plasma 25-OH vitamin D level measurement. NR1I1 genotype data and combined effects of plasma 25-OH vitamin D level were analysed regarding therapy response (sustained virological response). A strong association was observed between therapy non-response and the NR1I1 CCA (bAt) haplotype consisting of rs1544410 (BsmI) C, rs7975232 (ApaI) C and rs731236 (TaqI) A alleles. Of the HCV patients carrying the CCA haplotype, 50.3% were non-responders (odds ratio [OR] 1.69, 95% CI 1.07, 2.67; P=0.028). A similar association was observed for the combinational CCCCAA genotype (OR 2.94, 95% CI 1.36, 6.37; P=0.007). The combinational CCCCAA genotype was confirmed as an independent risk factor for non-response in multivariate analysis (OR 2.50, 95% CI 1.07, 5.87; P=0.034). Analysing combined effects, a significant impact of low 25-OH vitamin D levels on sustained virological response were only seen in patients with the unfavourable NR1I1 CCA (bAt) haplotype (OR for non-SVR 3.55; 95% CI 1.005, 12.57; P=0.049). NR1I1 vitamin D receptor polymorphisms influence response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C and exert an additive genetic predisposition to previously described low 25-OH vitamin D serum levels.

  10. Improvement in quality of life measures in patients with refractory hepatitis C, responding to re-treatment with Pegylated interferon alpha -2b and ribavirin

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    McGarrity Thomas J

    2006-05-01

    Full Text Available Abstract Background In this paper, we report the health related quality of life (HRQOL data from patients with hepatitis C viral infection (HCV who were refractory to prior therapy and had re-treatment with a combination of Pegylated interferon alpha-2b and ribavirin. We hypothesized that the HRQOL will improve in those patients who attain sustained viral response similar to naïve patients undergoing treatment for HCV. Methods HRQOL data was obtained from 152 patients enrolled into a randomized study for re-treatment of HCV refractory to prior therapy with interferon alpha-2b in combination with ribavirin. The treatment protocol was for 48 weeks and had a high and low dose arm. The HRQOL data was collected at baseline, weeks 24 and 48 of treatment, and at 24 week follow-up after treatment. A repeated measures statistical model was used for comparing the HRQOL domain scores between the responders and non-responders and the treatment groups. The responders and non-responders were also compared to the age and sex adjusted national mean scores. Results Twenty-five of the 152 (17% patients achieved a sustained viral response. At baseline, HRQOL is lower in HCV patients compared to national norms. The norm based HRQOL domain scores for the different domains of the SF-36 instrument were as follows: physical functioning = 47.13, role-physical = 46.87, bodily pain = 48.00, general health = 44.01, vitality = 45.39, social functioning = 47.05, role-emotional = 48.88, mental health = 48.76, physical component score 43.26 and mental component score = 46.17. The scores decreased during therapy in those who would be responders and non-responders, but the pattern of change was different. During the treatment, the HRQOL domain scores of responders decrease notably in the domain of vitality. At week 48 vitality scores were worst in responders. 5 of the 8 domain scores were lower compared to baseline in non-responders. At 24 weeks post treatment follow up, HRQOL

  11. Clinical study of pegylated interferon α-2a in treatment of children with HBeAg-positive chronic hepatitis B

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    LIU Yunhua

    2015-02-01

    Full Text Available ObjectiveTo investigate the clinical efficacy of pegylated interferon α-2a (PEG-IFNα-2a in the treatment of children with HBeAg-positive chronic hepatitis B (CHB. MethodsA total of 31 children with CHB aged from 2-16 years were randomly enrolled in this study and divided into two groups based on the age: younger group (age 2-6 years, n=17 and older group (age 7-16 years, n=14. All patients were administered PEG-IFNα-2a at the initial dose of 104 μg/m2/week, which gradually increased to 135 μg/week. The course of treatment ranged from 24 to 72 weeks. The indices including alanine aminotransferase (ALT, hepatitis B virus (HBV DNA, HBV serological markers, and HBsAg quantitative level were assayed at baseline and then regularly throughout the course of treatment. Treatment responses including biochemical, virological. and serological responses at different time points were compared between the two age groups. The safety of treatment and the relationship of treatment efficacy with age, course of treatment, and dynamics of HBsAg quantitative level during treatment were analyzed. Normally distributed continuous data were analyzed by t test.Comparison of categorical data was made by χ2 test. ResultsThere were no significant differences in biochemical and virological responses at different time points between the two groups (all P>0.05. The HBsAg clearance rate at week 24 of treatment was significantly higher in the younger group than in the older group (41.2% vs 7.1%,χ2=4.644,P005. In patients whose treatment was extended to 72 weeks, the HBV DNA clearance rate and seroconversion rates of HBeAg and HBsAg were 100%, 80%, and 60%, respectively. None of the 25 patients who finished the course of treatment experienced recurrence. Common adverse effects of interferon treatment were flu-like symptoms, changes in blood manifestation, and anorexia. No significant differences in body height and body weight were observed between the patients and

  12. Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals.

    Science.gov (United States)

    Alexopoulou, Alexandra; Karayiannis, Peter

    2015-01-01

    The development of protease inhibitors (PIs) such as telaprevir and boceprevir constitutes a milestone in chronic hepatitis C antiviral treatment since it has achieved sustained virological response (SVR) rates of up to 75% in naïve and 29-88% in treatment-experienced patients with genotype 1 infection. Both require combination treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) as PI monotherapy results in resistant mutations. New direct acting antiviral agents (DAAs) have recently been approved or their approval is imminent. Simeprevir administered orally as one pill per day in combination with PEG-IFN/RBV will be the next PI to be approved. The SVR rates at about 72-80% for treatment-naïve patients are not a major improvement over telaprevir or boceprevir. However, this treble combination has fewer side effects and drug-drug interactions and most patients undergo shorter treatment duration (24 months) due to earlier treatment responses. Sofosbuvir is the first available once-daily NS5B polymerase inhibitor which has been approved in combination with PEG-IFN/RBV for just 12 weeks with 89% SVR in treatment-naïve patients with genotype 1 infection and 83-100% in treatment-experienced patients with genotypes 2/3. The current review focuses on the recent rapid and continuous developments in the management of chronic HCV infection with DAAs in combination with PEG-IFN/RBV.

  13. Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

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    Helen Kovari

    Full Text Available Ribavirin (RBV is an essential component of most current hepatitis C (HCV treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR.We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24 and IL28B genotype (CC versus CT/TT.SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80] and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73], regardless of treatment phase, and IL28B genotype.In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

  14. Extrahepatic manifestations of chronic hepatitis C and their influence on response to treatment with Pegylated interferon alfa-2a and ribavirin

    Directory of Open Access Journals (Sweden)

    Fabri Milotka

    2013-01-01

    Full Text Available Introduction. Thirty to 50% of patients with chronic hepatitis C (CHC have one or more extrahepatic manifestations (EHMs of hepatitis C virus (HCV infection. Objective. The aim of this study was to evaluate the frequency of EHMs and to investigate the efficacy of pegylated interferon (Peg­IFN­α­2a plus ribavirin therapy in patients with HCV­related EHMs. Methods. The study included 280 patients suffering from CHC and treated with Peg­IFN­α­2a and ribavirin. The patients were divided in two groups according to presence or absence of EHMs. We evaluated virological response to antiviral therapy. Results. One or more EHMs were found among 27.9% of patients. Most frequently they had rheumatoid factor in serum (12.5%, organ­nonspecific antibodies ANA and AGMA (12.4%, thyroid hormone disorders (9.3%, vasculitis (5.7%, diabetes mellitus (4.65%, glomerulonephritis (0.71%, and porphyria cutanea tarda (0.36%. Among the patients with EHMs there was 52.6% of females vs. 30.2% of females in the group of patients without EHMs (p=0.001. HCV genotypes 1 and 4 had 85.9% patients with EHMs vs. 58.4% of patients without EHMs (p=0.000. Progressive fibrosis and cirrhosis were more frequently recorded in the EHM group of patients (32% vs. 23.2%, but without statistically significant difference (p=0.532. Serious adverse events of Peg­IFN­α­2a and ribavirin were statistically significantly recorded among the patients with EHMs (46.1% vs. 12.9%; p=0.000. Sustained virological response among the patients with and without EHMs rated 56.9% and 70.8% respectively (p=0.125. Conclusion. Patients with CHC and EHMs treated with combined Peg­IFN­α­2a and ribavirin experience handling difficulties, more often have serious adverse events, while successful outcome is achieved in about 50% of patients.

  15. HBsAg clearance in chronic hepatitis B patients with add-on pegylated interferon alfa-2a to ongoing tenofovir treatment: A randomized controlled study.

    Science.gov (United States)

    Al Ashgar, Hamad; Peedikayil, Musthafa C; Al Quaiz, Mohammed; Al Sohaibani, Fahad; Al Fadda, Abdulrahman; Khan, Mohammed Q; Thoralsson, Einar; Al Thawadi, Sahar; Al Jedai, Ahmed; Al Kahtani, Khalid

    2017-01-01

    The ideal end point of treatment for chronic hepatitis B virus (HBV) infection is sustained off-therapy hepatitis B surface antigen (HBsAg) loss with or even without seroconversion to anti-HBs. We investigated the role of adding PEGylated interferon (PEG IFN) to ongoing tenofovir treatment in chronic HBV patients for achieving HBsAg clearance. In this randomized controlled trial, chronic HBV patients who have been receiving tenofovir for >6 months with HBV viral load add-on therapy) was given subcutaneous PEG IFN 180 mcg weekly for 12 months in addition to tenofovir. Patients in the other group received only tenofovir 300 mg orally on a daily basis. Patients in both groups were followed up for a total of two years, and patients in both groups were given tenofovir 300 mg daily indefinitely until they developed HBsAg clearance. Twenty-three patients were allocated to the PEG IFN and tenofovir (add-on therapy) group, and another 25 patients were recruited to the tenofovir monotherapy group. Before randomization, patients had received tenofovir for 1135 mean days (range203 to 1542 days). One patient (4.3%) in add-on therapy lost HBsAg and seroconverted. Within two years, mean HBsAg decreased significantly with add-on therapy (from 4753 IU/ml to 2402; P= 0.03); and it decreased from 5957 IU/ml to 4198; P= 0.09 in tenofovir monotherapy group. More patients in the add-on group developed serious side effects, with treatment discontinuation, and dose reductions (P = 0.3). PEG IFN and tenofovir add-on therapy was successful in achieving HBsAg clearance and seroconversion in 4.3% of the patients. Add-on therapy patients had a significant decrease in HBsAg levels in two years; and no significant decrease in HBsAg levels with the tenofovir monotherapy. With no significant HBsAg clearance, the utility of this combination regimen is questionable.

  16. The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive individuals

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    Vogel M

    2010-03-01

    Full Text Available Abstract Objective This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated. Methods Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day for 24 - 48 weeks in one of four treatment arms: HIV-negative (A, HIV-positive without HAART (B and HIV-positive on HAART (C. Patients within arm C were randomized to receive open label either a nucleoside containing (C1 or a nucleoside free HAART (C2. Results 168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000. Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708. Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209. Conclusions Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.

  17. Predictors of Early Discontinuation of Pegylated Interferon for Reasons Other Than Lack of Efficacy in United States Veterans With Chronic Hepatitis C.

    Science.gov (United States)

    LaFleur, Joanne; Hoop, Robert; Korner, Eli; DuVall, Scott; Morgan, Timothy; Pandya, Prashant; Han, Jian; Knippenberg, Kristin; Nelson, Richard E

    2015-01-01

    During the dual-therapy era, many patients with chronic hepatitis C discontinued therapy for reasons other than lack of efficacy (non-LOE). We determined whether selected patient characteristics predicted non-LOE discontinuation using national databases of U.S. veterans with Genotypes 1-4. We identified U.S. veterans in the Veterans Health Administration system in 2004-2009 who had hepatitis C-confirming RNA laboratory results and initiated therapy with pegylated interferon and ribavirin. We used a rule to classify patients who discontinued pegylated interferon early, based on pharmacy refill and viral response data. Multivariate Cox regression was used to identify predictors of non-LOE discontinuation. Of 321,238 patients with a hepatitis C International Classification of Diseases, Ninth Revision, code, 15,297 (4.8%) met all inclusion criteria. Non-LOE discontinuers comprised 30.3% of patients. For Genotypes 1-4, the predictors (adjusted hazard ratio) of greatest magnitude were comorbidities of myocardial infarction/congestive heart failure (1.36), renal disease (1.34), and platelets 100/mm or more (1.38). For Genotypes 2 and 3, predictors of greatest magnitude were Black race (1.30), myocardial infarction/congestive heart failure (1.84), albumin 3.5 mg/dl or more (1.65), sleep aid use (1.32), and poor persistence with antidepressants (1.31) and antihypertensive agents (1.37). Our study suggests that many host factors may have contributed to non-LOE dual-therapy discontinuation in veterans and may possibly predict non-LOE discontinuation in triple therapy.

  18. [Which patients with ovarian cancer shows the combination of trabectedin with pegylated liposomal doxorubicin].

    Science.gov (United States)

    Khokhlova, S V; Cherkasova, M V; Orel, N F; Limareva, S V; Bazaeva, I Ia; Gorbunova, V A

    2013-01-01

    Given the high rate of recurrence of ovarian cancer, the search for new therapeutic strategies are topical issue. According to various studies the effectiveness of drug treatment relapse depends on the platinum-free interval, increasing in proportion to its duration. If therapy is platinum-resistant recurrent ovarian cancer is a standard approach, the treatment of platinum-sensitive recurrent algorithm is not fully defined. Comparison of platinum and non-platinum combinations revealed the advantage of combined platinum- treatment for patients with platinum-free interval of more than 6 months without an increase in life expectancy. Non-platinum combination of trabected in with pegylated liposomal doxorubicin has shown comparable efficacy with an advantage in overall survival in patients with platinum-free interval of 6-12 months. A platinum-free interval prolongation by the use of non-platinum mode increases the efficiency of subsequent platinum-based therapy, increasing the life expectancy of patients. Currently under study molecular markers and prognostic factors allowing to define a group of patients who have the greatest benefit from the use trabectedin with pegylated liposomal doxorubicin as second-line chemotherapy.

  19. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial.

    Science.gov (United States)

    Masarova, Lucia; Patel, Keyur P; Newberry, Kate J; Cortes, Jorge; Borthakur, Gautam; Konopleva, Marina; Estrov, Zeev; Kantarjian, Hagop; Verstovsek, Srdan

    2017-04-01

    follow-up: 49% maintained their best molecular response (nine of ten patients who had a complete response, five of 20 who had a partial response, and three of five who had a minor response). The incidence of major venous-thrombotic events during the study was 1·22 per 100 person-years. Overall, 18 (22%) of 83 patients discontinued therapy due to treatment-related toxicity. Although toxicity rates decreased over time, five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy. 32 patients are still enrolled on the study. Pegylated interferon alfa-2a can induce durable haematological and molecular responses in patients with essential thrombocythaemia and polycythaemia vera. This drug alone and in combination with other drugs could be explored further in clinical trials. US National Cancer Institute. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. [Efficacy and safety of pegylated interferon α-2b injection (Y shape, 40 kD) in treatment of patients with genotype 1/6 chronic hepatitis C].

    Science.gov (United States)

    Feng, B; Shang, J; Wu, S H; Chen, H; Han, Y; Li, Y Q; Zhang, D Z; Zhao, L F; Wei, S F; Mao, Q; Yin, C B; Han, T; Wang, M R; Chen, S J; Li, J; Xie, Q; Zhen, Z; Gao, Z L; Zhang, Y X; Gong, G Z; Yang, D L; Pan, C; Sheng, J F; Tang, H; Ning, Q; Shi, G F; Niu, J Q; Luo, G H; Sun, Y T; You, H; Wang, G Q; Zhang, L L; Peng, J; Zhang, Q; Liu, J J; Chen, C W; Chen, X Y; Zhao, W; Wang, R H; Sun, L; Wei, L

    2017-03-20

    Objective: To investigate the efficacy and safety of the new investigational drug pegylated interferon α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 µg/week) combined with ribavirin in the treatment of patients with genotype 1/6 chronic hepatitis C (CHC), with standard-dose Peg-IFN-α-2a combined with ribavirin as a positive control. Methods: A multicenter, randomized, open-label, and positive-controlled phase III clinical trial was performed. Eligible patients with genotype 1/6 CHC were screened out and randomly divided into Peg-IFN-α-2b(Y shape, 40kD) group and Peg-IFN-α-2a group at a ratio of 2:1. The patients in both groups were given oral ribavirin for 48 weeks in addition and then followed up for 24 weeks after drug withdrawal. Abbott Real Time HCV Genotype II was used to determine HCV genotype, and Cobas TaqMan quantitative real-time PCR was used to measure HCV RNA level at 0, 4, 12, 24, 48, and 72 weeks. Adverse events were recorded in detail. The primary efficacy endpoint was sustained virological response (SVR), and a non-inferiority test was also performed. Results: A total of 561 patients with genotype 1/6 CHC were enrolled, among whom 529 received treatment; 90.9% of these patients had genotype 1 CHC. The data of the full analysis set showed that SVR rate was 69.80% (95% CI 65.00%-74.60%) in the trial group and 74.16% (95% CI 67.73%-80.59%) in the control group (P = 0.297 0). The data of the per protocol set (PPS) showed that SVR rate was 80.63% (95% CI 76.04%-85.23%) in the trial group and 81.33% (95% CI 75.10%-87.57%) in the control group (P = 0.849 8), and the 95% CI of rate difference conformed to the non-inferiority standard. The analysis of the PPS population showed that of all subjects, 47.9% achieved rapid virologic response, with a positive predictive value of 93.8%. The incidence rate of adverse events was 96.30% in the trial group and 94.94% in the control group, and the incidence rate of serious adverse events was 5.13% in the

  1. Cost-effectiveness of sofosbuvir plus ribavirin with or without pegylated interferon for the treatment of chronic hepatitis C in Italy.

    Science.gov (United States)

    Cure, Sandrine; Guerra, Ines; Cammà, Calogero; Craxì, Antonio; Carosi, Giampiero

    2015-01-01

    Across Italy up to 7.3% of the population is infected with hepatitis C virus (HCV), with long-term complications resulting in high medical costs and significant morbidity and mortality. Current treatment options have limitations due to side effects, interferon intolerability and ineligibility, long treatment durations and low sustained virological response (SVR) rates, especially for the most severe patients). Sofosbuvir is the first nucleotide polymerase inhibitor with pan-genotypic activity. Sofosbuvir, administered with ribavirin (RBV) and with or without pegylated interferon (PEG-INF), resulted in >90% SVR across treatment-naïve (TN) genotype (GT) 1-6 patients. It is also the first treatment option for patients that are unsuitable for interferon (UI). This analysis evaluates the cost - effectiveness of sofosbuvir for GTs 1-6 in Italy. A Markov model followed a cohort of 10,000 patients until they reached 80 years old. Approximately 20% of naïve and 30% of experienced patients initiated treatment at the cirrhosis stage. Comparators included PEG-INF + RBV for all GTs and plus telaprevir or boceprevir for GT1, or no treatment. Costs and outcomes were discounted at 3% and the cost perspective was that of the National Health Service in Italy. Sofosbuvir was cost-effective with incremental cost-effectiveness ratios (ICERs) below €40,000/QALY in all patient populations, particularly in cirrhotic patients. The exception was for a mixed cohort of GT2 TN patients where the ICER was €68,500/QALY and for a cirrhotic cohort of GT4/5/6 where the ICER was €68,434/QALY. Nevertheless, the prevalence of HCV in this patient population is expected to be low. Results were robust to sensitivity analysis. Sofosbuvir-based regimens are cost-effective in Italy, particular for the most severe patients. The interferon-free regimens are a real treatment option for UI patients. The high cure rates of this breakthrough treatment are expected to substantially reduce the burden of

  2. Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison.

    Science.gov (United States)

    Andersohn, Frank; Claes, Anne-Kathrin; Kulp, Werner; Mahlich, Jörg; Rockstroh, Jürgen Kurt

    2016-01-11

    About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available. This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. This

  3. Effects of Smoking on Pegylated Interferon alpha 2a and First Generation Protease Inhibitor-based Antiviral Therapy in Naïve Patients Infected with Hepatitis C Virus Genotype 1.

    Science.gov (United States)

    Zimmermann, Tim; Hueppe, Dietrich; Mauss, Stefan; Buggisch, Peter; Pfeiffer-Vornkahl, Heike; Grimm, Daniel; Galle, Peter R; Alshuth, Ulrich

    2016-03-01

    Smoking has multiple effects on factors influencing hepatitis C and antiviral therapy, including lipid metabolism, fibrosis, platelet count and adherence aspects. The aim of this analysis was to determine the impact of smoking on hepatitis C virus antiviral therapy. Data of two cohorts of an observational multicenter study including therapy-naïve patients infected with genotype 1 hepatitis C virus (HCV) treated with dual antiviral therapy (n=7,796) with pegylated interferon alpha 2a in combination with ribavirin, or triple antiviral therapy (n=1,122) containing telaprevir or boceprevir, were analysed. In the univariate matched pair analysis of dual antiviral therapy patients (n=584), smoking was significantly associated with lower sustained viral response rates (p=0.026, OR 0.69 CI: 0.50 - 0.96). The effect of smoking on sustained viral response remained significant (p=0.028, OR 0.67 CI: 0.47 - 0.96) in the multivariate analysis when adjusting for all other baseline parameters with a significant association in the univariate analysis, i.e. diabetes, fibrosis, body mass index, transaminases and baseline viral load. Under protease inhibitors the influence of smoking on virological response did not arise. Smoking has a negative impact on antiviral therapy in naïve patients infected with HCV genotype 1 independently of age, gender, history of drug use or alcoholic liver disease. The effects of smoking might be overcome by the new antiviral agents.

  4. Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis.

    Science.gov (United States)

    Druyts, Eric; Thorlund, Kristian; Wu, Ping; Kanters, Steve; Yaya, Sanni; Cooper, Curtis L; Mills, Edward J

    2013-04-01

    A systematic review and meta-analysis were conducted to examine the efficacy and safety of pegylated interferon (peg-IFN) alfa-2a and peg-IFN alfa-2b plus ribavirin (RBV) in children and adolescents with chronic hepatitis C virus (HCV). Medline, Embase, and Cochrane Central Register of Controlled Trials were searched. Clinical trials examining peg-IFN alfa-2a or peg-IFN alfa-2b plus RBV among persons ages 3-18 years with HCV were included. Data were abstracted for complete early virologic response (EVR), sustained virologic response (SVR), relapse, treatment discontinuations, hematologic and dermatologic adverse events, and growth inhibition. Eight trials met the inclusion criteria. Results indicate that 70% of subjects (95% confidence interval [CI], 58%-81%) achieved EVR, and 58% (95% CI, 53%-64%) achieved SVR. EVR and SVR were higher for those with HCV genotypes 2/3 than 1/4. Discontinuation due to adverse events and discontinuation due to viral breakthrough were each 4%, discontinuation due to a lack of response was 15%, and relapse was 7%. Anemia, neutropenia, leukopenia, and thrombcytopenia were 11%, 32%, 52%, and 5%, respectively. Alopecia, injection site erythema, and pruritus were 13%, 27%, and 10%, respectively. Small growth inhibitions were observed during treatment. The results of this meta-analysis indicate that peg-IFN/RBV combination treatment is effective and safe in treating children and adolescents with HCV.

  5. Dual treatment with sofosbuvir plus ribavirin is as effective as triple therapy with pegylated interferon plus sofosbuvir plus ribavirin in predominant genotype 3 patients with chronic hepatitis C.

    Science.gov (United States)

    Satsangi, Sandeep; Mehta, Manu; Duseja, Ajay; Taneja, Sunil; Dhiman, Radha K; Chawla, Yogesh

    2017-04-01

    Sofosbuvir (SOF) was the first directly acting antiviral made available for chronic hepatitis C (CHC) in India. We describe our "real life" experience of using SOF with ribavirin (RBV) with or without pegylated interferon (Peg-IFN) in predominant genotype 3 patients with CHC. A total of 158 patients (men 99 [62.6%], mean age 40.3 ± 12.8 years) with CHC treated with dual therapy (SOF + RBV) for 24 weeks or triple therapy (Peg-IFN + SOF + RBV) for 12 weeks were included prospectively. Patients with co-infection, decompensated liver disease, and post-organ transplantation were excluded. Data were analysed for the preference of treatment regimen, end of treatment response (ETR), sustained virological response at 12 weeks, and side effects. Genotype 3 was the predominant genotype (105 [66.4%]) followed by genotype 1 (40 [25.3%]) and genotype 4 (13[8.2%]). Forty-eight (30.37%) patients had cirrhosis (LSM ≥ 13 kPa), and 30 (19%) were treatment experienced with Peg-IFN + RBV. A total of 103 (65.18%) patients received dual therapy, and 55 (34.81%) received triple therapy. Resentment to receive injections, inaccessibility to a facility, fear of injection or its side effects, and financial constraints were the reasons to refuse triple therapy. All patients in triple therapy group and all but two patients (98%) in the dual therapy group attained ETR. All those who achieved ETR achieved sustained virological response at 12 weeks in both groups. But for anemia in three patients (two in triple, one in dual therapy), there were no major side effects. Most patients with CHC prefer an oral treatment with directly acting antivirals. Both oral and interferon-based regimens achieve high response rate. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  6. Irsogladine maleate for the treatment of recurrent aphthous stomatitis in hepatitis C virus patients on pegylated-interferon and ribavirin: a pilot study.

    Science.gov (United States)

    Hayashi, Nobuhiko; George, Joseph; Shiroeda, Hisakazu; Saito, Takashi; Toshikuni, Nobuyuki; Tsuchishima, Mutsumi; Arisawa, Tomiyasu; Tsutsumi, Mikihiro

    2013-06-01

    Aphthous stomatitis is one of the adverse effects associated with interferon (IFN) that forces dose reduction of IFN and there is no established therapy. This study was aimed to investigate whether irsogladine maleate, which enhances the functions of intercellular communication through the gap junctions, is effective for the treatment of aphthous stomatitis developed in hepatitis C virus (HCV) patients on pegylated-interferon (PEG-IFN) and ribavirin. Nineteen patients with HCV were treated with PEG-IFN and ribavirin for 48 weeks. Ten out of 19 patients developed aphthous stomatitis during treatment with PEG-IFN and ribavirin. Within 1-2 weeks after development of aphthous stomatitis, 4 mg irsogladine maleate was orally administered daily to all patients and the therapeutic and adverse effects of irsogladine maleate were examined on every week. The degree of aphthous stomatitis was evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Out of 10 patients, aphthous stomatitis was evaluated as grade 3 in three patients (30%) and grade 2 in seven patients (70%) by CTCAE. CTCAE grade was improved to 0 after 1 week in six patients, after 2 weeks in two patients, and after 3 weeks in two patients after the start of administration of irsogladine maleate. Aphthous stomatitis has not recurred in patients who had been on irsogladine maleate continuously during treatment of PEG-IFN and ribavirin. Irsogladine maleate is effective for the treatment of aphthous stomatitis developing during PEG-IFN and ribavirin administration in HCV patients. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  7. Preliminary results of treatment with pegylated interferon alpha 2A for chronic hepatitis C virus in kidney transplant candidates on hemodialysis.

    Science.gov (United States)

    Casanovas-Taltavull, T; Baliellas, C; Llobet, M; Cruzado, J M; Castellote, J; Casanova, A; Niubó, J; Valls, C; Serrano, T

    2007-09-01

    At present, there is little published information on the outcome of treatment with pegylated interferon (Peg-IF alpha 2a) in hepatitis C virus (HCV)-infected hemodialysis patients awaiting renal transplantation. The objective of this study was to assess the efficacy and tolerance of Peg-IF alpha 2a in this population. Twelve noncirrhotic HCV-infected patients (10 men, 50 +/- 8 years of age, genotype 1b 84%), were prescribed Peg-IF alpha 2a, at 135 microg/wk for 48 weeks. Liver biopsy was performed in 11 of 12 cases. Six patients completed 48 weeks of treatment, with one end of treatment response (ETR), two sustained viral responses (SVRs), and three HCV relapses. Treatment was shorter in the six remaining patients: two cases 24 weeks (one due to medical reasons with relapse, one due to nonresponse), one patient chose to discontinue at 14 weeks (with relapse), one patient died of stroke at 10 weeks, and in two additional patients interferon was withdrawn at 18 weeks because of severe anemia (SVR) and at 26 weeks due to prolonged fever (relapse). Other secondary treatment-related events included anemia (requiring transfusion in two patients and major erythropoietin administration in six), and fever in four patients. Peg-IF had limited efficacy in this group, with ETR in 83%, SVR in only 25%, and recurrence in 50%. Tolerance was moderate, with 4/12 (33%) discontinuing treatment due to adverse events, personal decision, or death. Large randomized controlled studies are needed to determine the role of Peg-IF treatment in this population.

  8. Pegylated Interferon α-2a Triggers NK-Cell Functionality and Specific T-Cell Responses in Patients with Chronic HBV Infection without HBsAg Seroconversion.

    Directory of Open Access Journals (Sweden)

    Juliana Bruder Costa

    Full Text Available Pegylated interferon α-2a (Peg-IFN-α represents a therapeutic alternative to the prolonged use of nucleos(tide analog (NA in chronic hepatitis B (CHB infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs, natural killer (NK cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment.

  9. Platelet sparing effect of COX II inhibition used with pegylated interferon alfa-2a for the treatment of chronic hepatitis C: a short term pilot study.

    Science.gov (United States)

    George, Magdalene M; Li, S David; Mindikoglu, Ayse L; Baluch, Mehdi H; Dhillon, Sonu; Farr, Deborah; Van Thiel, David H

    2004-09-21

    The role of a cyclooxygenase (COX) II inhibitor in reducing microvascular inflammation and the platelet count associated with interferon (IFN) plus ribavirin therapy of chronic hepatitis C (HCV) was assessed. Three plasma mediators (biomarkers) associated with platelet activation, inflammation and fibrosis were measured. Eighteen IFN naïve patients were studied. Nine were treated with pegylated IFN alfa-2a (PEG-IFN alpha-2a) plus ribavirin and rofecoxib; nine were treated with PEG-IFN alpha-2a plus ribavirin. A complete blood count, liver panel and HCV-RNA were assayed weekly. Human soluble P-selectin (hs-P-selectin), human interleukin-8 (IL-8), human interleukin-13 (IL-13) and human thrombopoietin (TPO) were assayed at 4 week intervals. The COX II inhibitor reduced the platelet reduction experienced with PEG-IFN alpha-2a treatment of HCV despite a reduction in the plasma TPO level. Hs-P-selectin was increased in both groups. In contrast, human IL-8 levels declined to undetectable levels in virologic responders. Similarly, human IL-13 levels declined with therapy (P < 0.001). These data suggest that: (1) a COX II inhibition is associated with an increase in the platelet count despite a reduction in the TPO level; (2) human IL-8 and human IL-13 but not hs-P-selectin levels decline in those who experience an early virologic response.

  10. CD3(bright)CD56(+) T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients.

    Science.gov (United States)

    Guo, Chuang; Shen, Xiaokun; Fu, Binqing; Liu, Yanyan; Chen, Yongyan; Ni, Fang; Ye, Ying; Sun, Rui; Li, Jiabin; Tian, Zhigang; Wei, Haiming

    2016-05-13

    Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide, and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low, and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3(bright)CD56(+) T cells, a newly identified CD56(+) T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3(bright)CD56(+) T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3(bright)CD56(+) T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3(bright)CD56(+) T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3(bright)CD56(+) T cell population preferentially shown in CHB patients, and indicated that the presence of CD3(bright)CD56(+) T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment.

  11. Safety and Efficacy of Pegylated Interferon Alpha-2b Monotherapy in Hepatitis C Virus-Infected Children with End-Stage Renal Disease on Hemodialysis.

    Science.gov (United States)

    Mogahed, Engy A; Abdelaziz, Hanan; Helmy, Heba; Ghita, Haytham; Abdel Mawla, Mohamed A; Hassanin, Fetouh; Fadel, Fatina I; El-Karaksy, Hanaa

    2016-12-01

    Treatment of hepatitis C virus (HCV) in end-stage renal disease (ESRD) patients is an important issue before kidney transplantation (KT). The aim of the study is to assess the efficacy and tolerability of HCV treatment with pegylated interferon (PEG IFN)-α 2b in children with ESRD. The study included 17 children, aged 3-18 years with ESRD on hemodialysis (HD), with chronic HCV. They received 40 μg/m(2) of PEG IFN-α 2b once-weekly subcutaneous injections for 48 weeks. Early virological response (EVR) was achieved in 76.5%. At week 24, 8 patients had negative HCV RNA. Six patients received KT during therapy. Treatment was discontinued in 2 patients: one for anemia and another for retinopathy. Two patients completed 48 weeks of therapy and both achieved end-of-treatment response and sustained virological response (SVR). Constitutional symptoms were the most frequently reported side effects. Neutropenia occurred in 10 patients (58.8%), drop in hemoglobin in 10, and thrombocytopenia in 9. HCV-infected children with ESRD on HD have high EVR (76.5%) on IFN monotherapy. SVR could not be assessed due to the high dropout rate related mainly to early transplantation. Constitutional symptoms and hematological side effects were the most frequently reported side effects.

  12. Intensification of treatment with pegylated interferon alfa in patients coinfected with HIV and HBV genotype H or G being treated with a tenofovir/emtricitabine-containing regimen.

    Science.gov (United States)

    Mata-Marín, José Antonio; Mata-Marín, Luis Alberto; Arroyo-Anduiza, Carla Ileana; Huerta-García, Gloria; Sandoval-Ramirez, J L; Manjarrez-Tellez, Bulmaro; Gaytán-Martínez, J E

    2014-01-01

    The most common HBV genotypes in HIV-coinfected patients in Mexico are H and G; the response to treatment for these genotypes is unknown. The aim of the study was to examine the effectiveness of intensification with pegylated interferon (PEG-IFN) alfa-2a or alfa-2b in HBV/HIV-coinfected patients treated with a tenofovir/emtricitabine (TDF/FTC) backbone in an HIV clinic in Mexico City. We performed a single-arm open-label trial involving HBV/HIV-coinfected patients. Patients with chronic hepatitis B who were HBeAg positive were treated with TDF/FTC-containing regimen. Treatment was intensified by addition of PEG-IFN alfa-2b or alfa-2a for 24 weeks. The primary endpoint of effectiveness, assessed after 24 weeks, was suppression of HBV DNA to alfa-2a or alfa-2b is effective and well tolerated in patients with chronic hepatitis B who are HBeAg positive, have genotype H or G, and are coinfected with HIV while they are being treated with TDF/FTC-containing regimen.

  13. Influence of Host and Viral Factors on Patients with Chronic Hepatitis C Virus Genotype 6 Treated with Pegylated Interferon and Ribavirin: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Thong, Vo Duy; Poovorawan, Kittiyod; Tangkijvanich, Pisit; Wasitthankasem, Rujipat; Vongpunsawad, Sompong; Poovorawan, Yong

    2015-01-01

    We conducted a systematic review and meta-analysis of the influence of host and viral factors on the sustained virologic response (SVR) in hepatitis C virus genotype 6 (HCV-6) patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). Data were retrieved from Medline, Embase, PubMed and the Cochrane Library for 'genotype 6' studies published up to December 2014 and for abstracts from international scientific meetings. Inclusion criteria were efficacy of PEG-IFN+RBV based on SVR, 24- or 48-week therapy and treatment-naïve patients. Patients with hepatitis B, D and E and HIV coinfection or another concurrent liver disease were excluded. Pooled standard difference, odds ratio and confidence intervals (CIs) were calculated using a random-effect model with STATA 11. Fourteen studies were included in the meta-analysis. The pooled SVR rate was 80% (95% CI: 0.78-0.83, p type of PEG-IFN did not affect SVR rates. Treatment outcomes for HCV-6 patients are superior to those for HCV-1 patients and comparable to those of HCV-2 and HCV-3 patients, especially at 48 weeks. The level of fibrosis affects treatment outcome, but SVR rates are not significantly different between genders. IL28B and IFNL4 polymorphisms are not significantly associated with HCV-6 treatment outcome. © 2016 S. Karger AG, Basel.

  14. Combination of interferon and dexamethasone in refractory multiple myeloma.

    Science.gov (United States)

    San Miguel, J F; Moro, M; Bladé, J; Guerras, L; Hernandez, J; Jimenez-Galindo, R; Ortega, F; Gonzalez, M

    1990-01-01

    The present pilot study was designed to analyse the efficacy and toxicity of the association of interferon (IFN) and dexamethasone (Dx) in 32 resistant and relapsed myeloma patients. Among the evaluable cases, 15 (68 per cent) responded to treatment (32 per cent achieved an objective response--OR--and 36 per cent a partial response--PR--), the 'remission' status lasting for more than one year in six of them. Moreover, four out of the seven OR patients showed a reduction in B.M. plasma cells to less than 5 per cent. Five out of 11 patients that were previously refractory to VBAD, that includes high dose dexamethasone (Dx), responded to IFN-Dx. The protocol was generally well tolerated with only four patients discontinuing therapy due to adverse effects. The present results show that the combination IFN + Dx is a promising therapeutic approach for patients with refractory myeloma.

  15. Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C.

    Science.gov (United States)

    Gupta, Samir K; Kolz, Karen; Cutler, David L

    2011-06-01

    To examine the effect of pegylated interferon (PEG-IFN) alfa-2b on the activity of major drug-metabolizing enzymes. This nonrandomized, open-label, multiple-dose study examined the effects of PEG-IFN alfa-2b on the activity of CYP450 1A2, 2 C8/9, 2D6, and 3A4 enzymes and N-acetyltransferase in subjects with chronic hepatitis C. Eligible subjects received PEG-IFN alfa-2b 1.5 μg/kg subcutaneously once weekly for 4 weeks (days 3, 10, 17, and 24). Oral probe substrates (dextromethorphan hydrobromide 45 mg, caffeine 200 mg, tolbutamide 500 mg, and dapsone 100 mg) were administered after a 10-h fast on days 1 and 25. Midazolam 4 mg was administered orally on days 2 and 26. Enzyme activity for each CYP450 isozyme and for N-acetyltransferase was estimated based on the ratios of the observed concentrations of the substrates and metabolites in plasma or urine samples. Twenty-six subjects enrolled in the study. Mean age was 44.3 years, mean weight was 78.9 kg, and mean body mass index was 26.3 kg/m(2). Multiple doses of PEG-IFN alfa-2b inhibited CYP1A2 activity to a limited extent (point estimate = 84.2%, 90% confidence interval [CI] 79-90), increased CYP2C8/9 activity to a limited extent (point estimate = 127.6%, 90% CI 115-142), increased CYP2D6 activity (point estimate = 167%, 90% CI 125-223), and had no effect on the activity of CYP3A4 or N-acetyltransferase. Weekly administration of PEG-IFN alfa-2b to subjects with chronic hepatitis C increased CYP2C8/9 and CYP2D6 activity in some individuals.

  16. Induction pegylated interferon alfa-2a and high dose ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads.

    Science.gov (United States)

    Reddy, K Rajender; Shiffman, Mitchell L; Rodriguez-Torres, Maribel; Cheinquer, Hugo; Abdurakhmanov, Djamal; Bakulin, Igor; Morozov, Viacheslav; Silva, Giovanni Faria; Geyvandova, Natalia; Stanciu, Carol; Rabbia, Michael; McKenna, Michael; Thommes, James A; Harrison, Stephen A

    2010-12-01

    Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin. This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment. Sustained virologic response rates (HCV RNA level alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83-1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79-1.28; P = .974). In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. Clinical experiences with interferon as monotherapy or in combination with ribavirin in patients co-infected with HIV and HCV.

    Science.gov (United States)

    Puoti, Massimo; Zanini, Barbara; Bruno, Raffaele; Airoldi, Monica; Rossi, Stefania; Quiros Roldan, Eugenia; El Hamad, Issa; Moretti, Francesca; Castelli, Francesco; Sacchi, Paolo; Filice, Gaetano; Carosi, Giampiero

    2002-01-01

    Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNalpha) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNalpha monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNalpha monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNalpha and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.

  18. Dynamic interplay between CXCL levels in chronic hepatitis C patients treated by interferon.

    Science.gov (United States)

    Zekri, Abdel-Rahman N; Bahnassy, Abeer A; Mohamed, Waleed S; Alam El-Din, Hanaa M; Shousha, Hend I; Zayed, Naglaa; Eldahshan, Dina H; Abdel-Aziz, Ashraf Omar

    2013-07-01

    Combined pegylated interferon-α and ribavirin therapy has sustained virological response (SVR) rates of 54% to 61%. Pretreatment predictors of SVR to interferon therapy have not been fully investigated yet. The current study assesses a group of chemokines that may predict treatment response in Egyptian patients with chronic HCV infection. CXCL5, CXCL9, CXCL11, CXCL12, CXCL 13, CXCL 16 chemokines and E-Cadherin were assayed in 57 chronic HCV patients' sera using quantitative ELISA plate method. All studied patients were scheduled for combined pegylated interferon alpha and ribavirin therapy (32 patients received pegylated interferon α 2b, and 25 patients received pegylated interferon α 2a). Quantitative hepatitis C virus RNA was done by real time RT-PCR and HCV genotyping by INNOLIPAII. There was no significant difference (p > 0.05) in baseline HCV RNA levels between responders and non-responders to interferon. A statistically significant difference in CXCL13 (p = 0.017) and E-Cadherin levels (P = 0.041) was reported between responders and nonresponders at week 12. Significant correlations were found between changes in the CXCL13 levels and CXCL9, CXCL16, E-cadherin levels as well as between changes in E-cadherin levels and both CXCL16 and ALT levels that were maintained during follow up. Also, significant changes have been found in the serum levels of CXCL5, CXCL13, and CXCL16 with time (before pegylated interferon α 2 a and α 2 b therapy, and at weeks 12 and 24) with no significant difference in relation to interferon type and response to treatment. Serum levels of CXCL13 and E-Cadherin could be used as surrogate markers to predict response of combined PEG IFN-α/RBV therapy, especially at week 12. However, an extended study including larger number of patients is needed for validation of these findings. NCT01758939.

  19. Circulating sCD14 is associated with virological response to pegylated-interferon-alpha/ribavirin treatment in HIV/HCV co-infected patients.

    Directory of Open Access Journals (Sweden)

    Giulia Marchetti

    Full Text Available Microbial translocation (MT through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients.98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS, host response to MT (sCD14, CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10 reduction from baseline after 12 weeks of therapy and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy. Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR.71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053 and no cirrhosis (p = 0.052. EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively, but similar T-cell activation compared to Non-EVR (Null Responders, NR and Non-SVR (N-SVR subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015. SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014.In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.

  20. Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.

    Science.gov (United States)

    Zeuzem, Stefan; Sulkowski, Mark S; Lawitz, Eric J; Rustgi, Vinod K; Rodriguez-Torres, Maribel; Bacon, Bruce R; Grigorescu, Mircea; Tice, Alan D; Lurie, Yoav; Cianciara, Janusz; Muir, Andrew J; Cronin, Patrick W; Pulkstenis, Erik; Subramanian, G Mani; McHutchison, John G

    2010-10-01

    The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 μg every week, or albIFN 900 or 1200 μg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μg to 900 μg because of increased pulmonary adverse events (AEs) in the 1200-μg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. The primary objective of showing noninferiority of albIFN 900 μg (P < .001) and 1200 μg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-μg groups. albIFN 900 μg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  1. Evaluation of the absolute bioavailability of pegylated interferon alfa-2a after subcutaneous administration to healthy male volunteers: an open-label, randomized, parallel-group study.

    Science.gov (United States)

    Brennan, Barbara J; Xu, Zhi-Xin; Grippo, Joseph F

    2012-09-01

    Interferon (IFN)-based therapy is the recommended treatment for hepatitis C virus. Because pegylated IFN (PEG-IFN) alfa-2a is administered subcutaneously, it is of interest to determine the proportion of the dose that is absorbed from the subcutaneous (SC) tissue and ultimately reaches systemic circulation. The goal of this study was to characterize the absolute bioavailability of PEG-IFN alfa-2a (40 kDa) after SC dosing (180 μg) and to evaluate the pharmacokinetics of PEG-IFN alfa-2a after intravenous (IV) and SC administration. In this parallel-group study, 18 participants were given a single IV dose of PEG-IFN alfa-2a 90 μg and 18 participants received PEG-IFN alfa-2a 180 μg SC. Serum concentrations of PEG-IFN alfa-2a were measured predose and serially until 312 hours after the first dose. Pharmacokinetic parameters (CL/F, volume of distribution, C(max), and T(max)) were estimated using noncompartmental methods. Bioavailability was calculated by using the following formula: (AUC(SC)/AUC(IV)) · (dose(IV)/dose(SC)). Eighteen healthy males received IV PEG-IFN alfa-2a, and an additional 18 healthy males received SC PEG-IFN alfa-2a. Subjects in each group had comparable mean weight, height, and body mass index. After IV administration of PEG-IFN alfa-2a (90 μg), there was a slow decline in serum concentration, the mean rate of systemic clearance was low at 126 mL/h, and the estimated mean volume of distribution at steady state was 9 L. After SC administration of PEG-IFN alfa-2a 180 μg, absorption was sustained, with mean T(max) occurring 102 hours after administration. The mean absolute bioavailability was 84%. A higher rate of influenza-like symptoms was observed after IV administration, along with decreased neutrophil counts, compared with subjects who underwent SC dosing. Approximately 84% of a SC-administered dose of PEG-IFN alfa-2a reached the systemic circulation in these male healthy volunteers. The slow absorption, restricted distribution, and slow

  2. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group.

    NARCIS (Netherlands)

    Bottomley, A.; Coens, C.; Suciu, S.; Santinami, M.; Kruit, W.; Testori, A.; Marsden, J.; Punt, C.J.A.; Sales, F.; Gore, M.; MacKie, R.; Kusic, Z.; Dummer, R.; Patel, P.; Schadendorf, D.; Spatz, A.; Keilholz, U.; Eggermont, A.M.M.

    2009-01-01

    PURPOSE: Interferon (IFN) -based adjuvant therapy in melanoma is associated with significant side effects, which necessitates evaluation of health-related quality of life (HRQOL). Our trial examined the HRQOL effects of adjuvant pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) versus observation in

  3. Safety profile of trabectedin in combination with liposomal pegylated doxorrubicin in relapsed ovarian carcinoma: considerations for optimal management.

    Science.gov (United States)

    González Martín, Antonio

    2011-05-01

    The toxicity profile of trabectedin in the OVA-301 trial, that combined trabectedin with pegylated liposomal doxorubicin for the treatment of patients with ovarian cancer, has shown to be predictable and manageable. No unexpected toxicities were found, with neutropenia and transient increase in transaminases as the most common adverse events reported. The elevation in transaminases appeared early and generally decreased in incidence and intensity over subsequent cycles, with no major clinical consequences. A similar safety profile was seen in the analysis of the older patients in the trial. There were no detrimental effects in quality of life with the combination. Moreover, the Global Health Status score was better for the combination arm in those patients with a PFI of 6 to 12 months that were in response after 5 cycles. Trabectedin with pegylated liposomal doxorubicin is not associated with cumulative end-organ toxicities (renal, cardiac, or neurological toxicities). The toxicity profile is different from other second-line strategies without the presence of inconvenient side effects, such as alopecia, hypersensitivity reactions, hand-foot syndrome, or mucositis.

  4. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial.

    Science.gov (United States)

    Bazinet, Michel; Pântea, Victor; Cebotarescu, Valentin; Cojuhari, Lilia; Jimbei, Pavlina; Albrecht, Jeffrey; Schmid, Peter; Le Gal, Frédéric; Gordien, Emmanuel; Krawczyk, Adalbert; Mijočević, Hrvoje; Karimzadeh, Hadi; Roggendorf, Michael; Vaillant, Andrew

    2017-12-01

    REP 2139 clears circulating hepatitis B virus (HBV) surface antigen (HBsAg), enhancing the restoration of functional control of HBV infection by immunotherapy. We assessed the safety and efficacy of REP 2139 and pegylated interferon alfa-2a in patients with chronic HBV and hepatitis D virus (HDV) co-infection. In this open-label, non-randomised, phase 2 trial, patients aged 18-55 years, who were treatment naive, hepatitis B e antigen [HBeAg] negative, anti-hepatitis D antigen [HDAg] positive, and HDV RNA positive, with serum HBsAg concentrations of more than 1000 IU/mL, and a history of HDV infection for 6 months or more before treatment, were recruited at Toma Ciorbă Hospital of Infectious Diseases in Chișinău, Moldova. Patients were excluded if they had HDV superinfection, liver infections other than HBV and HDV, or liver cirrhosis. Patients received 500 mg intravenous REP 2139 once per week for 15 weeks, followed by combined therapy with 250 mg intravenous REP 2139 and 180 μg subcutaneous pegylated interferon alfa-2a once per week for 15 weeks, then monotherapy with 180 μg pegylated interferon alfa-2a once per week for 33 weeks. The primary endpoints assessed at the end of treatment were the safety and tolerability of the treatment regimen, analysed in the intention-to-treat population. Secondary outcomes included the proportion of patients with serum HBsAg less than 50 IU/mL, the proportion of patients with suppressed HBV DNA, and the proportion of patients who maintained these responses through follow-up. The REP 301 trial is registered with ClinicalTrials.gov, number NCT02233075. We also did an additional follow-up at 1 year after the end of treatment, as an interim analysis of the REP 301-LTF trial (planned duration 3 years), registered with ClinicalTrials.gov, number NCT02876419, which is ongoing but not recruiting patients. Between Sept 8, 2014, and Jan 27, 2015, we enrolled 12 patients into the REP 301 study. All 12 patients experienced at least one

  5. Pegylated Interferon Alfa-2b Add-on Treatment in Hepatitis B Virus Envelope Antigen-Positive Chronic Hepatitis B Patients Treated with Nucleos(t)ide Analogue: A Randomized, Controlled Trial (PEGON).

    Science.gov (United States)

    Chi, Heng; Hansen, Bettina E; Guo, Simin; Zhang, Ning Ping; Qi, Xun; Chen, Liang; Guo, Qing; Arends, Pauline; Wang, Ji-Yao; Verhey, Elke; de Knegt, Robert J; Xie, Qing; Janssen, Harry L A

    2017-04-01

    We studied whether 48 weeks of pegylated interferon alfa-2b (peginterferon) add-on therapy increases serological response in hepatitis B virus (HBV) envelope antigen (HBeAg)-positive patients receiving nucleos(t)ide analogue (NA) therapy, compared with continued NA monotherapy. This randomized trial included HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of interferon-naive patients, add-on therapy led to a greater frequency of HBeAg seroconversion (30% vs 7%; P = .034) and response (26% vs 7%; P = .068) at week 96, compared with monotherapy. Among 8 responders at week 48 who discontinued NA therapy at week 72, 6 patients (75%) maintained a response until week 96 (4 of 6 [67%] in the add-on therapy group vs 2 of 2 [100%] in the monotherapy group; P = 1.00). Adverse events were mainly related to peginterferon. The primary end point was negative, but peginterferon add-on therapy appeared to result in a greater frequency of HBeAg seroconversion, compared with NA monotherapy, in interferon-naive patients receiving NA therapy. NCT01532843.

  6. Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial.

    Science.gov (United States)

    Bourlière, Marc; Rabiega, Pascaline; Ganne-Carrie, Nathalie; Serfaty, Lawrence; Marcellin, Patrick; Barthe, Yoann; Thabut, Dominique; Guyader, Dominique; Hezode, Christophe; Picon, Magali; Causse, Xavier; Leroy, Vincent; Bronowicki, Jean Pierre; Carrieri, Patrizia; Riachi, Ghassan; Rosa, Isabelle; Attali, Pierre; Molina, Jean Michel; Bacq, Yannick; Tran, Albert; Grangé, Jean Didier; Zoulim, Fabien; Fontaine, Hélène; Alric, Laurent; Bertucci, Inga; Bouvier-Alias, Magali; Carrat, Fabrice

    2017-03-01

    Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy. In this randomised, controlled, open-label trial, we enrolled patients aged 18-75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392. Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] to pegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analogues group from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI -2

  7. Interferon status at the women with recurrent genital herpes in combined liposomal RNA treatment

    Directory of Open Access Journals (Sweden)

    A. Sh. Makhmutkhodzhayev

    2012-01-01

    Full Text Available The aim of this study was the estimation of the influence of liposomal ribonucleic acid (RNA medicine «Liprina» on interferon status of women with recurrent genital herpes. In this study 60 women were included, who combined (acyclovir and Liprina, n = 40 or monoterapy with acyclovir (n = 20 were received. The levels of serum interferon alpha and gamma along with cervical virus elimination were estimated. The medicine «Liprina» increased the therapy efficiency of the women with genital herpes, that perhaps related with endogen interferon production amplification.

  8. [Antiviral activity of recombinant interferon-alpha-2b in combination with certain antioxidant].

    Science.gov (United States)

    Vasil'ev, A N; Deriabin, P G; Galegov, G A

    2011-01-01

    In vitro activity of interferon-alpha-2b in combination with various antioxidants against the influenza virus and Herpes simplex was studied. The standard strains and a clinical strain of Herpes simplex isolated from a patient with resistance to acyclovir were used. The in vitro studie showed that antioxidants, such as alpho-tocoferol acetate (vitamin E), Unithiol and ascorbic acid had a significant antiinfluenzae and antiherpetic action on the influenza virus A/H5N1 and Herpes simplex variants. They protected up to 100% of the cell monolayer from the virus cytopathic effect. The taurin solutions had no antiviral activity irrespective of the infection dose. Combinations of interferon-alpha-2b with alpha-tocopherol acetate (vitamin E), Unithiol or ascorbic acid showed a significant synergistic effect: the antiviral activity of interferon increased several times. The antiinfluenza activity of interferon-a-2b in the presence of various concentrations of taurin did not change.

  9. Combination of interferon alfa-2b and ribavirin in relapsed or nonresponding chronic hepatitis C patients following interferon therapy

    Directory of Open Access Journals (Sweden)

    Laurentius A. Lesmana

    2001-12-01

    Full Text Available Twenty six patients (pts with chronic hepatitis C (CHC who reLapsed or non-responded following.interferon (IFN therapy were given lFN alfa-2b 3   MIU three times a week for 48 weeks in combination with Ribavirin 800-1000 mg daily 2I (80,8% of the 26.pts completed the study consisted of 12 relapsers and 9 non-responders. Five pts dropped out due to drug adverse events in three pts and non-drug related reason in the other two. In the relapsed group complete response, relapse and sustained response rates were obtained in 9/12(75%, 2/2 (16,5% and 7/12(58,3% pts respectively. In the non- responding group, these figures were 3/9 (33,3%, 1/9(I1,1%, and 2/9(22,2% pts, respectively. The most frequent adverse event was flu-like syndrome, which was found in 18 pts (85,7%. Combination therapy of IFN alfa-2b and ribavirin may induce sustained virological response in relapsed and non-responding CHC patients. This combination therapy is more effective for relapsers compared to for non-responders. (Med J Indones 2001; 10: 214-8Keywords: Chronic hepatitis C, combination therapy, interferon, ribavirin

  10. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Jacobson, Ira M; Dore, Gregory J; Foster, Graham R; Fried, Michael W; Radu, Monica; Rafalsky, Vladimir V; Moroz, Larysa; Craxi, Antonio; Peeters, Monika; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; De La Rosa, Guy; Kalmeijer, Ronald; Scott, Jane; Sinha, Rekha; Beumont-Mauviel, Maria

    2014-08-02

    Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; palfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. Janssen Infectious Diseases-Diagnostics. Copyright © 2014 Elsevier Ltd. All rights

  11. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

    Science.gov (United States)

    Manns, Michael; Marcellin, Patrick; Poordad, Fred; de Araujo, Evaldo Stanislau Affonso; Buti, Maria; Horsmans, Yves; Janczewska, Ewa; Villamil, Federico; Scott, Jane; Peeters, Monika; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; De La Rosa, Guy; Kalmeijer, Ronald; Sinha, Rekha; Beumont-Mauviel, Maria

    2014-08-02

    Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [alfa 2a or

  12. Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

    Science.gov (United States)

    Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

    2014-06-01

    Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

  13. Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT

    NARCIS (Netherlands)

    Boers-Sonderen, M.J.; Geus-Oei, L.F. de; Desar, I.M.E.; Graaf, W.T.A. van der; Oyen, W.J.G.; Ottevanger, P.B.; Herpen, C.M.L. van

    2014-01-01

    Pegylated liposomal doxorubicin (PLD) is active in breast, endometrial, and ovarian cancer. Preclinical data suggest that the combination of PLD with a mammalian target of rapamycin (mTOR) inhibitor has an additive effect. The safety and recommended phase two dose (RPTD) of temsirolimus in

  14. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

    NARCIS (Netherlands)

    P. Sonneveld (Pieter); R. Hajek (Roman); A. Nagler (Arnon); A. Spencer (Andrew); J. Bladé (Joan); T. Robak (Tadeusz); S.H. Zhuang (Sen); J-L. Harousseau (Jean-Luc); R.Z. Orlowski (Robert)

    2008-01-01

    textabstractBACKGROUND. Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In

  15. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy.

    NARCIS (Netherlands)

    Sonneveld, P.; Hajek, R.; Nagler, A.; Spencer, A.; Blade, J.; Robak, T.; Zhuang, S.H.; Harousseau, J.L.; Orlowski, R.Z.

    2008-01-01

    BACKGROUND: Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current

  16. Quantification of a pegylated interferon-alpha2a product by a customised and validated reverse phase-high performance liquid chromatography method.

    Science.gov (United States)

    El Ghazaly, Maria; Meager, Anthony; Zikry, Heidi; Ebaed, Mina; Shaker, Sami; Mueller, Frank; Rohde, Jan

    2013-10-01

    There is increasing development of pegylated proteins as clinical products for therapeutic interventions in human disease. Quantification of such products relies on appropriately calibrated traditional methods, including reverse phase-high performance liquid chromatography (RP-HPLC). However, currently available pharmacopoeia calibrants, e.g., chemical reference substances (CRS), are highly purified non-pegylated proteins of known concentration. These are uncertain to be suitable for calibration purposes where the precise quantification of the mass of pegylated proteins, often heterogeneous with respect to polyethylene glycol (PEG) chain size, structure, attachment sites and isomer numbers and proportions, is required. In this study, a customised RP-HPLC method was developed and validated for the analysis of a pegylated IFN-α2a product having a linear 20kDa PEG chain (PEG20-IFN-α2a; Reiferon Retard(®)). Since the PEG20 moiety generated no signal at the detection wavelength of 210nm, the concentration of the base IFN-α2a molecules in PEG-IFN-α2a could be determined. By calculating the UV absorbance at 210nm of peak areas in their respective chromatographic profiles, a high correlation (r(2) ≥ 0.995) of PEG20-IFN-α2a concentrations with equal concentrations of the CRS of IFN-α2a, or of a well-characterised PEG20-IFN-α2a internal reference substance (IRS) was found. This finding confirmed the suitability of this CRS as a primary calibrant for mass determinations of PEG20-IFN-α2a by the customised RP-HPLC method. Application of this method to the quantitative analysis of 10 batches of Reiferon Retard(®) yielded accurate and consistent results, indicating its utility for mass determinations of current and future Reiferon Retard(®) batches. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Clinical Success With Imiquimod Alone and In Combination With Intralesional Interferon In Basal Cell Carcinoma

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    Hayriye Sarıcaoğlu

    2013-12-01

    Full Text Available Background: Basal cell carcinoma (BCC is the most common type of skin cancer in humans. Surgery is still the gold standart for treatment of BCCs. However, there are also less-invasive, nonsurgical therapies such as imiquimod cream and intralesional interferon (IFN alpha-2b for the patients who are poor candidates for surgery and who care cosmetic outcomes. Objective: We report 11 BCC cases with various subtypes successfully treated with either imiquimod alone or in combination with interferon alfa-2b. Methods: Patients with various subtypes of histopathologically proven BCCs who were treated with imiquimod or combination of imiquimod and IFN alpha-2b between 2005-2010 years at our outpatient clinic are included in this report. Results: Of 11 patients we reported, only 4 patients (3 infiltrative, 1 solid types recieved intralesional interferon alpha-2b 3 million IU, 3 times a week combined with topical imiquimod. The rest 7 patients recieved only imiquimod 5% cream. All patients were cured with these regimens. Conclusion: Imiquimod is found to be effective not only in superficial, but also infiltrative, solid, and nodular types. Intralesional interferon alpha-2b is also known to be effective in BCCs and it has a synergistic effect when combined with imiquimod.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  19. A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin

    DEFF Research Database (Denmark)

    Mirza, Mansoor Raza; Lund, Bente; Lindegaard, Jacob Christian

    2010-01-01

    Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting....

  20. A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin

    DEFF Research Database (Denmark)

    Mirza, Mansoor Raza; Lund, Bente; Lindegaard, Jacob Christian

    2010-01-01

    Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting.......Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting....

  1. Real-life experience using trabectedin plus pegylated liposomal doxorubicin combination to treat patients with relapsed ovarian cancer

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    Saad Tahir

    2014-12-01

    Full Text Available The goal of recurrent ovarian cancer (ROC treatment is no longer just palliation, but prolonging survival. This is usually through administering a new line of chemotherapy at each relapse. A novel treatment sequencing strategy to achieve this is through the intercalation of an effective non-platinum alternative, in between platinum-based therapies. Trabectedin in combination with pegylated liposomal doxorubicin (PLD has been fully available privately in the UK since 2009 for treating patients with ROC. A single institution's experience with the trabectedin + PLD combination, as a non-platinum/non-taxane alternative, to intercalate between platinum-based therapies is reported here. To date 6 patients have been successfully treated with trabectedin + PLD at Broomfield Hospital, Chelmsford, Essex. Here we describe a new, practice-changing treatment approach in a real-life case study of a heavily-treated patient with advanced ROC treated with trabectedin + PLD at fourth-line and then subsequently rechallenged at seventh-line; with treatment continuing until disease progression.

  2. Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B

    DEFF Research Database (Denmark)

    Mellerup, M T; Krogsgaard, K; Mathurin, P

    2005-01-01

    Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon....

  3. Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B

    DEFF Research Database (Denmark)

    Mellerup, M T; Krogsgaard, K; Mathurin, P

    2002-01-01

    Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon....

  4. Treatment of naïve patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

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    Benjamin Heidrich

    Full Text Available Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV. It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47% while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%. According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR. However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.

  5. HBsAg seroconversion after pegylated interferon alfa 2a rescue in a lamivudine-resistant patient with HBeAg-negative chronic hepatitis B and favourable IL28-B genotype.

    Science.gov (United States)

    Stanzione, Maria; Stornaiuolo, Gianfranca; Rizzo, Viviana; Pontarelli, Agostina; Gaeta, Giovanni Battista

    2016-06-01

    Hepatitis B virus (HBV) surface antigen (HBsAg) seroconversion to anti-HBs antibody is the best final objective for all available chronic hepatitis B (CHB) treatments. Unfortunately, this goal is rarely achieved with the currently applied therapeutic approaches. Here we describe the case of an anti-HBe-positive CHB patient who was successfully treated with a particular therapeutic schedule. The patient was initially treated with lamivudine (LAM) for nine years. Breakthrough was observed after eight years of LAM therapy. HBV-DNA was 3x10E4 IU/mL and LAM resistance mutations were present. Subcutaneous pegylated interferon (PEG-IFN) alfa 2a, 180 mcg/week, was added to LAM and after 4 weeks LAM was discontinued and PEG-IFN alone was continued up to week 52. HBV-DNA became undetectable at week 4 of therapy; serum HBsAg started to decline from week 4 and became undetectable at week 36, with the subsequent appearance of anti-HBs antibodies. IL28-B was genotyped at the polymorphic site rs12979860 and the CC allele was detected. Rescue therapy with Peg-IFN may be an option for selected patients with resistance to nucleos(t)ide analogues.

  6. Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma

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    Arai Hajime

    2007-08-01

    Full Text Available Abstract Background Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ, has demonstrated promising activity against recurrent glioma, the effects last only a few months and drug resistance develops thereafter in most cases. Induction of O6-methylguanine-DNA methyltransferase (MGMT in tumors is considered to be responsible for resistance to TMZ. Interferon-beta has been reported to suppress MGMT in an experimental glioma model. Here we report a patient with TMZ-refractory anaplastic astrocytoma (AA who was treated successfully with a combination of interferon-beta and TMZ. Case presentation A patient with recurrent AA after radiation-chemotherapy and stereotactic radiotherapy was treated with TMZ. After 6 cycles, the tumor became refractory to TMZ, and the patient was treated with interferon-beta at 3 × 106 international units/body, followed by 5 consecutive days of 200 mg/m2 TMZ in cycles of 28 days. After the second cycle the tumor decreased in size by 50% (PR. The tumor showed further shrinkage after 8 months and the patient's KPS improved from 70% to 100%. The immunohistochemical study of the initial tumor specimen confirmed positive MGMT protein expression. Conclusion It is considered that interferon-beta pre-administration increased the TMZ sensitivity of the glioma, which had been refractory to TMZ monotherapy.

  7. Phase 1/2 Study of Atrasentan Combined with Pegylated Liposomal Doxorubicin in Platinum-Resistant Recurrent Ovarian Cancer

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    Petronella O. Witteveen

    2010-11-01

    Full Text Available BACKGROUND: Ovarian cancer overexpresses ET-1, and in vitro studies have shown that ET-1 confers resistance to anthracycline-containing chemotherapy. Atrasentan has been developed as an oral selective endothelin-A receptor antagonist. The objective of the study was to investigate the feasibility and toxicity of adding increasing doses of atrasentan (to a maximum of 10 mg/d and liposomal doxorubicin in patients with progressive ovarian cancer, refractory for platinum and paclitaxel. METHODS:Patients with platinum-resistant ovarian cancer were treated with pegylated liposomal doxorubicin (PLD 50 mg/m2 on day 1 (and repeated every 4 weeks in combination with escalating doses of atrasentan once daily. The starting dose was 2.5 mg and escalated in cohorts of three patients from 5 to 10 mg. RESULTS:Twenty-six patients (mean age = 60 years, range = 42–74 years were treated at the three dose levels. Atrasentan could be safely administered in combination at a dose of 10 mg. All patients were evaluable for toxicity, and 19 patients, included in the phase 2 period, were evaluable for response. Adverse events included nausea, vomiting, mucositis, skin toxicity, and rhinitis. Clinical cardiac toxicity, intensively monitored, was not observed, although two patients had a decrease in cardiac ejection fraction. Three objective responses were observed and another six patients had stable disease with a median time to progression of 14 weeks and an overall survival of 13.1 months. CONCLUSIONS:The addition of atrasentan to standard dose PLD in platinum-resistant ovarian cancer is feasible with some suggestion of prolonged survival.

  8. How to evaluate combination therapy using interferon and nucleos(tide analogues

    Directory of Open Access Journals (Sweden)

    CHEN Lu

    2016-11-01

    Full Text Available Chronic hepatitis B is still one of the most important chronic diseases in China because of its high relevance to liver cirrhosis and hepatic cell cancer (HCC. Currently, interferon and nucleos(tide analogues are two main treatments for chronic hepatitis B, but they have advantages and disadvantages. More investigations are needed to explore better ways for treating this disease, and combination therapy might be one of the options. This article analyzes the advances in various combination therapies and points out views about the selection of combination therapies and patients.

  9. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study.

    Science.gov (United States)

    Grob, Jean Jacques; Jouary, Thomas; Dréno, Brigitte; Asselineau, Julien; Gutzmer, Ralf; Hauschild, Axel; Leccia, Marie Thérèse; Landthaler, Michael; Garbe, Claus; Sassolas, Bruno; Herbst, Rudolf A; Guillot, Bernard; Chene, Genevieve; Pehamberger, Hubert

    2013-01-01

    Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN. Patients with resected melanoma ≥1.5mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3-4. Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73-1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80-1.32) and OS (HR 1.09, 95% CI 0.82-1.45). Peg-IFN was associated with higher rates of grade 3-4 AEs (47.3% versus 25.2%; p<0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN. This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702. Copyright © 2012. Published by Elsevier Ltd.

  10. Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV–HCV co-infected patients: final results of the Spanish BOC HIV–HCV Study

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    M. Laguno

    2016-12-01

    Conclusions: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC + PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

  11. Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C.

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    Akihito Tsubota

    Full Text Available Despite advances in chronic hepatitis C treatment, a proportion of patients respond poorly to treatment. This study aimed to explore hepatic mRNA and microRNA signatures involved in hepatitis C treatment resistance. Global hepatic mRNA and microRNA expression profiles were compared using microarray data between treatment responses. Quantitative real-time polymerase chain reaction validated the gene signatures from 130 patients who were infected with hepatitis C virus genotype 1b and treated with pegylated interferon-alpha and ribavirin combination therapy. The correlation between mRNA and microRNA was evaluated using in silico analysis and in vitro siRNA and microRNA inhibition/overexpression experiments. Multivariate regression analysis identified that the independent variables IL28B SNP rs8099917, hsa-miR-122-5p, hsa-miR-17-5p, and MAP3K8 were significantly associated with a poor virologic response. MAP3K8 and miR-17-5p expression were inversely correlated with treatment response. Furthermore, miR-17-5p repressed HCV production by targeting MAP3K8. Collectively, the data suggest that several molecules and the inverse correlation between mRNA and microRNA contributed to a host genetic refractory hepatitis C treatment response.

  12. Genetic variation in the vitamin D pathway CYP2R1 gene predicts sustained HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon: A multicenter study.

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    Kessarin Thanapirom

    Full Text Available Evidence of a role of vitamin D in the immune system is increasing. Low serum vitamin D is associated with increased hepatitis B virus replication. Genome-wide association study (GWAS data has revealed a number of the single nucleotide polymorphisms (SNPs within the vitamin D synthetic pathway that affect vitamin D functions. We aimed to determine the association between SNPs in the vitamin D gene cascade and response to pegylated interferon (PegIFN therapy in hepatitis B e-antigen (HBeAg-positive patients. One hundred and eleven patients treated for 48 weeks with PegIFN-alfa 2a at 13 hospitals were retrospectively evaluated. Thirteen SNPs derived from vitamin D cascade-related genes, including DHCR7 (rs12785878, CYP27B1 (rs10877012, CYP2R1 (rs2060793, rs12794714, GC (rs4588, rs7041, rs222020, rs2282679, and VDR (FokI, BsmI, Tru9I, ApaI, TaqI, were genotyped. Thirty-one patients (27.9% seroconverted to HBeAg after 24 weeks of treatment. Multivariate analysis found pretreatment qHBsAg 2 times the upper limit of normal (OR = 3.83, 95% CI: 1.31-11.22, P = 0.014 predicted sustained HBeAg seroconversion after completion of PegIFN treatment. HBV DNA during study period tended to be lower with the rs12794714 CYP2R1 TT than the non-TT genotype. The rs12794714 CYP2R1 polymorphism may be a useful pretreatment factor predictive of sustained HBeAg seroconversion after PegIFN therapy. This study provides evidence that not only vitamin D level but also genetic variation of CYP2R1 in the vitamin D cascade influences host immune response in chronic HBV infection.

  13. Hepatitis B Virus Pregenomic RNA Is Present in Virions in Plasma and Is Associated With a Response to Pegylated Interferon Alfa-2a and Nucleos(t)ide Analogues.

    Science.gov (United States)

    Jansen, L; Kootstra, Neeltje A; van Dort, Karel A; Takkenberg, R Bart; Reesink, Hendrik W; Zaaijer, Hans L

    2016-01-15

    Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA pregenome or HBV messenger RNA. Whether HBV RNA-containing particles continue to be secreted into the bloodstream remains controversial. We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir. Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN-based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen-negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen-specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions. HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CHB. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  14. Greater decline in memory and global neurocognitive function in HIV/hepatitis C co-infected than in hepatitis C mono-infected patients treated with pegylated interferon and ribavirin.

    Science.gov (United States)

    Miller, Theodore R; Weiss, Jeffrey J; Bräu, Norbert; Dieterich, Douglas T; Stivala, Alicia; Rivera-Mindt, Monica

    2017-04-01

    The human immunodeficiency virus (HIV), hepatitis C virus (HCV), and the treatment of HCV with pegylated interferon and ribavirin (IFN/RBV) have been associated with neurocognitive and psychiatric abnormalities. The goal of this research was to prospectively evaluate neurocognitive functioning among a group of HCV mono-infected and HIV/HCV co-infected patients during the first 24 weeks of IFN/RBV treatment while accounting for practice effects, normal variations in change over time, and variations in IFN/RBV treatment exposure. Forty-four HCV mono-infected and 30 HIV/HCV co-infected patients were enrolled in a prospective study of patients beginning on IFN/RBV for chronic HCV infection. Patients were administered a depression inventory, a measure of fatigue, a structured psychiatric interview, and a neurocognitive battery at baseline and 24 weeks after initiation of treatment. Analyses were conducted to explore possible associations between neurocognitive functioning and the following: HIV/HCV co-infection vs. HCV mono-infection, IFN and RBV treatment exposure, psychiatric status, liver disease stage, and other medical characteristics. At baseline, there were no significant differences between the two groups' neuropsychiatric or neurocognitive function other than the mono-infected group had significantly higher reports of fatigue (p = 0.033). Over the course of 24 weeks of treatment after controlling for practice effects, the HIV/HCV co-infected patients experienced significantly greater declines in memory (t(56) = 2.14, p = 0.037) and global neurocognitive functioning (t(53) = 2.28, p = 0.027). In a well-characterized sample of mono-infected and co-infected patients, it appears that persons with HIV/HCV co-infection are potentially more vulnerable to neurocognitive sequalae during HCV treatment.

  15. Association of SNPs in interferon receptor genes in chronic hepatitis C with response to combined therapy of interferon and ribavirin.

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    Zohreh Heidari

    2014-10-01

    Full Text Available Hepatitis C Virus is one of the main reasons for chronic liver disease and hepatocellular carcinoma. Combination therapy with Interferon (peg-IFN-α and Ribavirin (RBV clear the virus more likely than the others. Different factors like virus and host characteristics influence on response to treatment. The most important viral factors include virus genotype and viral load; host factors like genetic, gender, race, age, weight and liver enzymes are also important. Previous studies have shown that single nucleotide polymorphisms (SNPs in IFNR genes can regulate and influence on treatment with IFN. The purpose of this study is to investigate the association between SNPs in IFN-α receptor (IFNAR1 & IFNAR2 genes among subjects affected with chronic hepatitis C, who have treated with IFN and RBV, and also relationship between HCV genotypes and response to combination antiviral therapy. Peripheral blood mononuclear cells (PBMCs were taken from whole blood of 61 patients affected with chronic hepatitis C who were treated with IFN and Ribavirin. Then, DNA was extracted from PBMCs and quality of DNA was assessed with Nanodrop finally two SNPs [Ex4-30G>C] and [Ivs1-4640 G>A] of IFN receptor genes (IFNAR1 and IFNAR2 were measured by TaqMan Real-Time PCR in ABi Prism 7900 system. Also to confirm the response rate to therapy, RNA was extracted then RT PCR was performed and final product was studied with gel electrophoresis and UV spectroscopy. Statistical analysis was performed using SPSS version 18.0 for Windows. The analysis of results from TaqMan SNP Genotyping has been shown that two SNPs (Ex4-30G>C and Ivs1-4640 G>A of IFNAR1 and IFNAR2 didn't show any relationship with response to combined therapy in subjects affected with chronic hepatitis C who have treated with peg-IFN-α and Ribavirin. 61 patients complete the treatment period. 54 patients (%88/5 of them responded to treatment and 7 patients (%11/5 did not. Research and data analysis have shown that

  16. Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial: A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial.

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    Benjamin Heidrich

    Full Text Available Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3, many parts of the world still consider pegylated Interferon alpha (P and ribavirin (R as standard of care for G2/3. Patients with rapid virological response (RVR show response rates >80%. However, SVR (sustained virological response in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR. Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A or additional 12 weeks (total 36 weeks, group B of 1.5 μg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31. The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70% was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group.ClinicalTrials.gov NCT00803309.

  17. Telaprevir for HIV/hepatitis C virus-coinfected patients failing treatment with pegylated interferon/ribavirin (ANRS HC26 TelapreVIH): an open-label, single-arm, phase 2 trial.

    Science.gov (United States)

    Cotte, Laurent; Braun, Joséphine; Lascoux-Combe, Caroline; Vincent, Corine; Valantin, Marc-Antoine; Sogni, Philippe; Lacombe, Karine; Neau, Didier; Aumaitre, Hugues; Batisse, Dominique; de Truchis, Pierre; Gervais, Anne; Michelet, Christian; Morlat, Philippe; Vittecoq, Daniel; Rosa, Isabelle; Bertucci, Inga; Chevaliez, Stéphane; Aboulker, Jean-Pierre; Molina, Jean-Michel

    2014-12-15

    Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed. Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955. © The Author 2014. Published by Oxford University Press on

  18. Adverse Event Profile by Folate Receptor Status for Vintafolide and Pegylated Liposomal Doxorubicin in Combination, Versus Pegylated Liposomal Doxorubicin Alone, in Platinum-Resistant Ovarian Cancer: Exploratory Analysis of the Phase II PRECEDENT Trial.

    Science.gov (United States)

    Herzog, Thomas J; Kutarska, Elżbieta; Bidzińsk, Mariusz; Symanowski, Jim; Nguyen, Binh; Rangwala, Reshma A; Naumann, R Wendel

    2016-11-01

    This exploratory analysis evaluated the incidence of adverse events (AEs) by folate receptor (FR) status in the randomized, multicenter, open-label PRECEDENT study in women with platinum-resistant ovarian cancer receiving pegylated liposomal doxorubicin (PLD) ± the small-molecule drug conjugate vintafolide. Women 18 years or older with platinum-resistant ovarian cancer were randomized 2:1 to vintafolide (2.5 mg intravenously, 3 times per week, weeks 1 and 3, every 28 days) + PLD (50 mg/m intravenously, day 1, every 28 days) or PLD alone (same dose/schedule). The expression of functionally active FR was evaluated by single-photon emission computed tomography with etarfolatide. Patients were categorized according to FR positivity: patients with all target lesions positive for FR expression (FR 100%), patients with 1 or more but not all target lesions positive for FR expression (FR 10%-90%), and patients with all lesions negative for FR expression (FR 0%). Data on FR status were available for 94 patients: 38 were FR 100%, 36 were FR 10% to 90%, and 20 were FR 0%. Across all FR subgroups, the duration of treatment was longer, and the number of cycles was higher in combination-therapy arms than PLD-alone arms. Although the frequency of AEs was relatively consistent across subgroups, the FR 100% subgroup had a higher incidence of patients with at least 1 AE for combination therapy versus PLD alone. No surprising safety signals were shown according to FR status. The incidence of grade 3 or 4 treatment-emergent drug-related AEs was generally low across all FR subgroups and treatment arms. This exploratory analysis suggests that FR status does not influence the AE profile of vintafolide + PLD combination therapy or PLD alone in patients with platinum-resistant ovarian cancer. Future a priori analyses in larger populations are needed to confirm these findings.

  19. Histological response study of chronic viral hepatitis C patients treated with interferon alone or combined with ribavirin

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    Kleber Prado

    Full Text Available Chronic hepatitis C is often a progressive, fibrotic disease that can lead to cirrhosis and other complications. The recommended therapy is a combination of interferon and ribavirin. Besides its antiviral action, interferon is considered to have antifibrotic activity. We examined the outcome of hepatic fibrosis and inflammation in chronic hepatitis C patients who were non-responders to interferon. We made a case series, retrospective study, based on revision of medical records and reassessment of liver biopsies. For inclusion, patients should have been treated with interferon alone or combined with ribavirin, with no virological response (non responders and relapsers and had a liver biopsy before and after treatment. Histological evaluation included: i-outcome of fibrosis and necroinflammation; ii-annual fibrosis progression rate evaluation, before and after treatment. Seventy-five patients were included. Fifty-seven patients (76% did not show progression of fibrosis after treatment, compared to six (8% before treatment (p < 0.001. The mean annual fibrosis progression rate was significantly reduced after treatment (p = 0.036. Inflammatory activity improved in 19 patients (25.3%. The results support the hypothesis of an antifibrotic effect of interferon-based therapy, in non-responder patients. There was evidence of anti-inflammatory effects of treatment in some patients.

  20. Histological response study of chronic viral hepatitis C patients treated with interferon alone or combined with ribavirin.

    Science.gov (United States)

    Prado, Kleber; Patzina, Rosely; Bergamaschi, Denise; Focaccia, Roberto

    2008-10-01

    Chronic hepatitis C is often a progressive, fibrotic disease that can lead to cirrhosis and other complications. The recommended therapy is a combination of interferon and ribavirin. Besides its antiviral action, interferon is considered to have antifibrotic activity. We examined the outcome of hepatic fibrosis and inflammation in chronic hepatitis C patients who were non-responders to interferon. We made a case series, retrospective study, based on revision of medical records and reassessment of liver biopsies. For inclusion, patients should have been treated with interferon alone or combined with ribavirin, with no virological response (non responders and relapsers) and had a liver biopsy before and after treatment. Histological evaluation included: i-outcome of fibrosis and necroinflammation; ii-annual fibrosis progression rate evaluation, before and after treatment. Seventy-five patients were included. Fifty-seven patients (76%) did not show progression of fibrosis after treatment, compared to six (8%) before treatment (p < 0.001). The mean annual fibrosis progression rate was significantly reduced after treatment (p = 0.036). Inflammatory activity improved in 19 patients (25.3%). The results support the hypothesis of an antifibrotic effect of interferon-based therapy, in non-responder patients. There was evidence of anti-inflammatory effects of treatment in some patients.

  1. PREDICTORS OF SUSTAINED VIROLOGICAL RESPONSE (SVR TO PEGYLATED INTERFERON ALPHA (PEG-IFN α AND RIBAVIRIN (RBV IN PATIENTS WITH CHRONIC HEPATITIS C INFECTED WITH GENOTYPE 1.

    Directory of Open Access Journals (Sweden)

    Krasimir Antonov

    2011-12-01

    Full Text Available Objective: The combined PEG-IFN alpha and RBV therapy achieved SVR in 40 - 50% of patients infected with HCV genotype 1. Identification of virological and host paramemeters predicting SVR will be useful to tailor therapy. Methods: 71 patients with chronic HCV genotype 1 infection were treated with PEG-IFN alpha2a and RBV for 12 months. Predictors of SVR were analyzed by using nonparametric correlation test. Results: SVR was found in 57 / 71 of subjects (80,3%. The significant differences in baseline level of HCV RNA, sex, age, baseline ALT and present of liver cirrhosis between the patients with or without SVR were not found. Correlation was not proved between SVR and all these factors when they were analyzed separately. High correlation was found between serum levels of HCV RNA at the end of 3-th month therapy (Early Virological Response and SVR (r=0,759; p=0,011.Conclusion: The viral response during the first 3 months of PEG-IFN alpha and RBV therapy is the strongest independent predictor among the all baseline viral and host predictive factors for achieving of SVR.

  2. Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a.

    Science.gov (United States)

    Gallegos, Karen M; Drusano, George L; D Argenio, David Z; Brown, Ashley N

    2016-10-15

    We evaluated the antiviral activities of ribavirin (RBV) and interferon (IFN) alfa as monotherapy and combination therapy against chikungunya virus (CHIKV). Vero cells were infected with CHIKV in the presence of RBV and/or IFN alfa, and viral production was quantified by plaque assay. A mathematical model was fit to the data to identify drug interactions for effect. We ran simulations using the best-fit model parameters to predict the antiviral activity associated with clinically relevant regimens of RBV and IFN alfa as combination therapy. The model predictions were validated using the hollow fiber infection model (HFIM) system. RBV and IFN alfa were effective against CHIKV as monotherapy at supraphysiological concentrations. However, RBV and IFN alfa were highly synergistic for antiviral effect when administered as combination therapy. Simulations with our mathematical model predicted that a standard clinical regimen of RBV plus IFN alfa would inhibit CHIKV burden by 2.5 log10 following 24 hours of treatment. In the HFIM system, RBV plus IFN alfa at clinical exposures resulted in a 2.1-log10 decrease in the CHIKV burden following 24 hours of therapy. These findings validate the prediction made by the mathematical model. These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  3. Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.

    Science.gov (United States)

    Nelson, David R; Rustgi, Vinod; Balan, Vijayan; Sulkowski, Mark S; Davis, Gary L; Muir, Andrew J; Lambiase, Louis R; Dickson, Rolland C; Weisner, Russell H; Fiscella, Michele; Cronin, Patrick W; Pulkstenis, Erik; McHutchison, John G; Subramanian, G Mani

    2009-02-01

    Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. A total of 115 patients were assigned to 5 groups given 1200 microg albinterferon every 4 weeks or 900, 1200, 1500, or 1800 microg every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17% (11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1800-microg group. In patients with CHC who did not respond to interferon-based regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon.

  4. Thioredoxin Reductase Mediates Cell Death Effects of the Combination of Beta Interferon and Retinoic Acid

    Science.gov (United States)

    Hofman, Edward R.; Boyanapalli, Madanamohan; Lindner, Daniel J.; Weihua, Xiao; Hassel, Bret A.; Jagus, Rosemary; Gutierrez, Peter L.; Kalvakolanu, Dhananjaya V.

    1998-01-01

    Interferons (IFNs) and retinoids are potent biological response modifiers. By using JAK-STAT pathways, IFNs regulate the expression of genes involved in antiviral, antitumor, and immunomodulatory actions. Retinoids exert their cell growth-regulatory effects via nuclear receptors, which also function as transcription factors. Although these ligands act through distinct mechanisms, several studies have shown that the combination of IFNs and retinoids synergistically inhibits cell growth. We have previously reported that IFN-β–all-trans-retinoic acid (RA) combination is a more potent growth suppressor of human tumor xenografts in vivo than either agent alone. Furthermore, the IFN-RA combination causes cell death in several tumor cell lines in vitro. However, the molecular basis for these growth-suppressive actions is unknown. It has been suggested that certain gene products, which mediate the antiviral actions of IFNs, are also responsible for the antitumor actions of the IFN-RA combination. However, we did not find a correlation between their activities and cell death. Therefore, we have used an antisense knockout approach to directly identify the gene products that mediate cell death and have isolated several genes associated with retinoid-IFN-induced mortality (GRIM). In this investigation, we characterized one of the GRIM cDNAs, GRIM-12. Sequence analysis suggests that the GRIM-12 product is identical to human thioredoxin reductase (TR). TR is posttranscriptionally induced by the IFN-RA combination in human breast carcinoma cells. Overexpression of GRIM-12 causes a small amount of cell death and further enhances the susceptibility of cells to IFN-RA-induced death. Dominant negative inhibitors directed against TR inhibit its cell death-inducing functions. Interference with TR enzymatic activity led to growth promotion in the presence of the IFN-RA combination. Thus, these studies identify a novel function for TR in cell growth regulation. PMID:9774665

  5. Additively Enhanced Antiproliferative Effect of Interferon Combined with Proanthocyanidin on Bladder Cancer Cells

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    Andrew I. Fishman, Blake Johnson, Bobby Alexander, John Won, Muhammad Choudhury, Sensuke Konno

    2012-01-01

    Full Text Available Although interferon (IFN has been often used as immunotherapy for bladder cancer, its efficacy is rather unsatisfactory, demanding further improvement. Combination therapy is one of viable options, and grape seed proanthocyanidin (GSP could be such an agent to be used with IFN because it has been shown to have anticancer activity. We thus investigated whether combination of IFN and GSP might enhance the overall antiproliferative effect on bladder cancer cells in vitro. Human bladder cancer T24 cells were employed and treated with the varying concentrations of recombinant IFN-α2b (0-100,000 IU/ml, GSP (0-100 μg/ml, or their combinations. IFN-α2b alone led to a ~50% growth reduction at 20,000 (20K IU/ml, which further declined to ~67% at ≥50K IU/ml. Similarly, GSP alone induced a ~35% and ~100% growth reduction at 25 and ≥50 μg/ml, respectively. When IFN-α2b and GSP were then combined, combination of 50K IU/ml IFN-α2b and 25 μg/ml GSP resulted in a drastic >95% growth reduction. Cell cycle analysis indicated that such an enhanced growth inhibition was accompanied by a G1 cell cycle arrest. This was further confirmed by Western blot analysis revealing that expressions of G1-specific cell cycle regulators (CDK2, CDK4, cyclin E and p27/Kip1 were distinctly modulated with such IFN-α2b/GSP treatment. Therefore, these findings support the notion that combination of IFN-α2b and GSP is capable of additively enhancing antiproliferative effect on T24 cells with a G1 cell cycle arrest, implying an adjuvant therapeutic modality for superficial bladder cancer.

  6. [Inhibitory effect of thalidomide combined with interferon on the proliferation of Kasumi-1 cells].

    Science.gov (United States)

    Xu, Hao; Mi, Ruihua; Fan, Ruihua; Yin, Qingsong; Wang, Xiaojiao; Wei, Xudong

    2015-09-01

    To explore the inhibitory effect of thalidomide combined with interferon (IFN) on the human acute myeloid leukemia cell line Kasumi- 1 and its mechanism. The inhibitiory effect of Kasumi- 1 cells by thalidomide, interferon or combination was detected by CCK- 8 method, the apoptosis by flow cytometry, the expression of apoptosis related proteins by Western blot, vascular endothelial growth factor (VEGF) concentration in culture supernatant by ELISA. Thalidomide inhibited the proliferation of Kasumi- 1 in a dose- dependent manner from 50 μg/ml to 500 μg/ml with an IC₅₀ of (451.13 ± 6.92)μg/ml at 24 h and (362.50 ± 14.52)μg/ml at 48 h. IFN also demonstrated the inhibitory capacity in a dose-dependent manner from 500 U/ml to 5 000 U/ml, with an IC₅₀ of (2 209 ± 127) U/ml at 24 h and (1 393±63) U/ml at 48 h. The apoptosis rates of Kasumi-1 cells treated with thalidomide 350 μg/ml or IFN 1 400 U/ml for 48 h were (14.68 ± 2.61) % and (21.71 ± 0.71)%, respectively, significantly higher than control group (Pthalidomide group [(141.11 ± 3.70) ng/L and IFN group [(119.90 ± 2.00) ng/L (P thalidomide 350 μg/ml or IFN 1 400 U/ml for 48 h. When treated with the combination agents, the expression of Bcl-2 further decreased and p-P38, Bax, cytochrome C, cleaved-Caspase-3, 8, 9 further increased as compared with each single agent (P Thalidomide and IFN could synergistically inhibit the proliferation of Kasumi-1 cells probably through inducing apoptosis via the mitochondrial pathway, death receptor pathway and P38 MAPK pathway, as well as inhibiting VEGF secretion.

  7. Interferon alfa combined with azathioprine for the uveitis of Behçet's disease: an open study.

    Science.gov (United States)

    Hamuryudan, Vedat; Ozyazgan, Yilmaz; Fresko, Yzzet; Mat, Cem; Yurdakul, Sebahattin; Yazici, Hasan

    2002-11-01

    Eye involvement is the main cause of morbidity in Behçet's syndrome. The efficacy of the combined use of azathioprine and interferon alfa in treating this condition has not been studied. Ten male BD patients with retinal involvement but no irreversible structural changes were treated with azathioprine 2.5 mg/kg/day and IFN alpha 2b three times weekly for 24 weeks in an open trial. At week 24, IFN alpha was stopped and the patients continued to use azathioprine or received other immunosuppressives as indicated. Clinical response was assessed by visual acuity changes of either eye under the combination treatment and during the follow-up after stopping interferon. As compared to the study entry, the mean visual acuities of either eye increased significantly at the end of the combination treatment (right eye 5.8 +/- 1.26 vs. 8.3 1.14; P = 0.043; left eye 6.3 1.15 SEM vs. 9.1 +/- 0.9 SEM; P = 0.027). The improvement in visual acuity persisted in the nine patients who were followed for 7.2 +/- 1.6 SEM months after stopping interferon. Reversible hematologic toxicity, mostly in the form of leukopenia, was detected in six patients during the combination treatment. The combination of IFN alpha and azathioprine appears to be effective for eye involvement of BD. However, the frequent occurrence of myelosuppression mandates close monitoring.

  8. Effect of the Combination of Trabectedin and Pegylated Liposomal Doxorubicin in a BRCA2 Mutation Carrier with Recurrent Platinum-Sensitive Ovarian Cancer.

    Science.gov (United States)

    Rubio Pérez, María Jesús

    2017-01-01

    The current standard of care for ovarian cancer is optimal cytoreduction with adjuvant chemotherapy based on a platinum/taxane combination. Although the response rate to this therapy is high, most patients ultimately relapse. Response to second-line therapy and prognosis are linked to the platinum-free interval (PFI); when both improve, the PFI increases. As a result, there is an increasing interest in the PFI extension strategies including platinum-free combinations. A 50-year-old postmenopausal woman presented with ovarian serous carcinoma with peritoneal carcinomatosis. First-line neoadjuvant chemotherapy with carboplatin plus paclitaxel was initiated, followed by surgery and carboplatin plus paclitaxel chemotherapy. Eight months after the last cycle, CT revealed extensive supra- and infradiaphragmatic node involvement, and second-line chemotherapy was initiated with trabectedin and pegylated liposomal doxorubicin (PLD). Partial response was achieved and successfully maintained for 18 cycles. After the 18th cycle and a 25-month PFI, CT imaging evidenced disease progression. As the patient was a BRCA2 mutation carrier, third-line chemotherapy was initiated with carboplatin and gemcitabine every 3 weeks. After the third cycle, imaging confirmed complete response, which was maintained after the sixth and final cycle. Maintenance treatment with olaparib was initiated. At present - 6 months after the start of maintenance chemotherapy with olaparib - the patient is disease free. Second-line chemotherapy with a nonplatinum combination - trabectedin plus PLD - was effective in a BRCA2 mutation carrier with recurrent partially platinum-sensitive ovarian cancer.

  9. Effects of Thalidomide Combined with Interferon on Inhibiting Kasumi-1 Cell Proliferation.

    Science.gov (United States)

    Xu, Hao; Mi, Ruihua; Fan, Ruihua; Yin, Qingsong; Wei, Xudong

    2016-01-01

    Our previous clinical observations proved that the combination of thalidomide and interferon (IFN) had certain effects in relapsed or refractory AML. The aim of this study was to investigate the effects and its mechanism of thalidomide and IFN on inhibiting the proliferation of Kasumi-1 cells. Thalidomide, IFN and a combination of both drugs were used to treat Kasumi-1 cells. The inhibition of cell proliferation and the apoptosis rate were measured. Vascular endothelial growth factor levels and the expression of apoptosis-related proteins were detected by ELISA and Western blotting, respectively. Thalidomide and IFN could both inhibit Kasumi-1 cell proliferation in a dose-dependent manner. When Kasumi-1 cells were treated with thalidomide 350 μg/mL or IFN1400 U/mL for 48 h, the proliferation inhibition rates were (48.8 ± 4.64)% and (50.19 ± 2.59)% and the rates of apoptosis were (14.68 ± 2.61)% and (21.71 ± 0.71)%, respectively; when treated with a combination, the cell proliferation inhibition rate and apoptotic rate were statistically significantly higher than both the control group and the groups treated with a single drug. The ELISA assay revealed that both 350 μg/mL of thalidomide and 1400 U/mL of IFN could reduce the VEGF levels in cell culture supernatants; the two-drug combination group had a further decreased VEGF concentration. Forty-eighthour treatment of thalidomide 350 μg/mL and IFN 1400 U/mL could significantly decrease Bcl-2 expression and increase the expression levels of phosphor-P38, BAX, cytochrome c, and cleaved caspase-3, -8, and -9 as compared to the control group. The combination group exhibited significantly greater extents of reduction in Bcl-2 protein and increases in p-P38, BAX, and cytochrome c, and cleaved caspase-3, -8, and -9 protein expression as compared to the single drug groups. Thalidomide and IFN can synergistically inhibit Kasumi-1 cell proliferation, which is possibly achieved through the mitochondrial and death

  10. Real-World Outcomes of Combination Chemotherapy with Trabectedin plus Pegylated Liposomal Doxorubicin in Patients with Recurrent Ovarian Cancer: A Single-Center Experience.

    Science.gov (United States)

    Moriceau, Guillaume; Rivoirard, Romain; Méry, Benoîte; Vallard, Alexis; Pacaut, Cécile; Trone, Jane-Chloé; Espenel, Sophie; Bosacki, Claire; Jacquin, Jean-Philippe; Magné, Nicolas

    2016-01-01

    Trabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC). We report a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life ROC patients. From February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48-78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%). Trabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients. © 2016 S. Karger AG, Basel.

  11. Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

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    Moore Carla L

    2010-03-01

    Full Text Available Abstract Background Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD in patients with platinum resistant ovarian cancer. Patients with platinum resistant ovarian carcinoma and measurable disease received canfosfamide at 960 mg/m2 in combination with PLD at 50 mg/m2, intravenously day 1 in every 28 day cycles until tumor progression or unacceptable toxicities. The primary endpoints were objective response rate (ORR and progression-free survival (PFS. Results Canfosfamide plus PLD combination therapy was administered at 960/50 mg/m2, respectively. Thirty-nine patients received a median number of 4 cycles (range 1.0-18.0. The ORR was 27.8% (95% CI, 14.2-45.2 with a disease stabilization rate of 80.6% (95% CI, 64.0-91.8 in the evaluable population. The CA-125 marker responses correlated with the radiological findings of complete response or partial response. The median PFS was 6.0 months (95% CI, 4.2-7.9 and median survival was 17.8 months. The combination was well tolerated. Myelosuppression was managed with dose reductions and growth factor support. Grade 3 febrile neutropenia was observed in 2 patients (5.1%. Non-hematologic adverse events occurred at the expected frequency and grade for each drug alone, with no unexpected or cumulative toxicities. Conclusions Canfosfamide in combination with PLD is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer. A randomized phase 3 study was conducted based on this supportive phase 2 study. Trial Registration This study was registered at www.clinicaltrials.gov: NCT00052065.

  12. Regression of central giant cell granuloma by a combination of imatinib and interferon: a case report

    NARCIS (Netherlands)

    de Lange, J.; van Rijn, R.R.; van den Berg, H.; van den Akker, H.P.

    2009-01-01

    Central giant cell granuloma is a benign lesion of the jaws which is sometimes aggressive locally. The most common treatment is curettage which has a high recurrence rate. particularly, in more aggressive lesions. Other treatments Such as interferon (IFN) and calcitonin have been described. We

  13. Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT.

    Science.gov (United States)

    Boers-Sonderen, Marye J; de Geus-Oei, Lioe-Fee; Desar, Ingrid M E; van der Graaf, Winette T A; Oyen, Wim J G; Ottevanger, Petronella B; van Herpen, Carla M L

    2014-12-01

    Pegylated liposomal doxorubicin (PLD) is active in breast, endometrial, and ovarian cancer. Preclinical data suggest that the combination of PLD with a mammalian target of rapamycin (mTOR) inhibitor has an additive effect. The safety and recommended phase two dose (RPTD) of temsirolimus in combination with PLD were assessed. (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed for early response monitoring. Nineteen patients with advanced breast, endometrial, and ovarian cancer were treated with increasing doses of temsirolimus (10, 15, or 20 mg once weekly) and PLD (30 or 40 mg/m(2) once every 4 weeks). PLD was initiated 2 weeks after start of temsirolimus. FDG-PET/CT was performed at baseline, after 2 and 6 weeks. Standardized uptake values (SUV), metabolic volume, and total lesion glycolysis (TLG, SUV × metabolic volume) were calculated. The RPTD was 15 mg temsirolimus and 40 mg/m(2) PLD. Dose-limiting toxicities (DLT) were thrombocytopenia grade 3 with nose bleeding and skin toxicity grade 3. Most frequent treatment-related toxicities were nausea, fatigue, mucositis, and skin toxicity. Changes in TLG after 2 weeks predicted partial response (PR) after 10 weeks (p = 0.037). A rise in SUV between the second and sixth week predicted progression (PD) (p = 0.034) and was associated with worse progression free survival (PFS) (HR 1.068; p = 0.013). The RPTD was established at 15 mg temsirolimus weekly and PLD 40 mg/m(2) once every 4 weeks and the combination was safe. Early response evaluation with FDG-PET/CT may predict subsequent radiological PR and PD. This trial is registered under number NCT0098263.

  14. Effect of the Combination of Trabectedin and Pegylated Liposomal Doxorubicin in a BRCA2 Mutation Carrier with Recurrent Platinum-Sensitive Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    María Jesús  Rubio Pérez

    2017-05-01

    Full Text Available Introduction: The current standard of care for ovarian cancer is optimal cytoreduction with adjuvant chemotherapy based on a platinum/taxane combination. Although the response rate to this therapy is high, most patients ultimately relapse. Response to second-line therapy and prognosis are linked to the platinum-free interval (PFI; when both improve, the PFI increases. As a result, there is an increasing interest in the PFI extension strategies including platinum-free combinations. Case Presentation: A 50-year-old postmenopausal woman presented with ovarian serous carcinoma with peritoneal carcinomatosis. First-line neoadjuvant chemotherapy with carboplatin plus paclitaxel was initiated, followed by surgery and carboplatin plus paclitaxel chemotherapy. Eight months after the last cycle, CT revealed extensive supra- and infradiaphragmatic node involvement, and second-line chemotherapy was initiated with trabectedin and pegylated liposomal doxorubicin (PLD. Partial response was achieved and successfully maintained for 18 cycles. After the 18th cycle and a 25-month PFI, CT imaging evidenced disease progression. As the patient was a BRCA2 mutation carrier, third-line chemotherapy was initiated with carboplatin and gemcitabine every 3 weeks. After the third cycle, imaging confirmed complete response, which was maintained after the sixth and final cycle. Maintenance treatment with olaparib was initiated. At present – 6 months after the start of maintenance chemotherapy with olaparib – the patient is disease free. Conclusions: Second-line chemotherapy with a nonplatinum combination – trabectedin plus PLD – was effective in a BRCA2 mutation carrier with recurrent partially platinum-sensitive ovarian cancer.

  15. Superiority of aromatase inhibitor and cyclooxygenase-2 inhibitor combined delivery: Hyaluronate-targeted versus PEGylated protamine nanocapsules for breast cancer therapy.

    Science.gov (United States)

    Elzoghby, Ahmed O; Mostafa, Shaimaa K; Helmy, Maged W; ElDemellawy, Maha A; Sheweita, Salah A

    2017-08-30

    Despite several reports have revealed the beneficial effect of co-administration of COX-2 inhibitors with aromatase inhibitors in managing postmenopausal breast cancer; no nanocarriers for such combined delivery have been developed till now. Therefore, protamine nanocapsules (PMN-NCs) have been developed to co-deliver letrozole (LTZ) that inhibits aromatase-mediated estrogen biosynthesis and celecoxib (CXB) that synergistically inhibits aromatase expression. Inspired by the CD44-mediated tumor targeting ability of hyaluronate (HA), we developed HA-coated PMN-NCs (HA-NCs) via electrostatic layer-by-layer assembly. Moreover, multi-compartmental PEGylated phospholipid-CXB complex bilayer enveloping PMN-NCs (PEG-NCs) were designed for conferring biphasic CXB release from the phospholipid corona and oily core as well as enabling passive-targeting. The NCs demonstrated excellent stability, prolonged circulation and could be scaled up with the aid of spray-drying technology. Hemolysis, serum stability and cytotoxicity studies confirmed the superiority of combined LTZ-CXB nano-delivery. Mechanistically, the NCs especially HA-NCs and PEG-NCs demonstrated precious anti-tumor effects in vivo revealed as reduction in the tumor volume and aromatase level, increased apoptosis, as well as inhibition of VEGF, NF-κB and TNF-α augmented by histopathological and immunohistochemical studies. Overall, our approach provided for the first time a potential strategy for targeted LTZ-CXB combined therapy of hormone-dependent breast cancer via singular nanocapsule delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial.

    Science.gov (United States)

    Gore, Martin E; Griffin, Clare L; Hancock, Barry; Patel, Poulam M; Pyle, Lynda; Aitchison, Michael; James, Nicholas; Oliver, Roderick T D; Mardiak, Jozef; Hussain, Tahera; Sylvester, Richard; Parmar, Mahesh K B; Royston, Patrick; Mulders, Peter F A

    2010-02-20

    In metastatic renal cell carcinoma combinations of interferon alfa-2a, interleukin-2, and fluorouracil produce higher response rates and longer progression-free survival than do single agents. We aimed to compare overall survival in patients receiving combination treatment or interferon alfa-2a. RE04/30012 was an open-label randomised trial undertaken in 50 centres across eight countries. 1006 treatment-naive patients diagnosed with advanced metastatic renal cell carcinoma were randomly allocated (1 to 1) by minimisation to receive interferon alfa-2a alone or combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil. Treatment was not masked. The primary endpoint was overall survival. Treatment groups were compared with a non-stratified log-rank test. Analysis was by intention to treat. This study is registered, number ISRCTN 46518965. 502 patients were randomly assigned to receive interferon alfa-2a and 504 to receive combined treatment. Median follow-up was 37.2 months (24.8-52.3). Median overall survival was 18.8 months (17.0-23.2) for patients receiving interferon alfa-2a versus 18.6 months (16.5-20.6) for those receiving combination therapy. Overall survival did not differ between the two groups (hazard ratio 1.05 [95% CI 0.90-1.21], p=0.55; absolute difference 0.3% (-5.1 to 5.6) at 1 year and 2.7% (-8.2 to 2.9) at 3 years). Serious adverse events were reported in 113 (23%) patients receiving interferon alfa-2a and 131 (26%) of those receiving combined treatment. Although combination therapy does not improve overall or progression-free survival compared with interferon alfa-2a alone, immunotherapy might still have a role because it can produce remissions that are of clinically relevant length in some patients. Identification of patients who will benefit from immunotherapy is crucial. UK Medical Research Council. Copyright 2010 Elsevier Ltd. All rights reserved.

  17. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer.

    Science.gov (United States)

    Naumann, R Wendel; Coleman, Robert L; Burger, Robert A; Sausville, Edward A; Kutarska, Elzbieta; Ghamande, Sharad A; Gabrail, Nashat Y; Depasquale, Stephen E; Nowara, Elzbieta; Gilbert, Lucy; Gersh, Robert H; Teneriello, Michael G; Harb, Wael A; Konstantinopoulos, Panagiotis A; Penson, Richard T; Symanowski, James T; Lovejoy, Chandra D; Leamon, Christopher P; Morgenstern, David E; Messmann, Richard A

    2013-12-10

    Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

  18. Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C

    Directory of Open Access Journals (Sweden)

    Stephen E. Livingston

    2016-03-01

    Full Text Available Background: There have been few reports of hepatitis C virus (HCV treatment results with interferon-based regimens in indigenous populations. Objective: To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI population. Design: In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. Results: Sustained virologic response (SVR with standard interferon was 16.7% (3/18 and with standard interferon and ribavirin was 29.7% (11/37. Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%, including 10 of 46 with genotype 1 (21.7%, 38 of 51 with genotype 2 (74.5% and 13 of 22 with genotype 3 (59.1%. By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002, estimated duration of infection (p=0.034 and HCV genotype (p<0.0001. There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%. Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%. Conclusions: We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.

  19. PEGylated Silk Nanoparticles for Anticancer Drug Delivery

    DEFF Research Database (Denmark)

    Wongpinyochit, Thidarat; Uhlmann, Petra; Urquhart, Andrew

    2015-01-01

    is especially necessary to support their evolution. The aim of this study was to develop and examine the potential of PEGylated silk nanoparticles as an anticancer drug delivery system. We first generated B. mori derived silk nanoparticles by driving β-sheet assembly (size 104 ± 1.7 nm, zeta potential −56 ± 5.......6 mV) using nanoprecipitation. We then surface grafted polyethylene glycol (PEG) to the fabricated silk nanoparticles and verified the aqueous stability and morphology of the resulting PEGylated silk nanoparticles. We assessed the drug loading and release behavior of these nanoparticles using...... clinically established and emerging anticancer drugs. Overall, PEGylated silk nanoparticles showed high encapsulation efficiency (>93%) and a pH-dependent release over 14 days. Finally, we demonstrated significant cytotoxicity of drug loaded silk nanoparticles applied as single and combination nanomedicines...

  20. Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus.

    Science.gov (United States)

    Wolters, L M; van Nunen, A B; Honkoop, P; Vossen, A C; Niesters, H G; Zondervan, P E; de Man, R A

    2000-11-01

    Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine-high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 x 10(6) geq ml-(1)) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48-143) IU l(1). Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l(-1) (range 548-7,684) to 5300 PEU l(-1) (range 168-19,639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 10(5) geq ml(-1); range 10(3)-10(6) to median 10(3) geq ml(-1); range 10(2)-10(7)). Serum ALT did not change as reflected by a median of 68 IU l(-1) (range 48-143) at start of therapy to 63 IU l(-1) (range 20-171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5-9) at baseline to 5 (range 3-8) at the end of

  1. Rational design of liposomal drug delivery systems, a review: Combined experimental and computational studies of lipid membranes, liposomes and their PEGylation

    Czech Academy of Sciences Publication Activity Database

    Bunker, A.; Magarkar, Aniket; Viitala, T.

    2016-01-01

    Roč. 1858, č. 10 (2016), s. 2334-2352 ISSN 0005-2736 Institutional support: RVO:61388963 Keywords : nanomedicine * liposome * drug delivery * molecular dynamics simulation * label-free analytics * PEGylation Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.498, year: 2016

  2. Phase II study of the combination of pegylated liposomal doxorubicin and topotecan in platinum-resistant ovarian cancer.

    Science.gov (United States)

    Verhaar-Langereis, M; Karakus, A; van Eijkeren, M; Voest, E; Witteveen, E

    2006-01-01

    The combination of liposomal doxorubicin and topotecan was evaluated in a phase II study in patients with platinum-resistant ovarian cancer. Twenty-seven patients received liposomal doxorubicin (30 mg/m(2)) infused at day 1, followed by topotecan (1 mg/m(2)) infusion daily for 5 days. Cycles were repeated every 21 days. This combination regimen showed an overall response rate of 28%. Median time to progression was 30 weeks, with a median overall survival of 40 weeks. Grade 3/4 neutropenia was shown in 70% of patients and grade 3/4 thrombopenia in 41% of patients. Neutropenic fever was reported in 11% of patients. After reviewing the first 12 patients, the internal review board decided to administer topotecan at a dose of 0.75 mg/m(2) and liposomal doxorubicin at 40 mg/m(2) for the remainder of the study. However, this adjustment did not lead to reduction in bone marrow toxicity nor to an improvement in dose intensity. Palmar-plantar erythrodysesthesia and mucositis were more reported in the second cohort but usually mild. The combination of liposomal doxorubicin and topotecan demonstrates favorable response data in platinum-resistant ovarian cancer. However, substantial bone marrow toxicity limits further clinical use.

  3. Daily interferon induction regimen using different manufactured interferons (alpha-2a or alpha-2b in combination with ribavirin for treatment of chronic hepatitis C: a prospective randomized study Esquema de indução diário com interferon alfa 2-a ou alfa 2-b em combinação com ribavirina para tratamento da hepatite crônica C: estudo prospectivo randomizado

    Directory of Open Access Journals (Sweden)

    Eduardo Lorens Braga

    2006-12-01

    Full Text Available BACKGROUD: Studies on hepatitis C virus kinetics showed that serum levels of interferon fall 48 h after drug administration, when viral load is increasing again. Previously to the availability of pegylated interferon, daily induction therapy with standard interferon was under evaluation. AIMS: To evaluate the safety and efficacy of interferon alpha daily induction regimen in combination with ribavirin. PATIENTS AND METHODS: A randomized trial including 93 patients with chronic hepatitis C was carried out. On satisfying all eligibility criteria, patients were randomly allocated to two different treatment groups: 44 individuals in treatment arm A: IFN 3 MU thrice weekly + ribavirin 1.0-1.2 g daily for 48 weeks (IFN TIW and 49 individuals in treatment arm B: IFN 3 MU daily + ribavirin 1.0-1.2 g daily for 12 weeks followed by IFN 3 MU thrice weekly + ribavirin 1.0-1.2 g daily, until completion of 48 weeks of therapy (IFN QD. HCV genotyping was obtained in 85 subjects. A negative HCV-RNA 6 months after cessation of therapy was considered a sustained virological response RESULTS: Eighty three patients completed treatment, five dropped out (one from IFN TIW and four from IFN QD and in five patients therapy was discontinued due to medical request (two from IFN TIW and three from IFN QD. There was no statistically significant difference between groups with respect to therapy interruption. The frequency of cirrhosis was 29%, similar in both groups. In the "intention to treat" analysis the overall sustained virological response was 39.8%. There was no significant difference in sustained virological response rate between both treatment strategies (36.4% IFN TIW vs 42.9% IFN QD. In the 83 patients who finished the trial, sustained virological response was 44.6%. Among subjects with HCV genotype-1, the sustained virological response was 42% (40.9% IFN TIW vs 42.9% IFN QD and among patients with HCV genotype 2 or 3, the sustained virological response was 55

  4. Toward improving selectivity in affinity chromatography with PEGylated affinity ligands: the performance of PEGylated protein A.

    Science.gov (United States)

    González-Valdez, José; Yoshikawa, Alex; Weinberg, Justin; Benavides, Jorge; Rito-Palomares, Marco; Przybycien, Todd M

    2014-01-01

    Chemical modification of macromolecular affinity chromatography ligands with polyethylene glycol chains or "PEGylation" can potentially improve selectivity by sterically suppressing non-specific binding interactions without sacrificing binding capacity. For a commercial protein A affinity media and with yeast extract (YE) and fetal bovine serum (FBS) serving as mock contaminants, we found that the ligand accounted for more than 90% of the media-associated non-specific binding, demonstrating an opportunity for improvement. The IgG static binding affinity of protein A mono-PEGylated with 5.0 and 20.7 kDa poly(ethylene glycol) chains was found to be preserved using a biomolecular interaction screening platform. Similar in situ PEGylations of the commercial protein A media were conducted and the modified media was functionally characterized with IgG solutions spiked with YE and FBS. Ligand PEGylation reduced the mass of media-associated contaminants by a factor of two to three or more. Curiously, we also found an increase of up to 15% in the average recovery of IgG on elution after PEGylation. Combined, these effects produced an order of magnitude increase in the IgG selectivity on average when spiked with YE and a two- to three-fold increase when spiked with FBS relative to the commercial media. Dynamic binding capacity and mass-transfer resistance measurements revealed a reduction in dynamic capacity attributed to a decrease in IgG effective pore diffusivity and possibly slower IgG association kinetics for the PEGylated protein A ligands. Ligand PEGylation is a viable approach to improving selectivity in affinity chromatography with macromolecular ligands. © 2014 American Institute of Chemical Engineers.

  5. Retreatment of hepatitis C non-responsive to Interferon. A placebo controlled randomized trial of Ribavirin monotherapy versus combination therapy with Ribavirin and Interferon in 121 patients in the Benelux [ISRCTN53821378

    Directory of Open Access Journals (Sweden)

    Delwaide Jean

    2003-08-01

    Full Text Available Abstract Background Evidence based medicine depends on unbiased selection of completed randomized controlled trials. For completeness it is important to publish all trials. This report describes the first large randomised controlled trial where combination therapy was compared to placebo therapy and to ribavirin monotherapy, which has not been published untill now. Methods One hundred and twenty one patients with chronic hepatitis C and elevated transaminases who did not respond to previous treatment with standard interferon monotherapy, were included from 16 centers in Belgium, the Netherlands and Luxembourg between 1992 and 1996. Patient poor-response characteristics were: genotype 1 (69%, HCV RNA above 2 × 106 copies/ml (55% and cirrhosis (38%. Patients were randomized to 6 months combination therapy with interferon alpha-2b (3 MU tiw and ribavirin (1000–1200 mg / day, 6 months ribavirin monotherapy (1000–1200 mg / day or 6 months ribavirin placebo. The study was double blinded for the ribavirin / placebo component. One patient did not fit the entry criteria, and 3 did not start. All 117 patients who received at least one dose of treatment were included in the intention to treat analysis. Results At the end of treatment, HCV RNA was undetectable in 35% of patients on combination therapy and in none of the patients treated with ribavirin monotherapy or placebo. The sustained virological response rate at 6 months after therapy was 15% for patients treated with interferon and ribavirin. During the 6 months treatment period 13% of patients on interferon ribavirin combination therapy, 13% of patients on ribavirin monotherapy and 11% of patients on placebo withdrew due to side effects or noncompliance. At 24 weeks of treatment the mean Hb level was 85% of the baseline value, which means a mean decrease from 9.1 mmol/l to 7.8 mmol/l. The Hb levels at the end of treatment were not significantly different from patients treated with ribavirin

  6. Combined Interferon-α and Inosiplex Treatment of Subacute Sclerosing Panencephalitis: A Case Report

    Directory of Open Access Journals (Sweden)

    Chy-Yuan Han

    2003-08-01

    Full Text Available Subacute sclerosing panencephalitis (SSPE is rare in Taiwan. On admission to hospital, a 15-year-old boy was diagnosed with SSPE based on the clinical picture, electroencephalogram, cerebrospinal fluid studies, and brain biopsy. The initial clinical picture was a decline in school performance and a change in personality, followed by progressive tic-like involuntary movements and mental impairment for 8 months, then a rapidly progressive course. After the patient was treated with oral inosiplex and intraventricular interferon-! (IFN-!, his condition stabilized and the neurologic disability index score improved slightly. There were no major side effects during treatment except for a transient initial elevation of body temperature that lasted for several days. Oral inosiplex and intraventricular IFN-! appear to be safe and effective. Early identification and aggressive treatment of SSPE is important.

  7. Regression of esophageal varices and splenomegaly in two patients with hepatitis-C-related liver cirrhosis after interferon and ribavirin combination therapy

    Directory of Open Access Journals (Sweden)

    Soon Jae Lee

    2016-09-01

    Full Text Available Some recent studies have found regression of liver cirrhosis after antiviral therapy in patients with hepatitis C virus (HCV-related liver cirrhosis, but there have been no reports of complete regression of esophageal varices after interferon/peg-interferon and ribavirin combination therapy. We describe two cases of complete regression of esophageal varices and splenomegaly after interferon-alpha and ribavirin combination therapy in patients with HCV-related liver cirrhosis. Esophageal varices and splenomegaly regressed after 3 and 8 years of sustained virologic responses in cases 1 and 2, respectively. To our knowledge, this is the first study demonstrating that complications of liver cirrhosis, such as esophageal varices and splenomegaly, can regress after antiviral therapy in patients with HCV-related liver cirrhosis.

  8. Interferon Alfa-2b Injection

    Science.gov (United States)

    Interferon alfa-2b injection is used to treat a number of conditions.Interferon alfa-2b injection is used alone or in combination ... Hodgkin's lymphoma (NHL; a slow-growing blood cancer). Interferon alfa-2b is in a class of medications called ...

  9. Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents

    Directory of Open Access Journals (Sweden)

    Kamal SM

    2014-06-01

    Full Text Available Sanaa M Kamal1,21Department of Medicine, Division of Hepatology, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt, 2Department of Medicine, Salman Bin Abdul Aziz College of Medicine, Kingdom of Saudi ArabiaAbstract: Hepatitis C virus (HCV has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world's population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL

  10. High-dose regimen of interleukin-2 and interferon-alpha in combination with lymphokine-activated killer cells in patients with metastatic renal cell cancer

    NARCIS (Netherlands)

    W.H.J. Kruit (Wim); S.H. Goey (Swan Hoo); C.H.J. Lamers (Cor); J.W. Gratama (Jan-Willem); B. Visser (Bauke); P.I.M. Schmitz (Paul); A.M.M. Eggermont (Alexander); R.L.H. Bolhuis (Reinder); G. Stoter (Gerrit)

    1997-01-01

    textabstractSeventy-two patients with metastatic renal cell cancer were treated with the combination of high-dose interleukin-2 (IL2), interferon-alpha (IFNa), and lymphokine-activated killer cells (LAK). Seventeen patients were entered in a feasibility part of the study (protocol 1) and 55 in an

  11. Inhibitory effects on HAV IRES-mediated translation and replication by a combination of amantadine and interferon-alpha

    Science.gov (United States)

    2010-01-01

    Hepatitis A virus (HAV) causes acute hepatitis and sometimes leads to fulminant hepatitis. Amantadine is a tricyclic symmetric amine that inhibits the replication of many DNA and RNA viruses. Amantadine was reported to suppress HAV replication, and the efficacy of amantadine was exhibited in its inhibition of the internal ribosomal entry site (IRES) activities of HAV. Interferon (IFN) also has an antiviral effect through the induction of IFN stimulated genes (ISG) and the degradation of viral RNA. To explore the mechanism of the suppression of HAV replication, we examined the effects of the combination of amantadine and IFN-alpha on HAV IRES-mediated translation, HAV replicon replication in human hepatoma cell lines, and HAV KRM003 genotype IIIB strain replication in African green monkey kidney cell GL37. IFN-alpha seems to have no additive effect on HAV IRES-mediated translation inhibition by amantadine. However, suppressions of HAV replicon and HAV replication were stronger with the combination than with amantadine alone. In conclusion, amantadine, in combination of IFN-alpha, might have a beneficial effect in some patients with acute hepatitis A. PMID:20815893

  12. Inhibitory effects on HAV IRES-mediated translation and replication by a combination of amantadine and interferon-alpha

    Directory of Open Access Journals (Sweden)

    Yang Lingli

    2010-09-01

    Full Text Available Abstract Hepatitis A virus (HAV causes acute hepatitis and sometimes leads to fulminant hepatitis. Amantadine is a tricyclic symmetric amine that inhibits the replication of many DNA and RNA viruses. Amantadine was reported to suppress HAV replication, and the efficacy of amantadine was exhibited in its inhibition of the internal ribosomal entry site (IRES activities of HAV. Interferon (IFN also has an antiviral effect through the induction of IFN stimulated genes (ISG and the degradation of viral RNA. To explore the mechanism of the suppression of HAV replication, we examined the effects of the combination of amantadine and IFN-alpha on HAV IRES-mediated translation, HAV replicon replication in human hepatoma cell lines, and HAV KRM003 genotype IIIB strain replication in African green monkey kidney cell GL37. IFN-alpha seems to have no additive effect on HAV IRES-mediated translation inhibition by amantadine. However, suppressions of HAV replicon and HAV replication were stronger with the combination than with amantadine alone. In conclusion, amantadine, in combination of IFN-alpha, might have a beneficial effect in some patients with acute hepatitis A.

  13. Interferon Alpha in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Timothy B. Niewold

    2010-01-01

    Full Text Available The pleiotropic cytokine interferon alpha is involved in multiple aspects of lupus etiology and pathogenesis. Interferon alpha is important under normal circumstances for antiviral responses and immune activation. However, heightened levels of serum interferon alpha and expression of interferon response genes are common in lupus patients. Lupus-associated autoantibodies can drive the production of interferon alpha and heightened levels of interferon interfere with immune regulation. Several genes in the pathways leading to interferon production or signaling are associated with risk for lupus. Clinical and cellular manifestations of excess interferon alpha in lupus combined with the genetic risk factors associated with interferon make this cytokine a rare bridge between genetic risk and phenotypic effects. Interferon alpha influences the clinical picture of lupus and may represent a therapeutic target. This paper provides an overview of the cellular, genetic, and clinical aspects of interferon alpha in lupus.

  14. The preliminary efficacy of interferon-alpha and ribavirin combination treatment of chronic hepatitis C in HIV-infected patients.

    Science.gov (United States)

    Zheng, Yu-huang; Zhang, Chun-ying; He, Yan; Zhou, Hua-ying; Zou, Wen; Ding, Pei-pei; Huang, Li; Li, Hui

    2005-07-20

    It is internationally accepted that in drug-naïve individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection, chronic hepatitis C should be treated first if the CD4 cell count does not require the initiation of anti-retroviral therapy. Present paper evaluated the clinical effect and side-effect of interferon-alpha (IFN-alpha) and ribavirin (RBV) combination therapy for Chinese patients with HCV-HIV co-infection, and compared with them for HIV infection alone. Ten patients with HCV-HIV and 17 patients with HCV received 5 million unit IFNalpha-2b every other day intramuscularly, and 300 mg RBV triple daily by oral. Dynamic observations were made for HCV RNA and HIV RNA loads, CD4+ and CD8+ T lymphocyte counts, liver function and blood cell measurement, and the medicine side-effects. After 12-week and 24-week treatments of IFN-alpha and RBV combination therapy, mean HCV RNA levels reduced 1.14 logs and 1.56 logs from the baseline at week 0 in HCV-HIV co-infection, and reduced 1.48 logs and 1.75 logs in HCV infection, respectively. The HIV RNA levels decreased 1.22 logs and 1.32 logs from the base line; however, there were no obvious different changes at T lymphocyte counts of HCV-HIV and HCV patients through 24-week treatments. Whole 27 patients showed satisfactory biochemical response to therapy. There were some mild or mediate influence-like symptoms, intestinal uncomfortable and depressed blood cell counts in early stage of the treatments. No neuropsychiatric and auto-immune disorders were found. IFN-alpha and RBV combination therapy had similar anti-HCV effects during 24-week treatment for HCV-HIV and HCV infected Chinese patients, and some anti-HIV effect. There were no obvious different biochemical responses and side-effects between two groups above.

  15. [Interferon-alpha and ribavirin combination therapy for co-infection of hepatitis C virus and human immunodeficiency virus].

    Science.gov (United States)

    Zheng, Yu-huang; He, Yan; Yang, Xu; Gong, Guo-zhong; Zhou, Hua-ying; Zhang, Chun-ying; Zhou, Wen; Huang, Li; Ding, Pei-pei; Li, Hui

    2005-10-01

    To evaluate the clinical effect and side-effect of interferon-alpha (IFN-a) and ribavirin (RBV) combination therapy for Chinese patients with co-infection of hepatitis C virus (HCV) and human immunodeficiency virus (HIV), and to compare them with only HIV infection patients. 10 patients with HCV-HIV and 17 patients with only HCV infection received 5 million units of IFNalpha-2b every other day intramuscularly, and 300 mg RBV orally three times a day. Dynamic observations were done for HCV RNA and HIV RNA loads, CD4+ and CD8+ T lymphocyte counts, liver function and blood cell measures, and the side-effects of the medicines. After 12 weeks and 24 weeks of IFNalpha and RBV combination therapy, mean HCV RNA levels reduced 1.14 log (t = 3.843, P HIV co-infection group, and reduced 1.48 log (t = 6.438, P less than 0.01) and 2.33 log (t = 7.343, P HIV RNA levels decreased 1.22 log (t = 3.662, P HIV and HCV patients at week 0, week 12 and week 24. All 27 patients showed satisfactory biochemical response to therapy. There were some mild or moderate influenza-like symptoms, intestinal discomfort and decreased blood cell counts in the early stages of the treatments. No neuropsychic and auto-immune disorders were found. IFNalpha-2b and RBV combination therapy showed similar anti-HCV effects during the 24 week treatment for HCV-HIV and HCV infected patients, and some anti-HIV effect was also observed. No obvious different biochemical responses and side-effects were found between the above two groups.

  16. Sustained response to combination therapy in a patient with chronic hepatitis C and thrombocytopenia secondary to alpha-interferon.

    Science.gov (United States)

    Jiménez-Sáenz, M; Rojas, M; Piñar, A; Salas, E; Rebollo, J; Carmona, I; Herrerías-Esteban, J M; Herrerías-Gutiérrez, J M

    2000-05-01

    Recent data suggest that hepatitis C viral (HCV) infection may induce a significant autoimmune reaction to platelets, but the mechanism is unknown. Many patients with chronic hepatitis C, in fact, have high levels of platelet-associated immunoglobulin G (PAIgG) and HCV-RNA is present in the platelets of 100% of those patients with thrombocytopenia and high PAIgG levels. Hepatitis C virus infection has been associated with the development of thrombocytopenic purpura, sometimes triggered during interferon (IFN) therapy. In such cases, the treatment of the underlying disease is a difficult problem to solve. We report the case of a patient with chronic hepatitis C, who developed life-threatening thrombocytopenic purpura after a prolonged course of IFN-alpha2b over a 4-year period. Treatment with anti-immunoglobulin gammaglobulin (Polyglobin; Química Farmaceutica Bayer, Barcelona, Spain) had a transient effect on the platelet count, but prolonged therapy with prednisone was necessary for definitive relief of the haematological complication. Two years later, the patient was treated with combined therapy, including ribavirin (1200 mg/day) and IFN-alpha2b (5 mU, t.i.w.) for 12 months. This therapy induced a sustained response, both biochemical and virological, without haematological complications. This observation suggests that ribavirin may be of benefit in the treatment of immune-mediated thrombocytopenia in patients with chronic hepatitis C, preventing the harmful effect of IFN-alpha but also allowing both drugs to be combined so as to increase the probability of sustained remission of the liver disease.

  17. Genetic Variants in the Apoptosis Gene BCL2L1 Improve Response to Interferon-Based Treatment of Hepatitis C Virus Genotype 3 Infection

    DEFF Research Database (Denmark)

    Clausen, Louise Nygaard; Weis, Nina; Ladelund, Steen

    2015-01-01

    Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR) to pegylated interferon...

  18. Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa-2b in HBeAg-positive patients.

    Science.gov (United States)

    Ma, Hui; Yang, Rui-Feng; Wei, Lai

    2010-09-01

    To evaluate the usefulness of quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) for predicting HBeAg seroconversion in chronic hepatitis B patients treated with conventional interferon (IFN) alfa-2b or PegIFN alfa-2b. Fifty-eight patients were enrolled; 29 for the training group and 29 for the validating group. Quantification of HBsAg and HBeAg was carried out at baseline, week 12, week 24, and then again at 12 and 24 weeks follow up, respectively, for two groups. Sixteen patients in the training group were followed up for 5 years. The cutoff of 1500 IU/mL in serum HBsAg at week 12 had a positive predictive value (PPV) of 33% and a negative predictive value (NPV) of 91%, and 2890 IU/mL at week 24 had a PPV of 43% and an NPV of 95% for HBeAg seroconversion at week 48. The cutoff of 17.55 Paul Ehrlich Institute units/mL (PEI-U/mL) in serum HBeAg at week 12 had a PPV of 38% and an NPV of 95%, and 8.52 PEI-U/mL at week 24 had a PPV of 44% and a NPV of 100% for HBeAg seroconversion at week 48. Moreover the HBsAg and HBeAg levels of PegIFN alfa-2b group were lower than those of the conventional IFN alfa-2b group. During follow up, patients with HBeAg seroconversion remained HBeAg negative and none of them progressed to cirrhosis, but among the patients with non-HBeAg seroconversion, two progressed to cirrhosis. Two additional patients with negative HBeAg were observed. On-treatment serum HBsAg and HBeAg had high predictive values to predict sustained HBeAg seroconversion by PegIFN alfa-2b. Patients who cleared HBeAg had better survival free of hepatic complications during long-term follow-up study.

  19. The presence of non-organ-specific autoantibodies is associated with a negative response to combination therapy with interferon and ribavirin for chronic hepatitis C

    Directory of Open Access Journals (Sweden)

    Matern Siegfried

    2004-02-01

    Full Text Available Abstract Background Non-organ-specific autoantibodies are found in a considerable number of anti-HCV positive patients. Previous studies investigated the clinical relevance of these antibodies in patients treated with interferon monotherapy, but not combination therapies. Methods Anti-nuclear, anti-smooth muscle, anti-mitochondrial, anti-neutrophil-cytoplasmatic and anti-liver/kidney microsomal antibodies were determined in 78 consecutive anti-HCV positive patients by indirect immunofluorescence. The presence of these antibodies was related to demographic variables and to the outcome of antiviral combination therapy with interferon-α and ribavirin in 65 patients. Results In our study, positivity for autoantibodies was associated with higher alanine aminotransferase levels and higher mean values for HCV-RNA (p Conclusions The absence of non-organ-specific autoantibodies might indicate a significantly higher chance for viral clearance in response to combination therapy for chronic hepatitis C infection. Therefore, despite of an overall higher treatment response, the addition of the immunomodulatory drug ribavirin could accentuate immunological differences that affect treatment outcome and might have been less obvious in earlier studies analysing interferon monotherapy.

  20. Application of interferon-free treatment regimen in treatment of chronic hepatitis C in China

    Directory of Open Access Journals (Sweden)

    NIE Hongming

    2015-05-01

    Full Text Available With the release of new oral direct-acting antiviral agents (DAAs, the interferon (IFN-free treatment for hepatitis C comes out, and the clinical efficacy in phase II and III clinical trials is close to cure, which seems to announce the end of the era of hepatitis C. In China, an area of high incidence of hepatitis C, pegylated interferon (PEG-IFN combined with ribavirin (RBV (the standard of care has been the dominant treatment regimen for hepatitis C, and it is uncertain whether it will be completely replaced by interferon-free treatment regimen. In this background, this paper analyzes the possible problems of DAAs and the main treatment direction of hepatitis C in China at the present stage based on the history and present situation of treatment of hepatitis C, especially the advantage of PEG-IFN combined with RBV in the treatment of hepatitis C in China, and the research advances in DAAs at home and abroad. It is found that PEG-IFN combined with RBV will remain the dominant treatment regimen for chronic hepatitis C at the present stage.

  1. Analysis of the PKR-eIF2alpha phosphorylation homology domain (PePHD) of hepatitis C virus genotype 1 in HIV-coinfected patients by ultra-deep pyrosequencing and its relationship to responses to pegylated interferon-ribavirin treatment.

    Science.gov (United States)

    Bolcic, F; Sede, M; Moretti, F; Westergaard, G; Vazquez, M; Laufer, N; Quarleri, J

    2012-04-01

    Chronic coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is among the greatest challenges facing public health worldwide. In this population, the response to hepatitis C therapy by treatment with pegylated interferon plus ribavirin (PEG-IFN+RBV) is lower than in HCV-monoinfected patients, particularly in those infected by HCV genotype 1. A PKR/eIF-2α phosphorylation homology domain (PePHD) within the E2 protein has been found to interact with PKR and inhibit PKR in vitro, suggesting a possible mechanism for HCV to evade the antiviral effects of IFN. The aim of this work was to analyze the amino acid conservation in the HCV-E2-PePHD and quasispecies diversity among HCV-HIV-coinfected patients exhibiting sustained virological response, non-response, or partial response with viral relapse to PEG-IFN+RBV by ultra-deep pyrosequencing. For this purpose, HCV-E2-PePHD PCR products were generated and sequenced directly for four patients with a sustained response, seven patients with no virological response, and four patients with viral relapse before and after treatment with PEG-IFN+RBV. HCV-E2-PePHD amino acid sequences were obtained for isolates from serum collected before and during treatment (24 h, 4 weeks, and 12 weeks). Quasispecies analysis of the HCV-E2-PePHD and flanking genomic regions was performed using 454/Roche pyrosequencing, analyzing 39,364 sequence reads in total. The HCV-E2-PePHD sequence at the amino acid and nucleotide level was highly conserved among HCV genotype 1 strains, irrespective of the PEG-IFN+RBV response. This high degree of amino acid conservation and sporadic mutations in the HCV-E2-PePHD domain do not appear to be associated with treatment outcome. The HCV-E2-PePHD sequence before or during treatment cannot be used to predict reliably the outcome of treatment in patients coinfected with HCV genotype 1 and HIV.

  2. T-cell homeostasis in chronic HCV-infected patients treated with interferon and ribavirin or an interferon-free regimen

    DEFF Research Database (Denmark)

    Hartling, Hans Jakob; Birch, Carsten; Gaardbo, Julie C

    2015-01-01

    -cell homeostasis before, during, and after HCV treatment with or without interferon-α in patients with chronic HCV infection. A total of 20 patients with chronic HCV infection were treated with pegylated interferon-α and ribavirin, and six patients were treated with an interferon-free regimen. All patients were...... compared to prior treatment values. Finally, a proportion of CD8+ effector memory was lower while proportion of apoptotic T cells was higher after sustained virologic response compared to prior treatment. Despite lymphopenia during interferon, alterations in T-cell homeostasis during treatment were...

  3. Pegylated niosomal nanoparticles loaded with vincristine ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of pegylated niosomal vincristine (VCR) on enhanced performance, drug resistance and prolonged blood circulation time. Methods: Pegylated niosomal VCR was synthesized by reverse phase evaporation. The mean diameter, size distribution, and zeta potential of pegylated niosomal ...

  4. Pegylated liposomal doxorubicin in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Robert Strother

    2009-08-01

    Full Text Available Robert Strother1,2, Daniela Matei1–51Department of Medicine, 2Indiana University Melvin and Bren Simon Cancer Center, 3Department of Obstetrics and Gynecology, 4Department of Biochemistry and Molecular Biology, 5VA Roudebush Hospital Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202Abstract: The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Liposomal doxorubicin is devoid of the cardiac toxicity associated with doxorubicin, but is associated with predictable muco-cutaneous toxicity. The liposomal formulation leads to improved delivery to the target tumor tissue, allowing enhanced uptake by cancer cells. These properties translate into clinical utility in recurrent ovarian cancer as demonstrated by phase II and III trials, this proven clinical efficacy leading to FDA approval in second-line therapy for ovarian cancer. New combinations with cytotoxics, in particular with carboplatin, have demonstrated an acceptable toxicity profile and clinical utility in platinum-sensitive ovarian cancer. A favorable toxicity profile renders liposomal doxorubicin an ideal partner for combination regimens with other cytotoxics, and more recently with biological agents. Such combinations are the subject of ongoing clinical trials.Keywords: ovarian cancer, doxorubicin, liposomes, pegylated liposomal doxorubicin

  5. Osteopontin as a marker for response to pegylated interferon Alpha ...

    African Journals Online (AJOL)

    Cite as: Hussein YM, Alhazmi A, Alzahrani S, El-Askary A, Alghamdy A, Bayomy E, Selim A, Alghamdy M. Osteopontin as a marker for response to ..... cytokine network. The Th1 immune response is involved in the development of inflammation in chronic hepatitis. C, and the hepatocytes infected with HCV are eradicated.

  6. Preparation and PEGylation of recombinant human interferon lambda3

    African Journals Online (AJOL)

    ajl4

    2012-09-18

    Sep 18, 2012 ... functions in inherent immunological and adaptive immunological system. According to the differences in amino acid sequences and receptors, IFNs are classified ... sclerosis, chronic myeloid leukemia, myeloma, asthma exacerbations, chronic granulomatous disease and osteopetrosism (Peter et al., 2012).

  7. Pegylated liposomal doxorubicin in ovarian cancer.

    Science.gov (United States)

    Strother, Robert; Matei, Daniela

    2009-06-01

    The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Liposomal doxorubicin is devoid of the cardiac toxicity associated with doxorubicin, but is associated with predictable muco-cutaneous toxicity. The liposomal formulation leads to improved delivery to the target tumor tissue, allowing enhanced uptake by cancer cells. These properties translate into clinical utility in recurrent ovarian cancer as demonstrated by phase II and III trials, this proven clinical efficacy leading to FDA approval in second-line therapy for ovarian cancer. New combinations with cytotoxics, in particular with carboplatin, have demonstrated an acceptable toxicity profile and clinical utility in platinum-sensitive ovarian cancer. A favorable toxicity profile renders liposomal doxorubicin an ideal partner for combination regimens with other cytotoxics, and more recently with biological agents. Such combinations are the subject of ongoing clinical trials.

  8. Benefits and pitfalls of Peg-Interferon-α2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis, a French Intergroup of Myeloproliferative neoplasms (FIM) study.

    Science.gov (United States)

    Ianotto, Jean-Christophe; Chauveau, Aurélie; Boyer-Perrard, Françoise; Gyan, Emmanuel; Laribi, Kamel; Cony-Makhoul, Pascale; Demory, Jean-Loup; de Renzis, Benoit; Dosquet, Christine; Rey, Jerome; Roy, Lydia; Dupriez, Brigitte; Knoops, Laurent; Legros, Laurence; Malou, Mohamed; Hutin, Pascal; Ranta, Dana; Benbrahim, Omar; Ugo, Valérie; Lippert, Eric; Kiladjian, Jean-Jacques

    2017-12-07

    We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of sixty-two patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years-old, the median follow-up since pegylated interferon initiation was 58 months. At time of analysis, 30 (48.4%) patients were alive including 16 still treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and DIPSS scores treated with pegylated interferon was increased in comparison to historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 vs. 30 months after two years of treatment, p<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and 2 patients even achieved complete molecular response. Next generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survivals. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for intermediate or high-risk Lille and DIPSS score patients. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.(Clinicaltrials.gov #NCT02910258 and #NCT02897297). Copyright © 2017, Ferrata Storti Foundation.

  9. The efficacy and safety of pegylated liposomal doxorubicin monotherapy and combination therapy with carboplatin in Korean patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer: a single-institution experience.

    Science.gov (United States)

    Lee, Young-Jae; Kim, Yong-Man; Lee, Shin-Wha; Park, Jeong-Yeol; Kim, Dae-Yeon; Suh, Dae-Shik; Kim, Jong-Hyeok; Kim, Young-Tak; Nam, Joo-Hyun

    2017-09-01

    This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) with or without carboplatin in Korean patients with recurrent ovarian cancer (ROC), fallopian tube, or primary peritoneal cancer. This retrospective study included 52 patients with ROC, fallopian tube, or primary peritoneal cancer who received PLD (50 mg/m(2)) between 1(st) December 2014 and 31(th) July 2016. The mean number of chemotherapy cycles was 3.8 (range, 2 to 9) in the PLD monotherapy group and 7 (range, 2 to 13) in the PLD combined with carboplatin (PLD-C) group. In overall response rates and clinical beneficial rates, PLD monotherapy group shows 5.0% and 17.5%, and PLD-C group shows 33.3% and 75.0%. The mean progression-free survival (PFS) was 5 and 13 months in the PLD monotherapy and PLD-C groups, respectively. At 6 months after treatment initiation, absence of disease progression was confirmed in 6 (15%) and 10 (83.3%) patients in the PLD monotherapy and PLD-C groups. Hematological adverse events (e.g., neutropenia and thrombocytopenia) were more common in the PLD-C group (P<0.001, P=0.004). The incidence of anemia and non-hematological adverse events, including mucositis, hand-foot syndrome, and allergic reactions, was similar in both groups. This study demonstrated the efficacy and safety of PLD monotherapy and PLD-C combination in Korean patients with ROC. This study would be helpful to consider the degree of worry about side effects and treatment expectations after treatment. Further retrospective studies with larger samples are required to confirm the efficacy of PLD monotherapy in Asian patients with platinum-resistant ROC.

  10. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer.

    Science.gov (United States)

    Rose, Peter G

    2005-03-01

    The need for effective, well-tolerated, and convenient therapies for patients with advanced ovarian cancer has led researchers to continually refine chemotherapeutic regimens to balance efficacy with safety and tolerability in order to maintain or improve patient quality of life. In this article, we review current strategies for the optimal dosing of pegylated liposomal doxorubicin (DOXIL; Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., Bridgewater, NJ, http://www.tibotec.com; Caelyx, Schering-Plough Corporation, Kenilworth, NJ, http://www.sch-plough.com) in relapsed ovarian cancer. Pegylated liposomal doxorubicin has demonstrated efficacy in the treatment of recurrent/resistant ovarian cancer in several clinical trials utilizing a dose of 50 mg/m2 every 4 weeks. The most common adverse events associated with pegylated liposomal doxorubicin treatment in these studies-hand-foot syndrome (HFS, also known as palmar-plantar erythrodysesthesia) and stomatitis-are schedule and dose dependent, respectively, and do not typically lead to discontinuation of therapy. Several phase II and retrospective studies support the use of pegylated liposomal doxorubicin 40 mg/m2 every 4 weeks (dose intensity of 10 mg/m2 weekly) to optimize clinical efficacy and minimize the occurrence of schedule- and dose-related adverse events in patients with recurrent/relapsed ovarian cancer. Further reductions in dose intensity are necessary for use in combined chemotherapy regimens. Antitumor activity was maintained, with reduced incidences of HFS and stomatitis. Given the chronic course of ovarian cancer, the improved tolerability profile of pegylated liposomal doxorubicin 40 mg/m2 combined with a convenient once-monthly dosing schedule may translate into an improved quality of life for patients with ovarian cancer.

  11. The use of growth factors to manage the hematologic side effects of PEG-interferon alfa and ribavirin.

    Science.gov (United States)

    Collantes, Rochelle S; Younossi, Zobair M

    2005-01-01

    Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

  12. Interferon-alpha treatment rapidly clears Hepatitis e virus infection in humanized mice

    NARCIS (Netherlands)

    M.D.B. van de Garde (Martijn D.B.); S.D. Pas (Suzan); G.W. van Oord (Gertine); L. Gama (Lucio); Choi, Y. (Youkyung); R.A. de Man (Robert); P.A. Boonstra (André); T. Vanwolleghem (Thomas)

    2017-01-01

    textabstractAntiviral treatment options for chronic Hepatitis E Virus (HEV) infections are limited and immunological determinants of viral persistence remain largely unexplored. We studied the antiviral potency of pegylated interferon-α (pegIFNα) against HEV infections in humanized mice and modelled

  13. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission...

  14. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission...... of therapy. Lower doses of Peg-IFN-a2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent....

  15. Parkinsonism in Patients With Chronic Hepatitis C Treated With Interferons: Case Reports and Review of the Literature.

    Science.gov (United States)

    Wangensteen, Kirk J; Krawitt, Edward L; Hamill, Robert W; Boyd, James T

    2016-01-01

    Interferons are a set of cytokines that activate antiviral responses by the body's immune cells and have been a mainstay of treatment of hepatitis C. Well-known neuropsychiatric effects of interferons include depression, irritability, and impaired concentration. A condition reported rarely in association with this treatment is parkinsonism. We report 2 patients who developed parkinsonism in conjunction with treatment of hepatitis C with alpha interferons. The first is a 51-year-old man who developed intermittent rest and postural tremor during treatment with pegylated interferon alpha ribavirin, and amantadine, with resolution of the symptoms after completing a 36-week course. Similar tremor recurred 3 years later with progressive parkinsonism, compatible with Parkinson disease (PD). The second patient is a 71-year-old man who developed postural tremor 8 weeks into a regimen of consensus interferon. Tremor resolved at completion of 48 weeks of interferon. Pegylated interferon alpha and ribavirin were started 2 years later because of lack of sustained virologic response. At 24 weeks of treatment, postural tremor returned along with features and a progressive course compatible with PD. Thus, both patients presented here developed (rest and/or postural) tremor during interferon therapy followed by delayed onset of parkinsonism. We identified 10 other cases in the literature of parkinsonism/PD associated with interferon administration. This report reviews the clinical presentation and potential pathophysiological mechanisms and recommends that physicians who prescribe interferon be vigilant for symptoms of PD in their patients.

  16. Surface polyPEGylation of Eu{sup 3+} doped luminescent hydroxyapatite nanorods through the combination of ligand exchange and metal free surface initiated atom transfer radical polymerization

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Guangjian; Liu, Meiying [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Heng, Chunning [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R& D Center of Biomaterials and Fermentation Engineering, School of Chemical and Engineering, Northwest University, Xi’an 710069 (China); Huang, Qiang; Mao, Liucheng; Huang, Hongye [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Hui, Junfeng [Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R& D Center of Biomaterials and Fermentation Engineering, School of Chemical and Engineering, Northwest University, Xi’an 710069 (China); Deng, Fengjie, E-mail: fengjiedeng@aliyun.com [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Zhang, Xiaoyong, E-mail: xiaoyongzhang1980@gmail.com [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Wei, Yen, E-mail: weiyen@tsinghua.edu.cn [Department of Chemistry and The Tsinghua Center for Frontier Polymer Research, Tsinghua University, Beijing 100084 (China)

    2017-03-31

    Highlights: • Surface modification of HAp nanorods through the combination of ligand exchange reaction and metal free SI-ATRP. • HAp-polyPEGMA displayed high water dispersibility, good biocompatibility and biological imaging capability. • Metal free ATRP can overcome the toxic and fluorescence quenching effects of metal catalysts of conventional ATRP. - Abstract: The Eu{sup 3+} doped luminescent hydroxyapatite (HAp) nanorods with uniform size and morphology can be synthesized by hydrothermal route. However, these HAp nanorods are coated by hydrophobic oleylamine, which makes them difficult to be dispersed in aqueous solution and impede their biomedical applications. In this work, Eu{sup 3+} doped luminescent polymers functionalized HAp nanorods were prepared through the combination of ligand exchange reaction and metal free surface initiated atom transfer radical polymerization (ATRP) method. In this procedure, the amino group functionalized HAp nanorods were first prepared by ligand exchange reaction using adenosine monophosphate (AMP) as ligand. Then the Br-containing initiators (HAp-Br) were introduced onto the surface of HAp-AMP nanorods through the amidation reaction. Finally, polymers functionalized HAp nanorods were prepared by metal free ATRP method using poly(ethylene glycol) methacrylate (PEGMA) as monomer and 10-phenylphenothiazine (PTH) as organic photocatalyst. The properties of these obtained HAp nanocomposites (HAP-polyPEGMA nanorods) were characterized by means of transmission electron microscopy, Fourier transformed infrared spectroscopy, X-ray photoelectron spectroscopy and thermogravimetric analysis in detail. The cell imaging of these HAP-polyPEGMA nanorods was examined using laser scanning confocal microscope to evaluate their biomedical applications. We demonstrated for the first time that hydrophobic luminescent HAp nanorods can be functionalized with polyPEGMA through the combination of ligand exchange reaction and metal free surface

  17. Surface polyPEGylation of Eu3+ doped luminescent hydroxyapatite nanorods through the combination of ligand exchange and metal free surface initiated atom transfer radical polymerization

    Science.gov (United States)

    Zeng, Guangjian; Liu, Meiying; Heng, Chunning; Huang, Qiang; Mao, Liucheng; Huang, Hongye; Hui, Junfeng; Deng, Fengjie; Zhang, Xiaoyong; Wei, Yen

    2017-03-01

    The Eu3+ doped luminescent hydroxyapatite (HAp) nanorods with uniform size and morphology can be synthesized by hydrothermal route. However, these HAp nanorods are coated by hydrophobic oleylamine, which makes them difficult to be dispersed in aqueous solution and impede their biomedical applications. In this work, Eu3+ doped luminescent polymers functionalized HAp nanorods were prepared through the combination of ligand exchange reaction and metal free surface initiated atom transfer radical polymerization (ATRP) method. In this procedure, the amino group functionalized HAp nanorods were first prepared by ligand exchange reaction using adenosine monophosphate (AMP) as ligand. Then the Br-containing initiators (HAp-Br) were introduced onto the surface of HAp-AMP nanorods through the amidation reaction. Finally, polymers functionalized HAp nanorods were prepared by metal free ATRP method using poly(ethylene glycol) methacrylate (PEGMA) as monomer and 10-phenylphenothiazine (PTH) as organic photocatalyst. The properties of these obtained HAp nanocomposites (HAP-polyPEGMA nanorods) were characterized by means of transmission electron microscopy, Fourier transformed infrared spectroscopy, X-ray photoelectron spectroscopy and thermogravimetric analysis in detail. The cell imaging of these HAP-polyPEGMA nanorods was examined using laser scanning confocal microscope to evaluate their biomedical applications. We demonstrated for the first time that hydrophobic luminescent HAp nanorods can be functionalized with polyPEGMA through the combination of ligand exchange reaction and metal free surface initiated ATRP. As compared with the traditional ATRP, the metal free ATRP can overcome the toxic and fluorescence quenching effects of metal catalysts such as copper ions. More importantly, the strategy described in this work should also be utilized for fabrications of many other luminescent polymer nanocomposites due to its good monomer adoptability.

  18. The combination of arsenic, interferon-alpha, and zidovudine restores an “immunocompetent-like” cytokine expression profile in patients with adult T-cell leukemia lymphoma

    Science.gov (United States)

    2013-01-01

    Background HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN. Results Here we assessed Th1/Th2/Treg cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a Treg/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4+CD25+ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4+CD25+ cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30. Conclusions The observed shift from a Treg/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections. PMID:23962110

  19. Improving Performance and Operational Stability of Porcine Interferon-α Production by Pichia pastoris with Combinational Induction Strategy of Low Temperature and Methanol/Sorbitol Co-feeding.

    Science.gov (United States)

    Gao, Min-Jie; Zhan, Xiao-Bei; Gao, Peng; Zhang, Xu; Dong, Shi-Juan; Li, Zhen; Shi, Zhong-Ping; Lin, Chi-Chung

    2015-05-01

    Various induction strategies were investigated for effective porcine interferon-α (pIFN-α) production by Pichia pastoris in a 10 L fermenter. We found that pIFN-α concentration could be significantly improved with the strategies of low-temperature induction or methanol/sorbitol co-feeding. On this basis, a combinational strategy of induction at lower temperature (20 °C) with methanol/sorbitol co-feeding has been proposed for improvement of pIFN-α production. The results reveal that maximal pIFN-α concentration and antiviral activity reach the highest level of 2.7 g/L and 1.8 × 10(7) IU/mg with the proposed induction strategy, about 1.3-2.1 folds higher than those obtained with other sub-optimal induction strategies. Metabolic analysis and online multi-variable measurement results indicate that energy metabolic enrichment is responsible for the performance enhancement of pIFN-α production, as a large amount of ATP could be simultaneously produced from both formaldehyde oxidation pathway in methanol metabolism and tricarboxylic acid (TCA) cycle in sorbitol metabolism. In addition, the proposed combinational induction strategy enables P. pastoris to be resistant to high methanol concentration (42 g/L), which conceivably occur associating with the error-prone methanol over-feeding. As a result, the proposed combinational induction strategy simultaneously increased the targeted protein concentration and operational stability leading to significant improvement of pIFN-α production.

  20. What role do combinations of interferon and targeted agents play in the first-line therapy of metastatic renal cell carcinoma?

    Science.gov (United States)

    Bukowski, Ronald M

    2008-12-01

    Interferons (IFNs) are a class of cytokines with pleotropic actions that regulate a variety of cellular activities. Clinical trials with recombinant IFNs (IFN-alpha2a and IFN-alpha2b) have demonstrated clinical activity in patients with advanced renal cell carcinoma (RCC). Their efficacy is characterized by a low overall tumor regression rate of < 15%, progression-free survival of 4-5 months, and overall median survival of 10-18 months. This cytokine became the standard of care for patients with metastatic RCC and was then used as the comparator arm in a series of phase II and III clinical trials that have defined a new treatment paradigm for patients with advanced RCC. This paradigm uses the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, and the vascular endothelial growth factor monoclonal antibody bevacizumab. These 3 categories of agents were then investigated in combination with IFN-alpha in a series of preclinical and clinical studies. The collective data from these reports suggest the combination of IFN-alpha and bevacizumab is active and has a role in RCC therapy, whereas combinations with the TKIs or mTOR inhibitors have limited efficacy and/or excessive toxicity. The clinical and preclinical studies leading to these conclusions are reviewed herein.

  1. Oral Combination Vaccine, Comprising Bifidobacterium Displaying Hepatitis C Virus Nonstructural Protein 3 and Interferon-α, Induces Strong Cellular Immunity Specific to Nonstructural Protein 3 in Mice.

    Science.gov (United States)

    Kitagawa, Koichi; Omoto, Chika; Oda, Tsugumi; Araki, Ayame; Saito, Hiroki; Shigemura, Katsumi; Katayama, Takane; Hotta, Hak; Shirakawa, Toshiro

    2017-04-01

    We previously generated an oral hepatitis C virus (HCV) vaccine using Bifidobacterium displaying the HCV nonstructural protein 3 (NS3) polypeptide. NS3-specific cellular immunity is important for viral clearance and recovery from HCV infection. In this study, we enhanced the cellular immune responses induced by our oral HCV vaccine, Bifidobacterium longum 2165 (B. longum 2165), by combining interferon-α (IFN-α) as an adjuvant with the vaccine in a mouse experimental model. IFN-α is a widely used cytokine meeting the standard of care (SOC) for HCV infection and plays various immunoregulatory roles. We treated C57BL/6N mice with B. longum 2165 every other day and/or IFN-α twice a week for a month and then analyzed the immune responses using spleen cells. We determined the induction of NS3-specific cellular immunity by cytokine quantification, intracellular cytokine staining, and a cytotoxic T lymphocyte (CTL) assay targeting EL4 tumor cells expressing NS3/4A protein (EL4-NS3/4A). We also treated mice bearing EL4-NS3/4A tumor with the combination therapy in vivo. The results confirmed that the combination therapy of B. longum 2165 and IFN-α induced significantly higher IFN-γ secretion, higher population of CD4(+)T and CD8(+)T cells secreting IFN-γ, and higher CTL activity against EL4-NS3/4A cells compared with the control groups of phosphate-buffered saline, B. longum 2165 alone, and IFN-α alone (p < 0.05). We also confirmed that the combination therapy strongly enhanced tumor growth inhibitory effects in vivo with no serious adverse effects (p < 0.05). These results suggest that the combination of B. longum 2165 and IFN-α could induce a strong cellular immunity specific to NS3 protein as a combination therapy augmenting the current SOC immunotherapy against chronic HCV infection.

  2. Comparison of Native Escherichia Coli L-Asparaginase Versus Pegylated Asparaginase, in Combination with Ifosfamide, Methotrexate, Etoposide, and Prednisolone (IMEP), in Extranodal NK/T Cell Lymphoma, Nasal Type (NTCL).

    Science.gov (United States)

    Kim, Hyun Jee; Ock, Chan-Young; Kim, Tae Min; Lee, Sung Hee; Lee, Ju-Yeun; Jung, Sun Hoi; Cho, Yoon Sook; Kim, Miso; Keam, Bhumsuk; Kim, Dong-Wan; Kim, Il Han; Heo, Dae Seog

    2017-07-03

    The aim of this study was to compare asparaginase-related toxicities in two asparaginase preparations, namely native Escherichia coli (E. coli) L-asparaginase (L-ASP) and pegylated asparaginase (PEG-ASP) in combination with ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) in NK/T-cell lymphoma (NTCL). A total of 41 NTCL patients who received IMEP plus native E. coli L-ASP or PEG-ASP at Seoul National University Hospital were included in this study between January 2013 and March 2016. IMEP/ASP treatment consisted of ifosfamide, methotrexate, etoposide, plus native E. coli L-ASP (6000 IU/m2 on days 1, 3, 5, 7, 9, and 11) or PEG-ASP (2500 IU/m2 on day 1) every 3 weeks. ASP-related toxicities, toxicity patterns, length of hospital stay and clinical outcomes were compared between the different treatment groups. The frequency of ASP-related toxicities was similar between the IMEP plus native E. coli L-ASP group and the PEG-ASP group apart from hypofibrinogenemia (native E. coli L-ASP vs. PEG-ASP group, 86.4% vs. 36.8%, p=0.001). Although post-treatment transaminase and albumin levels were significantly high and low, respectively, hepatotoxicity gradients before and after treatment did not differ significantly between the groups. Since PEG-ASP was given at an outpatient clinic in some patients, length of hospital stay was significantly shorter in the IMEP plus PEG-ASP group (median 4.0 vs. 6.0 days, p=0.002). A favorable tendency of clinical outcomes was observed in NTCL patients treated with IMEP plus PEG-ASP (complete remission rate, 73.7% vs. 45.5%, p=0.067). IMEP plus PEG-ASP showed similar ASP-related toxicities, shorter length of hospital stay, and a trend towards improved clinical outcomes compared with IMEP plus native E. coli L-ASP in NTCL.

  3. Preparation of pegylated lumbrokinase and an evaluation of its thrombolytic activity both in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Mingji Jin

    2013-04-01

    Full Text Available Lumbrokinase (LK is a group of serine proteases with strong fibrinolytic and thrombolytic activities. In clinical practice, LK can only be administered orally because of its antigenicity, immunogenicity and potential to produce anaphylactic reactions after injection. However, many useful drugs such as interferon, insulin, erythropoietin and interleukin have been modified with polyethylene glycol (PEG to prepare injectable formulations. In this study, LK was modified with methoxy PEG succinimidyl carbonate (mPEG-SC with molecular weights of 5000, 10,000 and 20,000 and the pegylated products were isolated and purified using the Akta protein purification system. The extent of pegylation was determined by HPLC. Fibrinolytic activities of pegylated and unmodified LK were measured both in vitro against urokinase on fibrin plates and in vivo using a mouse carageenan black tail model. Optimal pegylation was obtained using mPEG-SC5000 in a buffer pH 8.0 with a reaction time of 5 h, reaction temperature of 0 °C and LK:mPEG-SC molar ratio of 1:25. The results show that mPEG modified LK has strong fibrinolytic and thrombolytic activities both in vitro and in vivo. It is suggested that the pegylated LK is a promising injectable thrombolytic agent for the treatment of thrombotic diseases in clinical practice.

  4. Combined interferon a2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial - Reply

    Directory of Open Access Journals (Sweden)

    M. Galeazzi

    2011-09-01

    Full Text Available Solo il 15-20% dei pazienti con epatite C cronica presenta una risposta virologica protratta dopo terapia con solo interferon (IFN. Lo scopo di questo studio è di confrontare l’efficacia e la sicurezza dell’IFN in combinazione con ciclosporina A (CsA orale con l’IFN in monoterapia nel trattamento dell’epatite C cronica. 120 pazienti affetti da epatite C cronica hanno ricevuto la dose standard Giapponese di IFN a2b da solo per 24 settimane o questa dose di IFN a2b in combinazione con CsA, alla dose di 200 mg/die per le prime 4 settimane e poi di 100 mg/die per altre 20 settimane. In tutti i pazienti sono stati valutati la sicurezza, l’efficacia e la tolleranza alla fine delle settimane 4, 12, 24 e 48. L’efficacia è stata valutata mediante la scomparsa dei livelli sierici del genoma di HCV (RNA-HCV ricercato con reazione polimerasica a catena (PCR, e la normalizzazione delle transaminasi. L’end point primario era il mantenimento della risposta virologica; cioè il mantenimento di RNA-HCV a livelli sierici indosabili fino alla 48esima settimana. Il grado di mantenimento della risposta virologica è stata significativamente più alto nel gruppo con terapia combinata, IFN-CsA, rispetto al gruppo con IFN in monoterapia (p = 0.01. Il grado di mantenimento della risposta biochimica era più alto nel gruppo con terapia combinata rispetto a quello con monoterapia (p = 0.017. Nei pazienti con genotipo virale 1 di HCV ed alta carica virale, il grado di mantenimento della risposta virologica era marcatamente più alto nel gruppo con terapia combinata rispetto al gruppo con IFN in monoterapia (p = 0.006. Il profilo di effetti collaterali era simile nei due gruppi. In pazienti con epatite C cronica il trattamento combinato IFNCsA è più efficace rispetto alla monoterapia con IFN, soprattutto nei pazienti con genotipo virale 1 di HCV ed alta viremia. Altri studi in vitro hanno recentemente dimostrato che la CsA, a differenza di altri

  5. USE OF A COMBINATION OF АVASTIN AND LOW-DOSE INTERFERON- α IN THE FIRST-LINE TREATMENT OF METASTATIC RENAL-CELL CANCER

    Directory of Open Access Journals (Sweden)

    A. S. Kalpinsky

    2013-01-01

    Full Text Available Background. The registered AVOREN Phase III trial demonstrated the efficacy of a combination of bevacizumab and interferon-α (IFN-α as first-line targeted therapy in patients with metastatic renal-cell cancer (mRCC. The median progression-free survival (PFS was significantly higher in the bevacizumab + IFN-α group, amounting to 10.2 months versus 5.4 months in the IFN-α group (p < 0.0001. The most common grade 3 and 4 side effects in the AVOREN study included the adverse events due to IFN-α use; this initiated a prospective multicenter BEVLiN (Bevacizumab and Low-Dose Interferon Phase II trial in 2008 to evaluate the efficacy and tolerability of a combination of bevacizumab and low-dose IFN-α in patients with mRCC to diminish the toxicity of treatment.Subjects and methods. The trial enrolled 146 patients having good and moderate prognosis according to the MSKCC scale. The patients received Avastin 10 mg/kg every 2 weeks and IFN-α 3,000,000 IU thrice weekly. The historical control group was taken from the AVOREN trial as a control group. The main purposes of the trial were to evaluate the tolerability of treatment (the frequency of adverse events due to IFN-α use, grade 3 or more toxicity and PFS. The additional goals were to estimate overall survival (OS, objective response rates, and the incidence of any adverse events of grade 3–4 toxicity.Results. The median follow-up was 29.4 months (range 1.5–35.4 months. The rate of objective responses was 28.8 % (95 % confidence interval (CI 21.4–37.1. The median PFS was 15.3 months (95 % CI 11.7–18.0 and PFS was 58.2 and 28.9 % at 12 and 24 months of treatment, respectively. The median OS was 30.7 months (95 % CI 25.7 was unachieved. In the IFN-α group, all grades of adverse reactions and their grade 3 or more were recorded in 53.4 and 10.3 % of the patients, respectively. The adverse events that were a reason for IFN-α discontinuation were recorded in 24.0 % of the patients

  6. The combination of bleomycin with suicide or interferon-β gene transfer is able to efficiently eliminate human melanoma tumor initiating cells.

    Science.gov (United States)

    Fondello, Chiara; Agnetti, Lucrecia; Villaverde, Marcela S; Simian, Marina; Glikin, Gerardo C; Finocchiaro, Liliana M E

    2016-10-01

    We explored the potential of a chemogene therapy combination to eradicate melanoma tumor initiating cells, key producers of recurrence and metastatic spread. Three new human melanoma cell lines, two obtained from lymph nodes and one from spleen metastasis were established and characterized. They were cultured as monolayers and spheroids and, in both spatial configurations they displayed sensitivity to single treatments with bleomycin (BLM) or human interferon-β (hIFNβ) gene or herpes simplex virus thymidine kinase/ganciclovir suicide gene (SG) lipofection. However, the combination of bleomycin with SG or hIFNβ gene transfer displayed greater antitumor efficacy. The three cell lines exhibited a proliferative behavior consistent with melan A and gp100 melanoma antigens expression, and BRAF V600E mutation. BLM and both genetic treatments increased the fraction of more differentiated and treatment-sensitive cells. Simultaneously, they significantly decreased the sub-population of tumor initiating cells. There was a significant correlation between the cytotoxicity of treatments with BLM and gene transfer and the fraction of cells exhibiting (i) high proliferation index, and (ii) high intracellular levels of reactive oxygen species. Conversely, the fraction of cells surviving to our treatments closely paralleled their (i) colony and (ii) melanosphere forming capacity. A very significant finding was that the combination of BLM with SG or hIFNβ gene almost abrogated the clonogenic capacity of the surviving cells. Altogether, the results presented here suggest that the combined chemo-gene treatments are able to eradicate tumor initiating cells, encouraging further studies aimed to apply this strategy in the clinic. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Combined etiology for bilateral and simultaneous optic neuropathy in a patient with ciancobalamin deficit and hepatitis C treated with peg-interferon and ribavirin

    Science.gov (United States)

    Pantalon, Anca Delia; Danielescu, Ciprian; Chiseliță, Dorin

    2016-01-01

    We report the case of a 53-year-old female patient who developed bilateral sudden visual acuity loss after 15 weeks from the initiation of Peg-Interferon and Ribavirin treatment for hepatitis C. Debut was simultaneous and asymmetric, reported in the morning, at awakening. No pain or other symptom was reported by the patient. Results. At presentation, visual acuity was 0.2 in RE and 3/ 50 in LE. Pupillary reflexes were sluggish and severe dyschromatopsia was documented in both eyes (Ishihara plates). Fundus examination revealed bilateral pale optic disc edema, more prominent in LE, with splinter hemorrhages in the RNFL around the optic disk. Visual field exam demonstrated severe defects in 3 quadrants of the RE, whereas in the LE, it was impossible to perform the investigation due to VA<0.1. Neurologic evaluation was normal; other possible causes of systemic vasculitis were excluded by negative lab tests. Acute inflammatory markers (fibrinogen and ESR) and mild pancytopenia were the only documented laboratory changes in this patient. Anamnesis cleared the traditional risk factors for conventional AION (hypertension, diabetes, ischemic heart disease, and hypercholesterolemia). Cranial and orbital CT scan and MRI findings were normal. Patient was withdrawn from the Interferon and Ribavirin treatment and was administered methyl prednisolone pulse therapy (1g/ day) for 3 days, continued with oral Prednisone (60 mg/ day) tapered slowly for over 12 weeks. VA increased to 0.8 during treatment in the RE, but visual recovery in the LE was not as spectacular (0.16) as in the fellow eye. Modified latencies and amplitudes in evoked visual potentials examination during 4 months time emphasized bilateral optic atrophy. Optic nerve sufferance was amplified by a low level of vitamin B12, detected by chance at the last eye visit. Due to the general condition, dietary supplementation was not possible. Conclusion. A case of a patient with bilateral and simultaneous NAION caused by IFN

  8. Synergetic responses after administration of interleukin-2 and Interferon-alpha combined with gamma knife radiosurgery in a patient with multiple lung and brain metastases: a case report

    National Research Council Canada - National Science Library

    Takada, Toshihiko; Yamada, Yoshiteru; Uno, Masahiro; Komeda, Hisao; Fujimoto, Yoshinori

    2005-01-01

    ...). Initially, Interferon-alpha (IFN-alpha) therapy was started for lung metastases. About 40 days after surgery, head magnetic resonance imaging revealed brain metastases, and therefore gamma knife radiosurgery(GKS) was performed...

  9. Efficacy in treatment of cervical HRHPV infection by combination of beta interferon, and herbal therapy in woman with different cervical lesions.

    Science.gov (United States)

    Iljazović, Ermina; Ljuca, Dzenita; Sahimpasić, Ademir; Avdić, Silvija

    2006-11-01

    almost same therapy was recommended to the male partner. Patients from the second group used B complex during the therapy. Patients were retested for the HPV presence after three or six month from therapy depend of the presence bacterial or fungal genital coinfection. Three months after applied therapy HPV infection was still present in more than 90% of the patients in the first group. In the second group treated according to the recommended therapy scheme HPV infection disappeared in 71.42% of the patients after three months and in 100% of patients after six months. Samples of the cervical smear for the HPV analysis were being taken during routine gynecological examinations, by using sticks with cotton, taken from the Digene Specimen Collection Kit, from the whole surface of a portion, and by mild rotating moves from the outer cervical entrance. Our results suggest that the combination of interferon and herbal therapy with B complex is effective, atraumatic and simple non-surgical treatment of HPV infection. Since prospective efficacy trials will take several years to complete, considering alternative approaches is also worthwhile.

  10. A Rapid Screening Assay Identifies Monotherapy with Interferon-ß and Combination Therapies with Nucleoside Analogs as Effective Inhibitors of Ebola Virus.

    Directory of Open Access Journals (Sweden)

    Stephen D S McCarthy

    2016-01-01

    Full Text Available To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD. While a number of candidate drugs have shown limited efficacy in vitro and/or in non-human primate studies, differences in experimental methodologies make it difficult to compare their therapeutic effectiveness. Using an in vitro model of Ebola Zaire replication with transcription-competent virus like particles (trVLPs, requiring only level 2 biosafety containment, we compared the activities of the type I interferons (IFNs IFN-α and IFN-ß, a panel of viral polymerase inhibitors (lamivudine (3TC, zidovudine (AZT tenofovir (TFV, favipiravir (FPV, the active metabolite of brincidofovir, cidofovir (CDF, and the estrogen receptor modulator, toremifene (TOR, in inhibiting viral replication in dose-response and time course studies. We also tested 28 two- and 56 three-drug combinations against Ebola replication. IFN-α and IFN-ß inhibited viral replication 24 hours post-infection (IC50 0.038μM and 0.016μM, respectively. 3TC, AZT and TFV inhibited Ebola replication when used alone (50-62% or in combination (87%. They exhibited lower IC50 (0.98-6.2μM compared with FPV (36.8μM, when administered 24 hours post-infection. Unexpectedly, CDF had a narrow therapeutic window (6.25-25μM. When dosed >50μM, CDF treatment enhanced viral infection. IFN-ß exhibited strong synergy with 3TC (97.3% inhibition or in triple combination with 3TC and AZT (95.8% inhibition. This study demonstrates that IFNs and viral polymerase inhibitors may have utility in EVD. We identified several 2 and 3 drug combinations with strong anti-Ebola activity, confirmed in studies using fully infectious ZEBOV, providing a rationale for testing combination therapies in animal models of lethal Ebola challenge. These studies open up new possibilities for novel therapeutic options, in particular combination therapies, which could prevent and treat Ebola infection and potentially reduce drug

  11. Peg-Interferon Alfa 2-b Related Cellulitis in a 40 Years Man

    Directory of Open Access Journals (Sweden)

    Shahnaaz Sali

    2016-01-01

    Full Text Available Background: Pegylated interferon and ribavirin are currently one of the accepted treatment for chronic Hepatitis C. Dermatologic complications of interferon have been reported, but to date a few cases of bacterial cellulitis; a rare and severe complication, have been published. Cellulitis is a common infectious process affecting the skin and subcutaneous tissues which results in significant morbidity and holds considerable healthcare costs.Cases Report: Herein, we report a case of chronic hepatitis C genotype 1a who was on medication since 8 weeks prior to developing leg cellulitis, an uncommon pegylated interferon injection site. Considering no other possible risk factors were found to be in favor of bacterial cellulitis, our case is unique in its kind. Some reports reveal necrotizing vasculitis as basis for cutaneous lesions, which could be due to the high concentrations of drug at the injection site, a toxic effect of the diluents, or an immunological reaction.Conclusion: According to the latter mechanism patients could develop bacterial cellulitis in their different organs. Conclusively, we propose the hypothesis of a possible association between cellulitis to occur at any site as the complication of pegylated interferon Alfa 2b and would highlight the role of a careful skin examination that could be an asset in preventing local skin infections.

  12. Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial.

    Science.gov (United States)

    Pessôa, Mario G; Cheinquer, Hugo; Almeida, Paulo R L; Silva, Giovanni F; Lima, Maria Patelli J S; Paraná, Raymundo; Lacerda, Marco A; Parise, Edison R; Pernambuco, José R B; Pedrosa, Suelene S; Teixeira, Rosângela; Sette, Hoel; Tatsch, Fernando

    2012-01-01

    A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care(pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

  13. A multicenter, randomized, controlled trial of S-1 monotherapy versus S-1 and interferoncombination therapy for hepatocellular carcinoma with extrahepatic metastases.

    Science.gov (United States)

    Nagano, Hiroaki; Obi, Shuntaro; Hatano, Etsuro; Kaneko, Shuichi; Kanai, Fumihiko; Omata, Masao; Tsuji, Akihito; Itamoto, Toshiyuki; Yamamoto, Kazuhide; Tanaka, Masatoshi; Kubo, Shoji; Hirata, Koichi; Nakamura, Hideji; Tomimaru, Yoshito; Yamanaka, Takeharu; Kojima, Shinsuke; Monden, Morito

    2018-01-27

    No effective therapies for extrahepatic metastases from hepatocellular carcinoma (HCC) have yet been identified. Previous studies suggested a potentially promising anti-tumor effect of combination therapy of S-1, a novel oral dihydropyrimidine dehydrogenase (DPD) inhibitor, and interferon (IFN)-α. The present study aimed to investigate the clinical efficacy of single agent S-1 and S-1/IFN-α for HCC patients with extrahepatic metastases in a randomized, open-label, multicenter trial. A total of 103 patients with HCC with extrahepatic metastases were randomly assigned to the S-1/IFN-α group, receiving the combination of S-1 and IFN-α, or the S-1 group, receiving the single agent of S-1. Clinical efficacy and adverse events were compared between the two groups. Forty-nine patients in the S-1/IFN-α group and 51 patients in the S-1 group were included in the efficacy analysis. The response rate was 22.4% (11/49) in the S-1/IFN-α group and 13.7% (7/51) in the S-1 group; there was no significant difference. Overall and progression-free survivals in the two groups were also not significantly different (1-year overall survival 50.8% vs 72.4%, median progression-free survival 127 days vs 157 days). The incidence of grade ≥ 3 adverse events in the S-1/IFN-α group was 62.7% (32/51), which tended to be higher than in the S-1 group [43.1% (22/51)]. Oncologic outcomes in both treatment groups were favorable compared to previous reports, though there was no significant beneficial effect of adding IFN-α to S-1 for the treatment of HCC patients with extrahepatic metastases. This article is protected by copyright. All rights reserved.

  14. Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d'Etude des Lymphomes de l'Adulte.

    Science.gov (United States)

    Solal-Celigny, P; Lepage, E; Brousse, N; Reyes, F; Haioun, C; Leporrier, M; Peuchmaur, M; Bosly, A; Parlier, Y; Brice, P

    1993-11-25

    Interferon alfa and cytotoxic drugs have synergistic effects in patients with non-Hodgkin's lymphoma. In 1986, we designed a clinical trial to evaluate the benefit of concomitant administration of recombinant interferon alfa with a regimen containing doxorubicin in patients with follicular non-Hodgkin's lymphoma. The trial involved 242 patients with advanced low-grade follicular non-Hodgkin's lymphoma selected on the basis of clinical, radiographic, and biologic criteria. All patients were treated with a regimen consisting of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP), given monthly for six cycles and then every two months for one year. After randomization, 123 patients also received interferon alfa-2b at a dosage of 5 million units three times weekly for 18 months. The remaining 119 patients received chemotherapy alone. As compared with the patients treated with CHVP only, the patients treated with CHVP plus interferon alfa had a higher overall rate of response (85 percent vs. 69 percent, P = 0.006), a longer median event-free survival (34 months vs. 19 months, P < 0.001), and a higher rate of survival at 3 years (86 percent vs. 69 percent, P = 0.02). Granulocyte toxicity was greater in the patients treated with CHVP plus interferon alfa than in those treated with CHVP alone. There were no treatment-related deaths. Interferon alfa had to be stopped because of toxic effects (fatigue and hepatitis) in 13 patients (11 percent). The addition of interferon alfa to a regimen containing doxorubicin increased the rate of response, event-free survival, and overall survival in patients with advanced follicular non-Hodgkin's lymphoma, without serious toxicity, although some patients were unable to tolerate the side effects.

  15. POLYMORPHIC VARIANTS OF THE GENE OF INTERFERON LAMBDA 3 AND FEATURES OF IMMUNE RESPONSE IN CHILDREN WITH CHRONIC VIRAL HEPATITIS C

    Directory of Open Access Journals (Sweden)

    T. B. Sentsova

    2017-01-01

    Full Text Available To study the immune manifestations of the interferon-lambda 3 genepolymorphism in chronic viral hepatitis C, 110 Russian children (54 girls and 56 boys with chronic HCV infection aged from 3 to 17 years were examined. All children were on combined therapy (pegylated interferon + ribavirin. It was found that among the studied polymorphic variants of the IFN-λ 3 gene in children with chronic HCV infection, T allele of the marker rs12979860 is associated with infection and chronization of HCV. The T/T rs12979860 genotype of the IFN-λ3 gene is unfavorable for the course of chronic HCV infection due to low levels of activated T-lymphocytes, intactness of the proinflammatory cytokines TNF-α, IL-6, IL-1α, and interferon-γ inducible protein IP-10. The revealed relation of the polymorphic variants of C/C + C/T locus rs12979860 of INF-λ3 gene with the expression of activated T-lymphocytes discloses the protective nature of these genotypes to the development of chronic HCV infection in children. 

  16. PEGylated nanoparticles: protein corona and secondary structure

    Science.gov (United States)

    Runa, Sabiha; Hill, Alexandra; Cochran, Victoria L.; Payne, Christine K.

    2014-09-01

    Nanoparticles have important biological and biomedical applications ranging from drug and gene delivery to biosensing. In the presence of extracellular proteins, a "corona" of proteins adsorbs on the surface of the nanoparticles, altering their interaction with cells, including immune cells. Nanoparticles are often functionalized with polyethylene glycol (PEG) to reduce this non-specific adsorption of proteins. To understand the change in protein corona that occurs following PEGylation, we first quantified the adsorption of blood serum proteins on bare and PEGylated gold nanoparticles using gel electrophoresis. We find a threefold decrease in the amount of protein adsorbed on PEGylated gold nanoparticles compared to the bare gold nanoparticles, showing that PEG reduces, but does not prevent, corona formation. To determine if the secondary structure of corona proteins was altered upon adsorption onto the bare and PEGylated gold nanoparticles, we use CD spectroscopy to characterize the secondary structure of bovine serum albumin following incubation with the nanoparticles. Our results show no significant change in protein secondary structure following incubation with bare or PEGylated nanoparticles. Further examination of the secondary structure of bovine serum albumin, α2-macroglobulin, and transferrin in the presence of free PEG showed similar results. These findings provide important insights for the use of PEGylated gold nanoparticles under physiological conditions.

  17. Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy.

    Science.gov (United States)

    Hu, Jin; Wang, Guilin; Zhao, Wenguo; Liu, Xinyu; Zhang, Libin; Gao, Weiping

    2016-07-01

    Conjugating poly(ethylene glycol) (PEG), PEGylation, to therapeutic proteins is widely used as a means to improve their pharmacokinetics and therapeutic potential. One prime example is PEGylated interferon-alpha (PEGASYS). However, PEGylation usually leads to a heterogeneous mixture of positional isomers with reduced bioactivity and low yield. Herein, we report site-specific in situ growth (SIG) of a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) POEGMA conjugate of interferon-alpha in high yield. The POEGMA conjugate showed significantly improved pharmacokinetics, tumor accumulation and anticancer efficacy as compared to interferon-alpha. Notably, the POEGMA conjugate possessed a 7.2-fold higher in vitro antiproliferative bioactivity than PEGASYS. More importantly, in a murine cancer model, the POEGMA conjugate completely inhibited tumor growth and eradicated tumors of 75% mice without appreciable systemic toxicity, whereas at the same dose, no mice treated with PEGASYS survived for over 58 days. The outperformance of a site-specific POEGMA conjugate prepared by SIG over PEGASYS that is the current gold standard for interferon-alpha delivery suggests that SIG is of interest for the development of next-generation protein therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Combined antigen-specific interferon-γ and interleukin-2 release assay (FluoroSpot for the diagnosis of Mycobacterium tuberculosis infection.

    Directory of Open Access Journals (Sweden)

    Dumitru Chesov

    Full Text Available To evaluate interleukin (IL-2 and interferon (IFN-γ secreting T-cells in parallel for the differentiation of latent infection with Mycobacterium tuberculosis infection (LTBI from active tuberculosis.Following ex-vivo stimulation of peripheral blood mononuclear cells (PBMC with M. tuberculosis-specific antigens early secretory antigenic target (ESAT-6 and culture filtrate protein (CFP-10, immune responses were assessed by enzyme-linked immunospot IFN-γ release assay (EliSpot-IGRA and a novel dual cytokine detecting fluorescence-linked immunospot (FluoroSpot in 18 patients with pulmonary tuberculosis, 10 persons with previously cured tuberculosis, 25 individuals with LTBI and 16 healthy controls.Correlation of IFN-γ+ spot-forming cells in EliSpot-IGRA and FluoroSpot were R2 = 0.67 for ESAT-6 and R2 = 0.73 for CFP-10. The number of IL-2- IFN-γ+ producing cells was higher in patients with tuberculosis compared with past tuberculosis (CFP-10-induced p = 0.0068 or individuals with LTBI (ESAT-6-induced p = 0.0136. A cutoff value of >16 CFP-10-induced IFN-γ+ secreting cells/200.000 PBMC in the EliSpot-IGRA discriminated with highest sensitivity and specificity (89% and 76%, respectively. However, overlap in cytokine responses precludes distinction between the cohorts on an individual basis.Combined analysis of IFN-γ and IL-2 secretion by antigen specific T-cells does not allow a reliable differentiation between different states of M. tuberculosis infection in clinical practice.

  19. Accordion Index: A new tool for the prediction of the efficacy of peg-interferon-alpha-2b and ribavirin combination therapy for chronic hepatitis C.

    Science.gov (United States)

    Satoh, Takeaki; Masumoto, Akihide

    2008-03-01

    An optimal treatment regimen based on individual virological response is essential to maximize the efficiency of interferon (IFN) therapy for chronic hepatitis C. Using indicators of the virological response and the treatment intensity, we developed the Accordion Index as a new tool for the efficacy prediction of peg-IFN and ribavirin (RBV) combination therapy. For the Accordion Index, the IFN-AC ratio and RBV-AC ratio were defined as follows: IFN-AC ratio = (total IFN dose given during the entire treatment period)/(total IFN dose required to achieve hepatitis C virus [HCV]-RNA negativity), RBV-AC ratio = (total RBV dose given during the entire treatment period)/(total RBV dose required to achieve HCV-RNA negativity). The analysis of the association between the Accordion Index and the sustained virological response (SVR)revealed that of 25 patients who had HCV-RNA negativity during treatment, all 10 patients with an IFN-AC ratio and RBV-AC ratio of at least 4.0 achieved SVR, while only four of 15 patients with an IFN-AC ratio or RBV-AC ratio of less than 4.0 achieved SVR. With the cut-off value for both the IFN-AC ratio and RBV-AC ratio at 4.0 or higher, the quality of SVR prediction was as follows: the positive predictive value was 100%, the negative predictive value was 73.3%, and accuracy was 84.0%. The Accordion Index will thus be a useful tool for planning optimal treatment regimens for individual patients.

  20. Natural Killer Cell Characteristics in Patients With Chronic Hepatitis B Virus (HBV) Infection Are Associated With HBV Surface Antigen Clearance After Combination Treatment With Pegylated Interferon Alfa-2a and Adefovir

    NARCIS (Netherlands)

    Stelma, Femke; de Niet, Annikki; Tempelmans Plat-Sinnige, Marjan J.; Jansen, Louis; Takkenberg, R. Bart; Reesink, Hendrik W.; Kootstra, Neeltje A.; van Leeuwen, Ester M. M.

    2015-01-01

    The role of natural killer (NK) cells in the process of hepatitis B virus (HBV) surface antigen (HBsAg) clearance and whether their phenotype is related to treatment outcome in patients with chronic hepatitis B are currently unknown. Patients with chronic hepatitis B (HBV DNA load, >17 000 IU/mL)

  1. EFFICACY AND SAFETY OF A NEW COMBINED MEDICATION WITH RECOMBINANT INTERFERON AND BETAMETHASONE IN THE TREATMENT OF HAY FEVER DURING PERIODS OF EXACERBATION

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    A. A. Ryabtseva

    2016-01-01

    Full Text Available Objective: to assess the efficacy, safety and tolerability of the new combined medication Allergoferon® beta in patients with moderate-to-severe hay fever (seasonal allergic rhinitis and conjunctivitis during periods of exacerbation. patients and methods: the object of our study was medication Allergoferon® beta (recombinant human interferon alpha-2b, not less than 5000 IU/ml + betamethasone sodium phosphate, 1.0 mg/ml in the form of eye and nasal drops. Total of 120 patients aged 18-65 years with hay fever for at least two years were enrolled in the clinical trial, including 76 women and 44 men. All patients had a clinical picture of moderate-to-severe hay fever during periods of exacerbation. Patients were divided into two equal groups. The main group received Allergoferon® beta, the control group was treated with Oftan® Dexamethasone and Nasobek medications. This trial used a randomized, open-label, multicenter, parallel, comparative, controlled study design. results: we found that new combined medication Allergoferon® beta had a significant therapeutic effect in relieving main clinical manifestations of acute hay fever and showed a higher efficacy, than the comparison remedies. By comparing similar symptoms in both groups, we observed that in patients treated with Allergoferon® beta clinical symptoms of acute hay fever were relieved earlier (on the 5th day of treatment, than in the control group (on the 10th day of treatment and the disease itself proceeded milder. Therapeutic efficacy of Allergoferon® beta was 85,96% (in the control group — 74,73%, p<0.05. During clinical trial we have not observed any adverse effects; general or local toxic and allergic reactions were also not discovered. The medication tolerability was rated as “good” for patients. Conclusion: according to the clinical study results, the medication Allergoferon® beta (eye and nasal drops is recommended for the state registration and can be used by medical

  2. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial

    DEFF Research Database (Denmark)

    Ravnborg, Mads; Sørensen, Per Soelberg; Andersson, Magnus

    2010-01-01

    over 6 months. All patients who received at least one dose of study drug were included in all planned analyses. This trial is registered with ClinicalTrials.gov, NCT00168766. FINDINGS: 341 patients were randomly assigned to methylprednisolone (n=172) or placebo (n=169); 171 patients...... therefore aimed to investigate the combination of cyclic methylprednisolone and interferon beta for the treatment of relapsing-remitting multiple sclerosis. METHODS: In 2001, we designed a multicentre, double-blind, randomised, parallel-group trial, termed the methylprednisolone in combination...

  3. Pegylated liposomal doxorubicin in the management of ovarian cancer

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    Gabriella Ferrandina

    2010-09-01

    Full Text Available Gabriella Ferrandina1,2, Giacomo Corrado1, Angelo Licameli1, Domenica Lorusso2, Gilda Fuoco1, Salvatore Pisconti3, Giovanni Scambia2 1Gynecologic Oncology Unit, Department of Oncology, Catholic University of Campobasso, Campobasso, Italy; 2Gynecologic Oncology Unit, Catholic University of Rome, Rome, Italy; 3Salvatore Pisconti, Oncology Unit, Taranto Hospital, Taranto, Italy Abstract: Among the pharmaceutical options available for treatment of ovarian cancer, much attention has been progressively focused on pegylated liposomal doxorubicin (PLD, whose unique formulation, which entraps conventional doxorubicin in a bilayer lipidic sphere ­surrounded by a polyethylene glycol layer, prolongs the persistence of the drug in the ­circulation and potentiates intratumor drug accumulation. These properties enable this drug to sustain its very favorable toxicity profile and to be used safely in combination with other drugs. PLD has been already approved for treatment of advanced ovarian cancer patients failing first-line platinum-based treatment. Moreover, phase III trials have been already completed, and results are eagerly awaited, which hopefully will expand the range of PLD clinical application in this neoplasia both in front-line treatment, and in the salvage setting in combination with other drugs. Moreover, attempts are continuing to enable this drug to be combined with novel cytotoxic drugs and target-based agents. This review aims at summarizing the available evidence and the new perspectives for the clinical role of PLD in the management of patients with epithelial ovarian cancer.Keywords: pegylated liposomal doxorubicin, ovarian cancer, clinical trials

  4. High-resolution, preparative purification of PEGylated protein using a laterally-fed membrane chromatography device.

    Science.gov (United States)

    Madadkar, Pedram; Nino, Sergio Luna; Ghosh, Raja

    2016-11-01

    We discuss the use of a laterally-fed membrane chromatography (or LFMC) device for single-step purification of mono-PEGylated lysozyme. Recent studies have shown such LFMC devices to be suitable for high-resolution, multi-component separation of proteins in the bind-and-elute mode. The device used in this study contained a stack of rectangular cation-exchange membranes having 9.25mL bed volume. PEGylation of lysozyme was carried out in batch mode using 5kDa methoxy-polyethyleneglycol propionaldehyde (or m-PEG propionaldehyde) in the presence of sodium cyanoborohydride as reducing agent. Membrane chromatographic separation was carried out at 1.62 membrane bed volumes per minute flow rate, in the bind-and-elute mode. When a salt gradient was applied, the higher PEGylated forms of lysozyme (i.e. the byproducts) eluted earlier than mono-PEGylated lysozyme (the target product), while lysozyme eluted last. Under elution conditions optimized for resolution and speed, the separation could be carried out in less than 15 membrane bed volumes. High purity and recovery of mono-PEGylated lysozyme was obtained. The resolution of separation of mono-PEGylated lysozyme obtained under the above condition was comparable to that reported in the literature for equivalent cation-exchange resin columns while the flow rate expressed in bed volumes/min was 21.7 times higher. Also, the number of theoretical plates per meter was significantly higher with the LFMC device. Therefore the LFMC based purification process discussed in this paper combined high-productivity with high-resolution. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Robust Protection against Highly Virulent Foot-and-Mouth Disease Virus in Swine by Combination Treatment with Recombinant Adenoviruses Expressing Porcine Alpha and Gamma Interferons and Multiple Small Interfering RNAs

    Science.gov (United States)

    Park, Jong-Hyeon; Lee, Kwang-Nyeong; Kim, Se-Kyung; You, Su-Hwa; Kim, Taeseong; Tark, Dongseob; Lee, Hyang-Sim; Seo, Min-Goo; Kim, Byounghan

    2015-01-01

    ABSTRACT Because the currently available vaccines against foot-and-mouth disease (FMD) provide no protection until 4 to 7 days postvaccination, the only alternative method to halt the spread of the FMD virus (FMDV) during outbreaks is the application of antiviral agents. Combination treatment strategies have been used to enhance the efficacy of antiviral agents, and such strategies may be advantageous in overcoming viral mechanisms of resistance to antiviral treatments. We have developed recombinant adenoviruses (Ads) for the simultaneous expression of porcine alpha and gamma interferons (Ad-porcine IFN-αγ) as well as 3 small interfering RNAs (Ad-3siRNA) targeting FMDV mRNAs encoding nonstructural proteins. The antiviral effects of Ad-porcine IFN-αγ and Ad-3siRNA expression were tested in combination in porcine cells, suckling mice, and swine. We observed enhanced antiviral effects in porcine cells and mice as well as robust protection against the highly pathogenic strain O/Andong/SKR/2010 and increased expression of cytokines in swine following combination treatment. In addition, we showed that combination treatment was effective against all serotypes of FMDV. Therefore, we suggest that the combined treatment with Ad-porcine IFN-αγ and Ad-3siRNA may offer fast-acting antiviral protection and be used with a vaccine during the period that the vaccine does not provide protection against FMD. IMPORTANCE The use of current foot-and-mouth disease (FMD) vaccines to induce rapid protection provides limited effectiveness because the protection does not become effective until a minimum of 4 days after vaccination. Therefore, during outbreaks antiviral agents remain the only available treatment to confer rapid protection and reduce the spread of foot-and-mouth disease virus (FMDV) in livestock until vaccine-induced protective immunity can become effective. Interferons (IFNs) and small interfering RNAs (siRNAs) have been reported to be effective antiviral agents against

  6. Preferential interactions and the effect of protein PEGylation

    DEFF Research Database (Denmark)

    Holm, Louise Stenstrup; Thulstrup, Peter Waaben; Kasimova, Marina Robertovna

    2015-01-01

    excipients that preferentially interact with the protein. METHODOLOGY/PRINCIPAL FINDINGS: The model protein hen egg white lysozyme was doubly PEGylated on two lysines with 5 kDa linear PEGs (mPEG-succinimidyl valerate, MW 5000) and studied in the absence and presence of preferentially excluded sucrose...... excipients. This suggests that formulation principles using preferentially interacting excipients are similar for PEGylated and non-PEGylated proteins.......BACKGROUND: PEGylation is a strategy used by the pharmaceutical industry to prolong systemic circulation of protein drugs, whereas formulation excipients are used for stabilization of proteins during storage. Here we investigate the role of PEGylation in protein stabilization by formulation...

  7. Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

    Science.gov (United States)

    Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

    2017-05-01

    Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

  8. Pegylated liposomal doxorubicin: a review of its use in metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma.

    Science.gov (United States)

    Duggan, Sean T; Keating, Gillian M

    2011-12-24

    Pegylated liposomal doxorubicin (Caelyx™, Doxil®) represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. This article reviews the efficacy and tolerability of pegylated liposomal doxorubicin in metastatic breast cancer, progressive ovarian cancer, relapsed or refractory multiple myeloma and AIDS-related Kaposi's sarcoma, as well as summarizing its pharmacological properties. In three randomized, open-label, multicentre trials, monotherapy with pegylated liposomal doxorubicin was as effective as doxorubicin or capecitabine in the first-line treatment of metastatic breast cancer, and as effective as vinorelbine or combination mitomycin plus vinblastine in taxane-refractory metastatic breast cancer. Pegylated liposomal doxorubicin alone was as effective as topotecan or gemcitabine alone in patients with progressive ovarian cancer resistant or refractory to platinum- or paclitaxel-based therapy, according to the results of three randomized multicentre trials. In addition, in patients with progressive ovarian cancer who had received prior platinum-based therapy, progression-free survival was significantly longer with pegylated liposomal doxorubicin plus carboplatin than with paclitaxel plus carboplatin, according to the results of a randomized, open-label multicentre trial. Combination therapy with pegylated liposomal doxorubicin plus bortezomib was more effective than bortezomib alone in patients with relapsed or refractory multiple myeloma, according to the results of a randomized, open-label, multinational trial. Randomized multinational trials also demonstrated the efficacy of pegylated liposomal doxorubicin in patients with advanced AIDS-related Kaposi's sarcoma. Pegylated liposomal doxorubicin exhibited a relatively favourable safety profile compared with conventional doxorubicin and other available chemotherapy agents. The most common treatment-related adverse events included

  9. PEGylated human serum albumin (HSA) nanoparticles: preparation, characterization and quantification of the PEGylation extent

    Science.gov (United States)

    Fahrländer, E.; Schelhaas, S.; Jacobs, A. H.; Langer, K.

    2015-04-01

    Modification with poly(ethylene glycol) (PEG) is a widely used method for the prolongation of plasma half-life of colloidal carrier systems such as nanoparticles prepared from human serum albumin (HSA). However, the quantification of the PEGylation extent is still challenging. Moreover, the influence of different PEG derivatives, which are commonly used for nanoparticle conjugation, has not been investigated so far. The objective of the present study is to develop a method for the quantification of PEG and to monitor the influence of diverse PEG reagents on the amount of PEG linked to the surface of HSA nanoparticles. A size exclusion chromatography method with refractive index detection was established which enabled the quantification of unreacted PEG in the supernatant. The achieved results were confirmed using a fluorescent PEG derivative, which was detected by photometry and fluorimetry. Additionally, PEGylated HSA nanoparticles were enzymatically digested and the linked amount of fluorescently active PEG was directly determined. All the analytical methods confirmed that under optimized PEGylation conditions a PEGylation efficiency of up to 0.5 mg PEG per mg nanoparticle could be achieved. Model calculations made a ‘brush’ conformation of the PEG chains on the particle surface very likely. By incubating the nanoparticles with fetal bovine serum the reduced adsorption of serum proteins on PEGylated HSA nanoparticles compared to non-PEGylated HSA nanoparticles was demonstrated using sodium dodecylsulfate polyacrylamide gel electrophoresis. Finally, the positive effect of PEGylation on plasma half-life was demonstrated in an in vivo study in mice. Compared to unmodified nanoparticles the PEGylation led to a four times larger plasma half-life.

  10. Tumor burden talks in cancer treatment with PEGylated liposomal drugs.

    Directory of Open Access Journals (Sweden)

    Yi-Yu Lin

    Full Text Available PURPOSE: PEGylated liposomes are important drug carriers that can passively target tumor by enhanced permeability and retention (EPR effect in neoplasm lesions. This study demonstrated that tumor burden determines the tumor uptake, and also the tumor response, in cancer treatment with PEGylated liposomal drugs in a C26/tk-luc colon carcinoma-bearing mouse model. METHODS: Empty PEGylated liposomes (NanoX and those encapsulated with VNB (NanoVNB were labeled with In-111 to obtain InNanoX and InVNBL in high labeling yield and radiochemical purity (all >90%. BALB/c mice bearing either small (58.4±8.0 mm(3 or large (102.4±22.0 mm(3 C26/tk-luc tumors in the right dorsal flank were intravenously administered with NanoVNB, InNanoX, InVNBL, or NanoX as a control, every 7 days for 3 times. The therapeutic efficacy was evaluated by body weight loss, tumor growth inhibition (using calipers and bioluminescence imaging and survival fraction. The scintigraphic imaging of tumor mouse was performed during and after treatment. RESULTS: The biodistribution study of InVNBL revealed a clear inverse correlation (r (2 = 0.9336 between the tumor uptake and the tumor mass ranged from 27.6 to 623.9 mg. All three liposomal drugs showed better therapeutic efficacy in small-tumor mice than in large-tumor mice. Tumor-bearing mice treated with InVNBL (a combination drug showed the highest tumor growth inhibition rate and survival fraction compared to those treated with NanoVNB (chemodrug only and InNanoX (radionuclide only. Specific tumor targeting and significantly increased tumor uptake after periodical treatment with InVNBL were evidenced by scintigraphic imaging, especially in mice bearing small tumors. CONCLUSION: The significant differences in the outcomes of cancer treatment and molecular imaging between animals bearing small and large tumors revealed that tumor burden is a critical and discriminative factor in cancer therapy using PEGylated liposomal drugs.

  11. Site-Specific PEGylation of Therapeutic Proteins

    Directory of Open Access Journals (Sweden)

    Jonathan K. Dozier

    2015-10-01

    Full Text Available The use of proteins as therapeutics has a long history and is becoming ever more common in modern medicine. While the number of protein-based drugs is growing every year, significant problems still remain with their use. Among these problems are rapid degradation and excretion from patients, thus requiring frequent dosing, which in turn increases the chances for an immunological response as well as increasing the cost of therapy. One of the main strategies to alleviate these problems is to link a polyethylene glycol (PEG group to the protein of interest. This process, called PEGylation, has grown dramatically in recent years resulting in several approved drugs. Installing a single PEG chain at a defined site in a protein is challenging. Recently, there is has been considerable research into various methods for the site-specific PEGylation of proteins. This review seeks to summarize that work and provide background and context for how site-specific PEGylation is performed. After introducing the topic of site-specific PEGylation, recent developments using chemical methods are described. That is followed by a more extensive discussion of bioorthogonal reactions and enzymatic labeling.

  12. A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.

    Science.gov (United States)

    Vergote, Ignace; Schilder, Russell J; Pippitt, Charles H; Wong, Shirley; Gordon, Alan N; Scudder, Sidney; Kridelka, Frederic; Dirix, Luc; Leach, Joseph W; Ananda, Sumitra; Nanayakkara, Nuwan; Melara, Rebeca; Bass, Michael B; Litten, Jason; Adewoye, Henry; Wenham, Robert M

    2014-10-01

    To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Dental problems delaying the initiation of interferon therapy for HCV-infected patients

    Directory of Open Access Journals (Sweden)

    Nagao Yumiko

    2010-08-01

    Full Text Available Abstract Background There has been little discussion about the importance of oral management and interferon (IFN therapy, although management of the side effects of therapy for chronic hepatitis C has been documented. This study determined whether dental problems delayed the initiation of IFN therapy for hepatitis C virus (HCV-infected patients. Results We analyzed 570 HCV-infected patients who were admitted to our hospital from December 2003 to June 2010 for treatment consisting of pegylated IFN (Peg-IFN monotherapy or Peg-IFN/ribavirin combination therapy. The group comprised 274 men and 296 women with a mean age 57.2 years. Of the 570 patients, six could not commence Peg-IFN therapy, despite their admission, because of dental problems such as periodontitis, pupitis, and pericoronitis. The ages of six whose dental problems delayed the initiation of Peg-IFN ranged from 25 to 67 years, with a mean age of 47.3 ± 15.2 years. IFN therapy was deferred for 61.3 ± 47.7 days. Among the six subjects for whom IFN treatment was delayed, only one had a salivary flow that was lower than the normal value. Conclusions Treatment of dental infections is required before IFN therapy for HCV infection can be started. To increase the depth of understanding of oral health care, it is hoped that dentists and medical specialists in all areas will hold discussions to generate cooperation.

  14. Dental problems delaying the initiation of interferon therapy for HCV-infected patients

    Science.gov (United States)

    2010-01-01

    Background There has been little discussion about the importance of oral management and interferon (IFN) therapy, although management of the side effects of therapy for chronic hepatitis C has been documented. This study determined whether dental problems delayed the initiation of IFN therapy for hepatitis C virus (HCV)-infected patients. Results We analyzed 570 HCV-infected patients who were admitted to our hospital from December 2003 to June 2010 for treatment consisting of pegylated IFN (Peg-IFN) monotherapy or Peg-IFN/ribavirin combination therapy. The group comprised 274 men and 296 women with a mean age 57.2 years. Of the 570 patients, six could not commence Peg-IFN therapy, despite their admission, because of dental problems such as periodontitis, pupitis, and pericoronitis. The ages of six whose dental problems delayed the initiation of Peg-IFN ranged from 25 to 67 years, with a mean age of 47.3 ± 15.2 years. IFN therapy was deferred for 61.3 ± 47.7 days. Among the six subjects for whom IFN treatment was delayed, only one had a salivary flow that was lower than the normal value. Conclusions Treatment of dental infections is required before IFN therapy for HCV infection can be started. To increase the depth of understanding of oral health care, it is hoped that dentists and medical specialists in all areas will hold discussions to generate cooperation. PMID:20712912

  15. PEG chain length impacts yield of solid-phase protein PEGylation and efficiency of PEGylated protein separation by ion-exchange chromatography: insights of mechanistic models.

    Science.gov (United States)

    Yoshimoto, Noriko; Isakari, Yu; Itoh, Daisuke; Yamamoto, Shuichi

    2013-07-01

    The mechanisms behind protein PEGylation are complex and dictated by the structure of the protein reactant. Hence, it is difficult to design a reaction process which can produce the desired PEGylated form at high yield. Likewise, efficient purification processes following protein PEGylation must be constructed on an ad hoc basis for each product. The retention and binding mechanisms driving electrostatic interaction-based chromatography (ion-exchange chromatography) of PEGylated proteins (randomly PEGylated lysozyme and mono-PEGylated bovine serum albumin) were investigated, based on our previously developed model Chem. Eng. Technol. 2005, 28, 1387-1393. PEGylation of each protein resulted in a shift to a smaller elution volume compared to the unmodified molecule, but did not affect the number of binding sites appreciably. The shift of the retention volume of PEGylated proteins correlated with the calculated thickness of PEG layer around the protein molecule. Random PEGylation was carried out on a column (solid-phase PEGylation) and the PEGylated proteins were separated on the same column. Solid-phase PEGylation inhibited the production of multi-PEGylated forms and resulted in a relatively low yield of selective mono-PEGylated form. Pore diffusion may play an important role in solid-phase PEGylation. These results suggest the possibility of a reaction and purification process development based on the mechanistic model for PEGylated proteins on ion exchange chromatography. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Retreatment of hepatitis C non-responsive to interferon. A placebo controlled randomized trial of ribavirin monotherapy versus combination therapy with Ribavirin and Interferon in 121 patients in the Benelux [ISRCTN53821378].

    NARCIS (Netherlands)

    B.J. Veldt (Bart); J.T. Brouwer (Johannes); M. Adler (Michael); F. Nevens (Frederik); P. Michielsen (Peter); J. Delwaide (Jean); B.E. Hansen (Bettina); S.W. Schalm (Solko)

    2003-01-01

    textabstractBACKGROUND: Evidence based medicine depends on unbiased selection of completed randomized controlled trials. For completeness it is important to publish all trials. This report describes the first large randomised controlled trial where combination therapy was compared

  17. A Multicenter Study To Evaluate The Safety And Efficacy Of Heber On (Interferon Alfa-2b In Combination With Ribavirin For The Treatment Of Chronic Hepatitis C In Iran

    Directory of Open Access Journals (Sweden)

    H. Mirmomen

    2005-05-01

    Full Text Available Combination therapy with interferon and ribavirin is the most effective treatment for chronic hepatitis C today. The aim of this study was to evaluate the efficacy and safety of thrice-weekly Heberon (interferon alfa-2b in combination with ribavirin as first -line treatment of chronic hepatitis C. Methods: A total of97 treatment-naive patients received Heberon three million units thrice-weekly subcutaneously in combination with ribavirin for 12 months. Serum HCV RNA levels were measured before and during therapy and 6 months after the end of therapy. End-of-treatment and sustained virological responses was defmed as an undetectable HCV-RNA level at the end of treatment, and 6 months after treatment was completed (end of follow-up, respectively. Results: In an intent-to-treat analysis, HCV-RNA was undetectable at the end of treatment in 49.5% of patients. At the end of follow-up, sustained virological response was 36.1 %. Combination treatment was generally well tolerated. Six patients stopped therapy because of side effects: severe cytopenia (n=4, depression (n=1, and hyperthyroidism (n= 1 . Common side effects of therapy include: Flu-like syndrome (85.6%, generalized alopecia (41.2% , injection site inflammation (37.1% , mood changes (36% , anorexia (34% and weight loss (32% . Conclusion: Heberon as an IFN product in combination with ribavirin for treat-ment of patients with chronic hepatitis Cis relatively safe, feasible, and potentially efficacious. It has comparable results in achieving end-of-treatment and sustained virological responses in chronic hepatitis C.

  18. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    Science.gov (United States)

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  19. Preferential Interactions and the Effect of Protein PEGylation.

    Directory of Open Access Journals (Sweden)

    Louise Stenstrup Holm

    Full Text Available PEGylation is a strategy used by the pharmaceutical industry to prolong systemic circulation of protein drugs, whereas formulation excipients are used for stabilization of proteins during storage. Here we investigate the role of PEGylation in protein stabilization by formulation excipients that preferentially interact with the protein.The model protein hen egg white lysozyme was doubly PEGylated on two lysines with 5 kDa linear PEGs (mPEG-succinimidyl valerate, MW 5000 and studied in the absence and presence of preferentially excluded sucrose and preferentially bound guanine hydrochloride. Structural characterization by far- and near-UV circular dichroism spectroscopy was supplemented by investigation of protein thermal stability with the use of differential scanning calorimetry, far and near-UV circular dichroism and fluorescence spectroscopy. It was found that PEGylated lysozyme was stabilized by the preferentially excluded excipient and destabilized by the preferentially bound excipient in a similar manner as lysozyme. However, compared to lysozyme in all cases the melting transition was lower by up to a few degrees and the calorimetric melting enthalpy was decreased to half the value for PEGylated lysozyme. The ratio between calorimetric and van't Hoff enthalpy suggests that our PEGylated lysozyme is a dimer.The PEGylated model protein displayed similar stability responses to the addition of preferentially active excipients. This suggests that formulation principles using preferentially interacting excipients are similar for PEGylated and non-PEGylated proteins.

  20. Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling

    Directory of Open Access Journals (Sweden)

    Craigon Marie

    2009-08-01

    Full Text Available Abstract Background Interferons (IFNs are potent antiviral cytokines capable of reprogramming the macrophage phenotype through the induction of interferon-stimulated genes (ISGs. Here we have used targeted RNA interference to suppress the expression of a number of key genes associated with IFN signalling in murine macrophages prior to stimulation with interferon-gamma. Genome-wide changes in transcript abundance caused by siRNA activity were measured using exon-level microarrays in the presence or absence of IFNγ. Results Transfection of murine bone-marrow derived macrophages (BMDMs with a non-targeting (control siRNA and 11 sequence-specific siRNAs was performed using a cationic lipid transfection reagent (Lipofectamine2000 prior to stimulation with IFNγ. Total RNA was harvested from cells and gene expression measured on Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. Network-based analysis of these data revealed six siRNAs to cause a marked shift in the macrophage transcriptome in the presence or absence IFNγ. These six siRNAs targeted the Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2 transcripts. The perturbation of the transcriptome by the six siRNAs was highly similar in each case and affected the expression of over 600 downstream transcripts. Regulated transcripts were clustered based on co-expression into five major groups corresponding to transcriptional networks associated with the type I and II IFN response, cell cycle regulation, and NF-KB signalling. In addition we have observed a significant non-specific immune stimulation of cells transfected with siRNA using Lipofectamine2000, suggesting use of this reagent in BMDMs, even at low concentrations, is enough to induce a type I IFN response. Conclusion Our results provide evidence that the type I IFN response in murine BMDMs is dependent on Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2, and that siRNAs targeted to these genes results in perturbation of key transcriptional networks associated

  1. Successful management of transfusion-dependent congenital dyserythropoietic anemia type 1b with interferon alfa-2a

    DEFF Research Database (Denmark)

    Rathe, Mathias; Møller, Michael Boe; Greisen, Pernille Wied

    2018-01-01

    The congenital dyserythropoietic anemias (CDAs) are a group of rare inherited blood disorders characterized by ineffective erythropoiesis as the principal cause of anemia. We present a child with CDA 1b-the rarest and least well-described type-due to a mutation in the C15orf41 gene. The patient...... deformities. The patient responded to treatment with pegylated interferon alfa-2a....

  2. Sustained major molecular response on interferon alpha-2b in two patients with polycythemia vera

    DEFF Research Database (Denmark)

    Larsen, T.S.; Pallisgaard, N.; Andersen, M.T.

    2008-01-01

    chromosome negative chronic myeloproliferative disorders. Reductions in the JAK2 V617F allele burden in patients treated with pegylated interferon alpha-2a (Peg-IFN-2a) have been demonstrated, although follow-up was relatively short. We report here the first profound and sustained molecular responses......Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response Udgivelsesdato: 2008/10...

  3. Sustained major molecular response on interferon alpha-2b in two patients with polycythemia vera

    DEFF Research Database (Denmark)

    Larsen, Thomas Stauffer; Bjerrum, O W; Pallisgaard, N

    2008-01-01

    Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia...... chromosome negative chronic myeloproliferative disorders. Reductions in the JAK2 V617F allele burden in patients treated with pegylated interferon alpha-2a (Peg-IFN-2a) have been demonstrated, although follow-up was relatively short. We report here the first profound and sustained molecular responses...... with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response....

  4. Recent advances in the anti-HCV mechanisms of interferon

    Directory of Open Access Journals (Sweden)

    Menghao Huang

    2014-08-01

    Full Text Available Interferon (IFN in combination with ribavirin has been the standard of care (SOC for chronic hepatitis C for the past few decades. Although the current SOC lacks the desired efficacy, and 4 new direct-acting antiviral agents have been recently approved, interferons are still likely to remain the cornerstone of therapy for some time. Moreover, as an important cytokine system of innate immunity, host interferon signaling provides a powerful antiviral response. Nevertheless, the mechanisms by which HCV infection controls interferon production, and how interferons, in turn, trigger anti-HCV activities as well as control the outcome of HCV infection remain to be clarified. In this report, we review current progress in understanding the mechanisms of IFN against HCV, and also summarize the knowledge of induction of interferon signaling by HCV infection.

  5. No development of neutralizing antibodies against recombinant interferon-alpha in Ph-negative myeloproliferative neoplasms-a prospective study

    DEFF Research Database (Denmark)

    Ocias, Lukas Frans; Lund Hansen, Dennis; Kielsgaard Kristensen, Thomas

    2015-01-01

    Background Treatment of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs) with recombinant pegylated interferon alpha2a/b (rIFN-alpha) has proven effective. It is well known that prolonged therapy with recombinant type 1 interferons (IFN-alpha and IFN-beta) may induce n......: ET: 67% CR, 29 % PR; PV: 64% CR, 31% PR (ELN 2009 criteria); PMF: 50% had at least a minor response (EUMNET). The median serum concentration of bioactive IFN-alpha at 12 months was 12,4 (range...

  6. Pegylated liposomal doxorubicin in ovarian cancer

    OpenAIRE

    Matei, Daniela

    2009-01-01

    Robert Strother1,2, Daniela Matei1–51Department of Medicine, 2Indiana University Melvin and Bren Simon Cancer Center, 3Department of Obstetrics and Gynecology, 4Department of Biochemistry and Molecular Biology, 5VA Roudebush Hospital Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202Abstract: The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Lip...

  7. Allometric scaling of pegylated liposomal anticancer drugs.

    Science.gov (United States)

    Caron, Whitney P; Clewell, Harvey; Dedrick, Robert; Ramanathan, Ramesh K; Davis, Whitney L; Yu, Ning; Tonda, Margaret; Schellens, Jan H; Beijnen, Jos H; Zamboni, William C

    2011-10-01

    Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil®), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil®, and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)(m) (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil®, and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.

  8. Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Joel M O'Bryan

    Full Text Available Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes.Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNα group for an additional 3.5 years. Significant telomere loss in naïve T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+CD45RA(+CD57(+ memory T cells and an inverse correlation of alanine aminotransferase levels with naïve CD8(+ T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index.Sustained interferon-alpha treatment increased telomere loss in naïve T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined.

  9. Effectiveness of combined antyviral therapy in children with chronic hepatitis C

    Directory of Open Access Journals (Sweden)

    G. P. Martynova

    2013-01-01

    Full Text Available The paper presents the results of the research on effectiveness of combined antiviral therapy conducted with pegylated interferon alpha 2b of prolonged action (Peginterferon alpha 2b at a dose of 60 mcg/m2 per week and Rebetol (Ribavirin at a dose of 15 mg/kg per day in 26 children with chronic viral hepatitis C aged from 3 to 17, who underwent regular medical check-ups in City Clinical Hospital № 20 named after I.S. Berzon in Krasnoyarsk. Evaluation of effectiveness of combined antiviral therapy revealed that patients with genotype 1 had an immediate virologic response in 78,5% of cases, 83,3% of patients with genotype 2, 3 had a stable virologic response.

  10. Pegylated silica nanoparticles: cytotoxicity and macrophage uptake

    Science.gov (United States)

    Glorani, Giulia; Marin, Riccardo; Canton, Patrizia; Pinto, Marcella; Conti, Giamaica; Fracasso, Giulio; Riello, Pietro

    2017-08-01

    Here, we present a thorough study of pegylated silica nanoparticle (SNP) interaction with different biological environments. The SNPs have a mean diameter of about 40 nm and are coated with polyethylene glycol (PEG) of different molecular weights. The physicochemical characterization of SNPs allowed the confirmation of the binding of PEG chains to the silica surface, the reproducibility of the synthesis and the narrow size-dispersion. In view of clarifying the SNP interaction with biological environments, we first assessed the SNP reactivity after the incubation with two cell lines (macrophages RAW 264.7 and primary human fibroblasts), observing a reduced toxicity of pegylated SNPs compared to the bare ones. Then, we investigated the effect of the protein adsorption on the SNP surface using the model serum protein, bovine serum albumin (BSA). We found that the protein adsorption takes place more heavily on poorly pegylated SNPs, promoting the uptake of the latter by macrophages and leading to an increased mortality of these cells. To better understand this mechanism by means of flow cytometry, the dye Ru(bpy)3Cl2 was incorporated in the SNPs. The overall results highlight the SNP potentialities as a drug delivery system, thanks to the low interactions with the macrophages.

  11. Pegylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer

    OpenAIRE

    Markman M

    2011-01-01

    Maurie MarkmanCancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USAAbstract: Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. The drug is frequently employed as a single agent in the platinum-resistant setting, and recently reported data reveal the superiority of the combination of PLD plus carboplatin, compared with the platinum drug plus paclitaxel, in delaying the time to disease...

  12. Non-conservative surface decoration of hemoglobin: influence of neutralization of positive charges at PEGylation sites on molecular and functional properties of PEGylated hemoglobin.

    Science.gov (United States)

    Li, Dongxia; Hu, Tao; Manjula, Belur N; Acharya, Seetharama A

    2008-10-01

    High hydrodynamic volume, high viscosity and high colloidal osmotic pressure (COP) of PEGylated hemoglobin (Hb) have been suggested to neutralize the vasoactivity of acellular Hb. Consequences of non-conservative PEGylation (positive charge of the amino groups at the PEGylation sites is neutralized) using succinimidyl-ester of propionic acid PEG5K on the properties of PEGylated Hb have now been investigated. Non-conservative PEGylation of Hb leads to a much higher increase in the COP and viscosity of Hb than conservative extension arm facilitated (EAF) PEGylation of Hb. Introduction of alphaalpha-fumaryl crosslinking decreased the COP of non-conservative PEGylated Hb by stabilization of interdimeric interactions. Compared to the EAF-PEGylated alphaalpha-fumaryl Hb, non-conservative PEGylated product shows a comparable COP and higher viscosity. Conservative PEGylation of alphaalpha-fumaryl Hb by reductive alkylation chemistry does not increase the COP to this level, but enhanced the molecular volume and viscosity comparable to EAF-PEGylated product. Thus, the molecular properties of PEGylated Hb can be fine tuned using different PEGylation platforms and provide a unique opportunity for the design of second generation PEGylated Hbs.

  13. Large-scale biophysical evaluation of protein PEGylation effects

    DEFF Research Database (Denmark)

    Vernet, Erik; Popa, Gina; Pozdnyakova, Irina

    2016-01-01

    of PEGylation on the thermal stability of a protein based on data generated by circular dichroism (CD), differential scanning calorimetry (DSC), or differential scanning fluorimetry (DSF). In addition, DSF was validated as a fast and inexpensive screening method for thermal unfolding studies of PEGylated...

  14. Biophysical characterisation of GlycoPEGylated recombinant human factor VIIa

    DEFF Research Database (Denmark)

    Plesner, Bitten; Westh, Peter; Nielsen, Anders D.

    2011-01-01

    The effects of GlycoPEGylation on the structural, kinetic and thermal stability of recombinant human FVIIa were investigated using rFVIIa and linear 10 kDa and branched 40 kDa GlycoPEGylated® recombinant human FVIIa derivatives. The secondary and tertiary structure of rFVIIa measured by circular...

  15. Chemoselective PEGylation of Cysteine Analogs of Human Basic ...

    African Journals Online (AJOL)

    electrophoresis [SDS-PAGE]. Stability of. PEGylated and non-PEGylated forms of hbFGF cysteine analog was studied by incubating them in the presence of denaturing agent such as guanidine HCl at 37 °C for 24 h. The effect of such reagent was determined by fluorescence spectrophotometry (Luminescence spectrometer.

  16. The effect of pegylation on the transfection activity of two ...

    African Journals Online (AJOL)

    Pegylated liposomes (80 - 150 nm diameter) formed electrostatic complexes with plasmid DNA in the 1.5:1 – 2.5:1 range of liposome (positive): DNA (negative) charge ratio, which afforded protection to the DNA cargo against serum nuclease digestion. Plasmid pGL3-containing pegylated lipoplexes were only weakly ...

  17. Solid-Phase Synthesis of PEGylated Lipopeptides Using Click Chemistry

    DEFF Research Database (Denmark)

    Jølck, Rasmus Irming; Berg, Rolf Henrik; Andresen, Thomas Lars

    2010-01-01

    A versatile methodology for efficient synthesis of PEGylated lipopeptides via CuAAC “Click” conjugation between alkyne-bearing solid-supported lipopeptides and azido-functionalized PEGs is described. This new and very robust method offers a unique platform for synthesizing PEGylated lipopeptides ...

  18. Potential of interferon-alpha in solid tumours: part 2.

    Science.gov (United States)

    Santhanam, Sundar; Decatris, Marios; O'Byrne, Ken

    2002-01-01

    The second part of this review examines the use of recombinant interferon-alpha (rIFNalpha) in the following solid tumours: superficial bladder cancer, Kaposi's sarcoma, head and neck cancer, gastrointestinal cancers, lung cancer, mesothelioma and ovarian, breast and cervical malignancies. In superficial bladder cancer, intravesical rIFNalpha has a promising role as second-line therapy in patients resistant or intolerant to intravesical bacille Calmette-Guérin (BCG). In HIV-associated Kaposi's sarcoma, rIFNalpha is active as monotherapy and in combination with antiretroviral agents, especially in patients with CD4 counts >200/mm(3), no prior opportunistic infections and nonvisceral disease. rIFNalpha has shown encouraging results when used in combination with retinoids in the chemoprevention of head and neck squamous cell cancers. It is effective in the chemoprevention of hepatocellular cancer in hepatitis C-seropositive patients. In neuroendocrine tumours, including carcinoid tumour, low-dosage (IFNalpha may be useful in malignant pleural effusions from mesothelioma. Similarly, intraperitoneal IFNalpha may have a role in the treatment of minimal residual disease in ovarian cancer. In breast cancer, the only possible role for IFNalpha appears to be intralesional administration for resistant disease. IFNalpha may have a role as a radiosensitising agent for the treatment of cervical cancer; however, this requires confirmation in randomised trials. On the basis of current evidence, the routine use of rIFNalpha is not recommended in the therapy of head and neck squamous cell cancers, upper gastrointestinal tract, colorectal and lung cancers, or mesothelioma. Pegylated IFNalpha (peginterferon-alpha) is an exciting development that offers theoretical advantages of increased efficacy, reduced toxicity and improved compliance. Further data from randomised studies in solid tumours are needed where rIFNalpha has activity, such as neuroendocrine tumours, minimal residual

  19. Effects of PEGylation on biomimetic synthesis of magnetoferritin nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Caiyun, E-mail: ycy@mail.iggcas.ac.cn; Cao, Changqian, E-mail: changqiancao@mail.iggcas.ac.cn; Cai, Yao, E-mail: caiyao@mail.iggcas.ac.cn; Xu, Huangtao, E-mail: xuhuangtao@mail.iggcas.ac.cn; Zhang, Tongwei, E-mail: ztw@mail.iggcas.ac.cn; Pan, Yongxin, E-mail: yxpan@mail.iggcas.ac.cn [Institute of Geology and Geophysics, Chinese Academy of Sciences, Key Laboratory of Earth and Planetary Physics (China)

    2017-03-15

    Recent studies have demonstrated that ferrimagnetic magnetoferritin nanoparticles are a promising novel magnetic nanomaterial in biomedical applications, including biocatalysis, imaging, diagnostics, and tumor therapy. Here we investigated the PEGylation of human H-ferritin (HFn) proteins and the possible influence on biomimetic synthesis of magnetoferritin nanoparticles. The outer surface of HFn proteins was chemically modified with different PEG molecular weights (PEG10K and PEG20K) and different modification ratios (HFn subunit:PEG20K = 1:1, 1:2, 1:4). The PEGylated HFn proteins were used for biomimetic synthesis of ferrimagnetic magnetoferritin nanoparticles. We found that, compared with magnetoferritin using non-PEGylated HFn protein templates, the synthesized magnetoferritin using the PEGylated HFn protein templates possessed larger magnetite cores, higher magnetization and relaxivity values, and improved thermal stability. These results suggest that the PEGylation of H-ferritin may improve the biomineralization of magnetoferritin nanoparticles and enhance their biomedical applications.

  20. Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Carmela Pisano

    2013-01-01

    Full Text Available Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD, whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.

  1. Clinical trials with pegylated liposomal Doxorubicin in the treatment of ovarian cancer.

    Science.gov (United States)

    Pisano, Carmela; Cecere, Sabrina Chiara; Di Napoli, Marilena; Cavaliere, Carla; Tambaro, Rosa; Facchini, Gaetano; Scaffa, Cono; Losito, Simona; Pizzolorusso, Antonio; Pignata, Sandro

    2013-01-01

    Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.

  2. Role of ledipasvir/sofosbuvir combination for genotype 1 hepatitis C virus infection

    Directory of Open Access Journals (Sweden)

    Sundaram V

    2016-06-01

    Full Text Available Vinay Sundaram,1 Kris V Kowdley21Department of Medicine and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, 2Liver Care Network, Swedish Medical Center, Seattle, WA, USAAbstract: Chronic hepatitis C virus (HCV infection is one of the most common etiologies of liver-related mortality throughout the world. Among the six HCV genotypes, genotype 1 was significantly more aggressive when utilizing the combination of pegylated interferon and ribavirin, as genotype 1-infected patients had the lowest likelihood of achieving cure (40%–50% and required twice as long duration of treatment, as compared to genotypes 2 and 3. Recently, however, significant advances have been made with the advent of all-oral direct-acting antiviral agents, which have significantly improved the safety, efficacy, and tolerability of the treatment of HCV genotype 1. Among the available treatments for HCV genotype 1, the combination therapy of ledipasvir/sofosbuvir provides several advantages compared to other regimens, including use of a single-pill regimen, possibility to shorten the duration of treatment to 8 weeks, efficacy in patients exposed to protease inhibitors, safety in decompensated cirrhosis, and potential to avoid ribavirin. In this review, we discuss the pharmacotherapy of the combination of ledipasvir/sofosbuvir therapy and summarize the results of the Phase III clinical trials for this treatment in HCV genotype 1 patients. We will also discuss the data for special populations, including decompensated cirrhosis, human immunodeficiency virus (HIV coinfected patients, African-Americans, the elderly, and those who failed sofosbuvir-containing regimens.Keywords: pegylated interferon, ribavirin, cirrhosis, liver transplantation, direct-acting antiviral

  3. Interferon-α treatment in systemic mastocytosis

    DEFF Research Database (Denmark)

    Bjerrum, Ole Weis

    2011-01-01

    Patients with systemic mastocytosis are rare, constitute a heterogeneous clinical entity and some may not require treatment until long after diagnosis. However, most patients who present with disabling symptoms, organ involvement and fulfill B or C findings as outlined in the 2008 WHO...... classification need treatment. This review on interferon treatment in systemic mastocytosis documents an effect of this biological agent in some patients with mastocytosis. However, the place of interferon-α, as mono- or combination therapy, in the treatment algorithm may only be definitely established...

  4. Interferon-α treatment in systemic mastocytosis

    DEFF Research Database (Denmark)

    Bjerrum, Ole Weis

    2011-01-01

    Patients with systemic mastocytosis are rare, constitute a heterogeneous clinical entity and some may not require treatment until long after diagnosis. However, most patients who present with disabling symptoms, organ involvement and fulfill B or C findings as outlined in the 2008 WHO...... classification need treatment. This review on interferon treatment in systemic mastocytosis documents an effect of this biological agent in some patients with mastocytosis. However, the place of interferon-a, as mono- or combination therapy, in the treatment algorithm may only be definitely established...

  5. Interferon Gamma-1b Injection

    Science.gov (United States)

    Interferon gamma-1b injection is used to reduce the frequency and severity of serious infections in people with chronic ... severe, malignant osteopetrosis (an inherited bone disease). Interferon gamma-1b is in a class of medications called ...

  6. Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer.

    Science.gov (United States)

    Kim, Kenneth H; Jelovac, Danijela; Armstrong, Deborah K; Schwartz, Benjamin; Weil, Susan C; Schweizer, Charles; Alvarez, Ronald D

    2016-02-01

    Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC. This multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5mg/kg plus carboplatin AUC5-6 and pegylated liposomal doxorubicin 30mg/m(2) every 4weeks for 6cycles. Subsequently, maintenance with single-agent farletuzumab 2.5mg/kg once weekly or farletuzumab 7.5mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin. Fifteen patients received a median of 12.0cycles (range, 3-26) of farletuzumab as combination therapy or maintenance, for a median of 45.0weeks (range 9-95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3-4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade ≥3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients. Farletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin. Copyright © 2015 The Authors. Published by Elsevier Inc

  7. The protein corona of circulating PEGylated liposomes.

    Science.gov (United States)

    Palchetti, Sara; Colapicchioni, Valentina; Digiacomo, Luca; Caracciolo, Giulio; Pozzi, Daniela; Capriotti, Anna Laura; La Barbera, Giorgia; Laganà, Aldo

    2016-02-01

    Following systemic administration, liposomes are covered by a 'corona' of proteins, and preserving the surface functionality is challenging. Coating the liposome surface with polyethylene glycol (PEG) is the most widely used anti-opsonization strategy, but it cannot fully preclude protein adsorption. To date, protein binding has been studied following in vitro incubation to predict the fate of liposomes in vivo, while dynamic incubation mimicking in vivo conditions remains largely unexplored. The main aim of this investigation was to determine whether shear stress, produced by physiologically relevant dynamic flow, could influence the liposome-protein corona. The corona of circulating PEGylated liposome was thoroughly compared with that formed by incubation in vitro. Systematic comparison in terms of size, surface charge and quantitative composition was made by dynamic light scattering, microelectrophoresis and nano-liquid chromatography tandem mass spectrometry (nanoLC-MS/MS). Size of coronas formed under static vs. dynamic incubation did not appreciably differ from each other. On the other side, the corona of circulating liposomes was more negatively charged than its static counterpart. Of note, the variety of protein species in the corona formed in a dynamic flow was significantly wider. Collectively, these results demonstrated that the corona of circulating PEGylated liposomes can be considerably different from that formed in a static fluid. This seems to be a key factor to predict the biological activity of a liposomal formulation in a physiological environment. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Safety Assessment of PEGylated oils as used in cosmetics.

    Science.gov (United States)

    Burnett, Christina L; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2014-01-01

    PEGylated oil is a terminology used to describe cosmetic ingredients that are the etherification and esterification products of glycerides and fatty acids with ethylene oxide. The Cosmetic Ingredient Review Expert Panel (Panel) considered the safety of PEGylated oils, which function primarily as surfactants in cosmetic products. The Panel reviewed relevant animal and human data provided in this safety assessment and concluded that the 130 chemically related PEGylated oils were safe as cosmetic ingredients in the present practices of use and concentration when formulated to be nonirritating. © The Author(s) 2014.

  9. Onset of Celiac Disease after Treatment of Chronic Hepatitis C with Interferon Based Triple Therapy

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    Amandeep Singh

    2015-01-01

    Full Text Available Background. Patients treated with interferon (IFN based therapies may develop exacerbation of autoimmune disease. We herein present the case of a 53-year-old female patient who developed celiac disease (CD as a result of triple therapy (interferon, ribavirin, and boceprevir for chronic HCV. Case. 53-year-old Caucasian female with past medical history of IV drug abuse was referred for abnormal LFTs. Laboratory data showed HCV RNA of 4,515,392 IU/mL, HCV genotype 1a, with normal LFTs. She was treated with 4 weeks of pegylated interferon alfa-2a plus ribavirin, followed by triple therapy using boceprevir for a total of 28 weeks. Approximately 4 weeks after initiation of triple therapy patient developed loose nonbloody bowel movements and was also found to have anemia. Biopsies from first and second portions of the duodenum were consistent with CD. The patient was treated with a gluten-free diet. Her intestinal symptoms improved and the hemoglobin returned to normal. Conclusion. Chronic HCV patients being treated with interferon alfa can develop celiac disease during or after therapy. For patients with positive autoantibodies, all-oral-IFN-free regimens should be considered. Celiac disease should be considered in patients who develop CD-like symptoms while on and shortly after cessation of interferon alfa therapy.

  10. Model-Based Investigation on the Mass Transfer and Adsorption Mechanisms of Mono-Pegylated Lysozyme in Ion-Exchange Chromatography.

    Science.gov (United States)

    Morgenstern, Josefine; Wang, Gang; Baumann, Pascal; Hubbuch, Jürgen

    2017-09-01

    Recent studies highlighted the potential of PEGylated proteins to improve stabilities and pharmacokinetics of protein drugs. Ion-exchange chromatography (IEX) is among the most frequently used purification methods for PEGylated proteins. However, the underlying physical mechanisms allowing for a separation of different PEGamers (proteins with a varying number of attached PEG molecules) are not yet fully understood. In this work, mechanistic chromatography modeling is applied to gain a deeper understanding of the mass transfer and adsorption/desorption mechanisms of mono-PEGylated proteins in IEX. Using a combination of the general rate model (GRM) and the steric mass action (SMA) isotherm, simulation results in good agreement with the experimental data are achieved. During linear gradient elution of proteins attached with PEG of different molecular weight, similar peak heights, and peak shapes at constant gradient length are observed. A superimposed effect of increased desorption rate and reduced diffusion rate as a function of the hydrodynamic radius of PEGylated proteins is identified to be the reason of this anomaly. That is why the concept of the diffusion-desorption-compensation effect is proposed. In addition to the altered elution orders, PEGylation results in a considerable decrease of maximum binding capacity. By using the SMA model in a kinetic formulation, the adsorption behavior of PEGylated proteins in the highly concentrated state is described mechanistically. An exponential increase in the steric hindrance effect with increasing PEG molecular weight is observed. This suggests the formation of multiple PEG layers in the interstitial space between bound proteins and an associated shielding of ligands on the adsorber surface to be the cause of the reduced maximum binding capacity. The presented in silico approach thus complements the hitherto proposed theories on the binding mechanisms of PEGylated proteins in IEX. © 2017 The Authors Biotechnology

  11. Hepatic microRNA expression is associated with the response to interferon treatment of chronic hepatitis C

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    Kuroda Masahiko

    2010-10-01

    Full Text Available Abstract Background HCV infection frequently induces chronic liver diseases. The current standard treatment for chronic hepatitis (CH C combines pegylated interferon (IFN and ribavirin, and is less than ideal due to undesirable effects. MicroRNAs (miRNAs are endogenous small non-coding RNAs that control gene expression by degrading or suppressing the translation of target mRNAs. In this study we administered the standard combination treatment to CHC patients. We then examined their miRNA expression profiles in order to identify the miRNAs that were associated with each patient's drug response. Methods 99 CHC patients with no anti-viral therapy history were enrolled. The expression level of 470 mature miRNAs found their biopsy specimen, obtained prior to the combination therapy, were quantified using microarray analysis. The miRNA expression pattern was classified based on the final virological response to the combination therapy. Monte Carlo Cross Validation (MCCV was used to validate the outcome of the prediction based on the miRNA expression profile. Results We found that the expression level of 9 miRNAs were significantly different in the sustained virological response (SVR and non-responder (NR groups. MCCV revealed an accuracy, sensitivity, and specificity of 70.5%, 76.5% and 63.3% in SVR and non-SVR and 70.0%, 67.5%, and 73.7% in relapse (R and NR, respectively. Conclusions The hepatic miRNA expression pattern that exists in CHC patients before combination therapy is associated with their therapeutic outcome. This information can be utilized as a novel biomarker to predict drug response and can also be applied to developing novel anti-viral therapy for CHC patients.

  12. Carbohydrate PEGylation, an approach to improve pharmacological potency

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    M. Eugenia Giorgi

    2014-06-01

    Full Text Available Conjugation with polyethylene glycol (PEG, known as PEGylation, has been widely used to improve the bioavailability of proteins and low molecular weight drugs. The covalent conjugation of PEG to the carbohydrate moiety of a protein has been mainly used to enhance the pharmacokinetic properties of the attached protein while yielding a more defined product. Thus, glycoPEGylation was successfully applied to the introduction of a PEGylated sialic acid to a preexisting or enzymatically linked glycan in a protein. Carbohydrates are now recognized as playing an important role in host–pathogen interactions in protozoal, bacterial and viral infections and are consequently candidates for chemotherapy. The short in vivo half-life of low molecular weight glycans hampered their use but methods for the covalent attachment of PEG have been less exploited. In this review, information on the preparation and application of PEG-carbohydrates, in particular multiarm PEGylation, is presented.

  13. Secondary hyperpigmentation during interferon alfa treatment for chronic hepatitis C virus infection.

    Science.gov (United States)

    Tsilika, Katerina; Tran, Albert; Trucchi, Régine; Pop, Sinziana; Anty, Rodolphe; Cardot-Leccia, Nathalie; Lacour, Jean-Philippe; Ortonne, Jean-Paul; Passeron, Thierry

    2013-06-01

    Interferon alfa remains the central treatment for chronic hepatitis C virus (HCV) infection. Cases of cutaneous and mucous hyperpigmentations during interferon alfa treatment have been reported, but they are considered rare adverse effects. To study the clinical presentation and frequency of hyperpigmentation in patients receiving interferon alfa treatment for chronic HCV infection. Prospective, descriptive clinical trial. Monocentric study performed in the Departments of Hepatology and Dermatology of the University Hospital of Nice, Nice, France. Consecutive patients treated with pegylated interferon alfa-2b and ribavirin for chronic HCV infection. Demographic data and medical history were noted. A systematic clinical and dermoscopic examination of skin, nails, and mucous membranes was performed, and skin biopsies were performed if needed. Of 77 patients who were included, 16 (21%) presented with hyperpigmentation. Hyperpigmentation of the oral mucous membrane, acquired longitudinal melononychia, and hyperpigmentation of the face were each observed in 7 patients (9%). All patients with hyperpigmentation of the skin had skin type III or IV and worked outside without sun protection. The intensity of pigmentation was reported to decrease progressively when interferon treatment was discontinued. Most patients with hyperpigmentation of the oral mucosa also had melanonychia. However, patients with hyperpigmentation of the skin did not have mucosal or nail involvement, suggesting 2 distinct mechanisms. Secondary hyperpigmentation during interferon alfa treatment occurs as an adverse event in 21% of patients, especially in those with dark skin types who have unprotected sun exposure. Physicians should be aware of the adverse effects of interferon treatment and advise patients in the use of sun protection, especially patients with darker skin types.

  14. Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b

    NARCIS (Netherlands)

    Haagsma, Elizabeth B.; Riezebos - Brilman, Annelies; van den Berg, Arie P.; Porte, Robert J.; Niesters, Hubert G. M.

    Hepatitis E virus (HEV) infections are known to run a self-limiting course. Recently, chronic hepatitis E has been described in immunosuppressed patients after solid-organ transplantation. Besides the general recommendation to lower the immunosuppressive medication in these patients, there is

  15. Preparation of PEGylated polymeric nanoprobes with aggregation-induced emission feature through the combination of chain transfer free radical polymerization and multicomponent reaction: Self-assembly, characterization and biological imaging applications.

    Science.gov (United States)

    Wan, Qing; Liu, Meiying; Mao, Liucheng; Jiang, Ruming; Xu, Dazhuang; Huang, Hongye; Dai, Yanfeng; Deng, Fengjie; Zhang, Xiaoyong; Wei, Yen

    2017-03-01

    Self-assembly of amphiphilic luminescent copolymers is a general route to fabricate fluorescent polymeric microparticles (FPMs). In this work, the FPMs with aggregation-induced emission (AIE) feature were fabricated via the combination of the chain transfer free radical polymerization and "one-pot" multicomponent reaction, which conjugated the aldehyde-containing AIE active dye AIE (CHO-An-CHO) and amino-terminated hydrophilic polymer (ATPPEGMA) using mercaptoacetic acid (MTA) as the "lock" molecule. The structure, chemical compositions, optical properties as well as biological properties of the PPEGMA-An-PPEGMA FPMs were characterized and investigated by means of a series of techniques and experiments in detail. We demonstrated the final copolymers showed amphiphilic properties, strong yellow fluorescence and high water dispersibility. Biological evaluation suggested that PPEGMA-An-PPEGMA FPMs possess low cytotoxicity and can be used for cell imaging. More importantly, many other AIE active FPMs are expected to be fabricated using the similar strategy because of the good substrate and monomer applicability of the multicomponent reaction and chain transfer living radical polymerization. Therefore, we could conclude that the strategy described in this work should be of great interest for fabrication of multifunctional AIE active nanoprobes for biomedical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Remodeling of B-Cell Subsets in Blood during Pegylated IFNα-2a Therapy in Patients with Chronic Hepatitis B Infection.

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    Caroline Aspord

    Full Text Available The ultimate goal of pegylated interferon-alfa-2a (Peg-IFN-α therapy in chronic hepatitis B (CHB infection is HBsAg seroconversion. Even though B cells are major mediators of a positive clinical outcome, their modulation during Peg-IFN-α therapy has not yet been described. We investigated here the effects of Peg-IFN-α on eight circulating B-cell subsets thanks to an original multi-gating approach based on CD19, CD27, IgD, CD10, and CD38 markers in patients with CHB treated with nucleos(tide analog alone or in combination with Peg-IFN-α. These dynamic changes were analyzed during the 48-weeks of Peg-IFN-α therapy and up to 2 years after the cessation of treatment. The CD19+CD27-IgD+CD10+CD38high transitional B cells and the CD19+CD27+IgD-CD10-CD38high plasmablasts continuously increased, whereas the CD19+CD27-IgD+CD10-CD38low naive, CD19+CD27+IgD+ natural memory, and CD19+CD27+IgD-CD10-CD38low post-germinal center B cells decreased during the course of Peg-IFNα treatment. Such modulations correlated with a sustained increase in sCD30 levels and the decrease in plasma HBsAg. However, no seroconversion occurred and all parameters returned to baseline after the stop of the treatment. Peg-IFN-α therapy mediates a remodeling of B-cell compartmentalization, without clinical relevance. Our study provides new insights into the immunomodulatory effects of Peg-IFN-α on circulating B-cells, and questioned the benefit of the add-on Peg-IFN-α treatment in CHB.

  17. In vitro IFN-α release from IFN-α- and pegylated IFN-α-loaded poly(lactic-co-glycolic acid) and pegylated poly(lactic-co-glycolic acid) nanoparticles.

    Science.gov (United States)

    Feczkó, Tivadar; Fodor-Kardos, Andrea; Sivakumaran, Muttuswamy; Haque Shubhra, Quazi Tanminul

    2016-08-01

    Interferon alpha (IFN-α) controlled release of nanoparticles was investigated under in vitro conditions. IFN-α and pegylated IFN-α (PEG-IFN-α) were encapsulated by poly(lactic-co-glycolic acid) (PLGA) and pegylated PLGA (PEG-PLGA) copolymers using double emulsion solvent evaporation method. The size of resulting four nanoparticles (IFN-α in poly(lactic-co-glycolic acids), IFN-α in poly(lactic-co-glycolic acid)-polyethylene glycol, PEG-IFN-α in poly(lactic-co-glycolic acids) and PEG-IFN-α in poly(lactic-co-glycolic acid)-polyethylene glycol) was below 130 nm diameter. IFN-α encapsulation efficiency of the nanoparticles was between 78 and 91%. The in vitro drug release studies conducted in phosphate-buffered saline and human plasma highlighted the role of incubation medium on the IFN release from the nanoparticles. The PEG-IFN-α in poly(lactic-co-glycolic acid)-polyethylene glycol was the most promising nanoparticle among the four formulations because of its remarkably constant release in both phosphate-buffered saline and plasma.

  18. Ledipasvir/sofosbuvir fixed-dose combination for treatment of hepatitis C virus genotype 4 infection.

    Science.gov (United States)

    Nehra, V; Tan, E M; Rizza, S A; Temesgen, Z

    2016-02-01

    Hepatitis C virus (HCV) genotype 4 accounts for 8-13% of all chronic HCV infections worldwide. Patients with HCV genotype 4 have been reported to have poor treatment responses to PEGylated interferon and ribavirin regimens. Recently a single tablet, fixed-dose combination of sofosbuvir, an RNA-directed RNA polymerase (NS5B) inhibitor, and ledipasvir, a nonstructural protein 5A (NS5A) inhibitor, has been approved for treatment of chronic HCV infection. Two studies using the fixed-dose combination in chronic HCV genotype 4 for 12 weeks reported sustained virologic response rates at 12 weeks (SVR12) of 93-95%. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 and HIV co-infection. Administered as a single once-daily oral regimen, this ribavirin- and interferon-free regimen is well tolerated, with low potential for adverse effects and represents a significant advancement in the treatment of chronic HCV genotype 4 infection. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

  19. Stability of hepatitis C virus (HCV) RNA levels among interferon-naïve HIV/HCV-coinfected individuals treated with combination antiretroviral therapy.

    Science.gov (United States)

    Grint, D; Peters, L; Reekie, J; Soriano, V; Kirk, O; Knysz, B; Suetnov, O; Lazzarin, A; Ledergerber, B; Rockstroh, J K; Mocroft, A

    2013-07-01

    Infection with hepatitis C virus (HCV) is a major cause of chronic liver disease. High HCV RNA levels have been associated with poor treatment response. This study aimed to examine the natural history of HCV RNA in chronically HCV/HIV-coinfected individuals. Mixed models were used to analyse the natural history of HCV RNA changes over time in HIV-positive patients with chronic HCV infection. A total of 1541 individuals, predominantly White (91%), male (73%), from southern (35%) and western central Europe (23%) and with HCV genotype 1 (58%), were included in the analysis. The median follow-up time was 5.0 years [interquartile range (IQR) 2.8 to 8.3 years]. Among patients not on combination antiretroviral therapy (cART), HCV RNA levels increased by a mean 27.6% per year [95% confidence interval (CI) 6.1-53.5%; P = 0.0098]. Among patients receiving cART, HCV RNA levels were stable, increasing by a mean 2.6% per year (95% CI -1.1 to 6.5%; P = 0.17). Baseline HCV RNA levels were 25.5% higher (95% CI 8.8 to 39.1%; P = 0.0044) in individuals with HCV genotype 1 compared with HCV genotypes 2, 3 and 4. A 1 log HIV-1 RNA copies/mL increase in HIV RNA was associated with a 10.9% increase (95% CI 2.3 to 20.2%; P = 0.012) in HCV RNA. While HCV RNA levels increased significantly in patients prior to receiving cART, among those treated with cART HCV RNA levels remained stable over time. © 2013 British HIV Association.

  20. Separation of mono- and di-PEGylate of exenatide and resolution of positional isomers of mono-PEGylates by preparative ion exchange chromatography.

    Science.gov (United States)

    Nguyen, Ngoc-Thanh Thi; Lee, Jae Sun; Yun, Soi; Lee, E K

    2016-07-29

    Exenatide is a synthetic version of the 39-mer peptide of Exendin-4, which is an FDA-approved therapeutic against Type II diabetes mellitus. However, exenatide has a very short in-serum half-life and PEGylation have been performed to improve its in-serum stability. PEGylation often yields multivalent binding to non-specific residues, and the desired species should be carefully separated by chromatographies. In this study, we first devised an aqueous-phase, two-step PEGylation process. This consists of thiolation of Lys 12 and 27 residues followed by attachment of PEG-maleimide (10kD) to thiol groups. This process yields various species: mono-PEGylates with positional isomers, di-PEGylate, and other higher MW substances. A prep-grade cationic exchange chromatography (HiTrap SP) at pH 3.0 partially separated mono- and di-PEGylates based on the molar ratio of conjugated PEG and peptide and thus molecular weight of the conjugates. To further investigate the chromatographic separation of positional isomers of mono-PEGylates, we prepared two kinds of exenatide analogs by point mutation; K12C and K27C. Each analog was mono-PEGylated with very high yield (>95%). When a mixture of the two positional isomers of mono-PEGylates was applied to HiTrap SP chromatography, K12C-PEGylate and K27C-PEGylate eluted separately at 0.22M and 0.33M NaCl, respectively. When the proportions of acid and its conjugate base of the amino acid residues adjacent to the PEGylation site at pH 3.0 were analyzed, K27C-PEGylate shows stronger positive charge than K12C-PEGylate, and we propose the residence time difference between the two mono-PEGylates could be due to the charge difference. ELISA result shows that the immuno-binding activity of both analogs and their mono-PEGylates are well maintained. Furthermore, both mono-PEGylates of the analogs show higher than 50-fold improved anti-trypsin stability. We expect that mono-PEGylates of the exenatide analogs are alternatives to the conventional C40

  1. Macrophages inhibit human osteosarcoma cell growth after activation with the bacterial cell wall derivative liposomal muramyl tripeptide in combination with interferon

    Science.gov (United States)

    2014-01-01

    Background In osteosarcoma, the presence of tumor-infiltrating macrophages positively correlates with patient survival in contrast to the negative effect of tumor-associated macrophages in patients with other tumors. Liposome-encapsulated muramyl tripeptide (L-MTP-PE) has been introduced in the treatment of osteosarcoma patients, which may enhance the potential anti-tumor activity of macrophages. Direct anti-tumor activity of human macrophages against human osteosarcoma cells has not been described so far. Hence, we assessed osteosarcoma cell growth after co-culture with human macrophages. Methods Monocyte-derived M1-like and M2-like macrophages were polarized with LPS + IFN-γ, L-MTP-PE +/− IFN-γ or IL-10 and incubated with osteosarcoma cells. Two days later, viable tumor cell numbers were analyzed. Antibody-dependent effects were investigated using the therapeutic anti-EGFR antibody cetuximab. Results M1-like macrophages inhibited osteosarcoma cell growth when activated with LPS + IFN-γ. Likewise, stimulation of M1-like macrophages with liposomal muramyl tripeptide (L-MTP-PE) inhibited tumor growth, but only when combined with IFN-γ. Addition of the tumor-reactive anti-EGFR antibody cetuximab did not further improve the anti-tumor activity of activated M1-like macrophages. The inhibition was mediated by supernatants of activated M1-like macrophages, containing TNF-α and IL-1β. However, specific blockage of these cytokines, nitric oxide or reactive oxygen species did not inhibit the anti-tumor effect, suggesting the involvement of other soluble factors released upon macrophage activation. While LPS + IFN-γ–activated M2-like macrophages had low anti-tumor activity, IL-10–polarized M2-like macrophages were able to reduce osteosarcoma cell growth in the presence of the anti-EGFR cetuximab involving antibody-dependent tumor cell phagocytosis. Conclusion This study demonstrates that human macrophages can be induced to exert direct anti

  2. Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer.

    Science.gov (United States)

    Rocca, Andrea; Cecconetto, Lorenzo; Passardi, Alessandro; Melegari, Elisabetta; Andreis, Daniele; Monti, Manuela; Maltoni, Roberta; Sarti, Samanta; Pietri, Elisabetta; Schirone, Alessio; Fabbri, Francesco; Donati, Caterina; Nanni, Oriana; Fedeli, Anna; Faedi, Marina; Amadori, Dino

    2017-05-01

    Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy. In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles. Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported. Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients. NCT02131506 (ClinicalTrials.gov identifier).

  3. The Combined Effects of Training on Serum Levels of Interferon Gamma (INF-γ and Expanded Scale Disability Status Scale of Patients with Multiple Sclerosis at Different Levels of Disability

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    Z Saberi

    2017-02-01

    Full Text Available Background and aim: Multiple sclerosis is a chronic and debilitating nervous system, leading to demyelination of the central nervous system (brain and spinal cord. Regular exercise and general physical activity is important to maintain health and prevent disease, already well known. Therefore the aim of this study was to evaluate the effect of 12 weeks of combined exercises (strength training, Strengthening Exercises, cardio respiratory endurance, a variety of static and dynamic balance exercises, exercises of the trunk (pilates training and walking on the treadmill training with body weight support on interferon gamma and Expanded Disability Status Scale women with multiple sclerosis. Methods: In the present experimental rsearch, female patients who were admitted to the MS Society of Shahrekord, Iran, were divided into three groups based on physical disability scores. In the first group (physical disability scale less than 4.5, 44 people were randomly selected to one experimental group (22 patients and control group (n = 22. In the second group (scale physical disability between 5 and 5.6, 26 patients were enrolled and randomly assigned to an experimental group (n = 13 and control group (n = 13. The third (Physical Disability Scale-up to 6.5, 26 patients were enrolled and randomly assigned to an experimental group (n = 13 and control group (n = 13. A total of 96 patients were participated in this study. Experimental groups of first, second and third were done its own intervention separately. While the control group received stretching exercises, workout schedule for the experimental group was of 12 weeks, three sessions of lasted one hour. Anthropometric factors and interferon-gamma were measured before and after training with the appropriate tools. Serum levels of INF-γ was determind using a commercial ELISA kit and EDSS scores were measured using the measure of disability in patients with MS. Data analysis was performed using descriptive

  4. Genetic Variants in the Apoptosis Gene BCL2L1 Improve Response to Interferon-Based Treatment of Hepatitis C Virus Genotype 3 Infection

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    Louise Nygaard Clausen

    2015-02-01

    Full Text Available Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR to pegylated interferon-α and ribavirin (pegIFN/RBV treatment of HCV genotypes 1 and 3 infections. We conducted a candidate gene association study in a prospective cohort of 201 chronic HCV-infected individuals undergoing treatment with pegIFN/RBV. Differences between groups were compared in logistic regression adjusted for age, HCV viral load and interleukin 28B genotypes. Four single nucleotide polymorphisms (SNPs located in the B-cell lymphoma 2-like 1 (BCL2L1 gene were significantly associated with SVR. SVR rates were significantly higher for carriers of the beneficial rs1484994 CC genotypes. In multivariate logistic regression, the rs1484994 SNP combined CC + TC genotypes were associated with a 3.4 higher odds ratio (OR in SVR for the HCV genotype 3 (p = 0.02. The effect estimate was similar for genotype 1, but the association did not reach statistical significance. In conclusion, anti-apoptotic SNPs in the BCL2L1 gene were predictive of SVR to pegIFN/RBV treatment in HCV genotypes 1 and 3 infected individuals. These SNPs may be used in prediction of SVR, but further studies are needed.

  5. Design and characterization of PEGylated terpolymer biomaterials.

    Science.gov (United States)

    Heath, Daniel E; Cooper, Stuart L

    2010-09-15

    A terpolymer copolymerized from hexyl methacrylate, methyl methacrylate, and poly(ethylene glycol) methacrylate (PEGMA) was synthesized. Polymers containing 0-25 mol % PEGMA were studied. As the mole fraction of PEGMA in the polymer chains increased, the material becomes more hydrophilic as observed by a decrease in the contact angle of water (81 degrees -68 degrees) and an increase in the equilibrium water absorption (0.7-237 wt %). Furthermore, the material shows nonfouling interfacial properties through resistance to protein adsorption and cellular attachment. A total of 1.2 microg/cm(2) fibrinogen, 18,000 HUVECs/cm(2), and 3,000,000 platelets/cm(2) adsorbed or adhered on non-PEGylated materials, whereas very low amounts of protein or cells were observed on materials containing >or=15 mol % PEGMA. Being thermoplastic, the polymer can be processed postsynthesis. To illustrate the processing capabilities of the material, polymer solutions were electrospun into nonwoven fibrous scaffold, which also retained their nonfouling character. (c) 2010 Wiley Periodicals, Inc.

  6. Chronic hepatitis C patients with a post-treatment virological relapse re-treated with an induction dose of 18 MU interferon-alpha in combination with ribavirin and amantadine: a two-arm randomized pilot study

    NARCIS (Netherlands)

    Weegink, C. J.; Sentjens, R. E.; Beld, M. G.; Dijkgraaf, M. G. W.; Reesink, H. W.

    2003-01-01

    Thirty-seven chronic hepatitis C patients with virological relapse (VR) after previous interferon-alpha (IFN) or IFN/ribavirin (Riba) therapy, were re-treated. Patients were randomized for either IFN/Riba and amantadine (Ama) including a 2-week initial high IFN induction course (18 MU IFN daily)

  7. Interferon Gamma in Leishmaniasis

    Science.gov (United States)

    Kima, Peter E.; Soong, Lynn

    2013-01-01

    Leishmaniasis is a complex disease that is caused by parasites of the Leishmania genus. Leishmania are further classified into several complexes, each of which can engage in distinct interactions with mammalian hosts resulting in differing disease presentations. It is therefore not unexpected that host immune responses to Leishmania are variable. The induction of interferon gamma (IFN-γ) and response to it in these infections has received considerable attention. In this review, we summarize our current understanding of some of the host responses during Leishmania infections that are regulated by IFN-γ. In addition, studies that explore the nature of parasite-derived molecular mediators that might affect the host response to IFN-γ are also discussed. PMID:23801993

  8. Interferon Induced Focal Segmental Glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Yusuf Kayar

    2016-01-01

    Full Text Available Behçet’s disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet’s disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon.

  9. Effect of Cytotoxicity of Pegylated Liposomal Recombinant Human ...

    African Journals Online (AJOL)

    Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today 2005; 10: 1451-. 1458. 13. Matteucci ML, Anyarambhatla G, Rosner G, Azuma C,. Fisher PE, Dewhirst MW, Needham D, Thrall DE. Hyperthermia increases accumulation of technetium-. 99m-labeled liposomes in feline sarcomas.

  10. Chemoselective PEGylation of cysteine analogs of human basic ...

    African Journals Online (AJOL)

    Purpose: To improve the stability and bioactivity of human basic fibroblast growth factor (hbFGF) by site-specific pegylation. Methods: Four new mutants of hbFGF were designed with substituted Asp68, Lys77, Glu78 and Arg81 with cysteine with the aid of bioinformatics technique, and then cloned into pET21a plasmid, ...

  11. Clinical evaluation of glycoPEGylated recombinant FVIII

    DEFF Research Database (Denmark)

    Giangrande, Paul; Andreeva, Tatiana; Chowdary, Pratima

    2016-01-01

    Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products...

  12. Evaluation of anti-cancer properties of pegylated ethosomal ...

    African Journals Online (AJOL)

    Purpose: To prepare pegylated ethosomal Paclitaxel® by reverse phase evaporation technique, and evaluate its cytotoxic effect on SK-MEL-3 cell line. Methods: Nanodrug was prepared by reverse phase evaporation technique. The characteristics of the nanoparticles were evaluated by a zetasizer and scanning electron ...

  13. Effects of PEGylation on Liposome Degradation by a Model Phospholipase

    Science.gov (United States)

    Zhang, Pin; Villanueva, Veronica; Donovan, Alexander; Lin, Binhua; Bu, Wei; Liu, Ying; Department Of Chemical Engineering, University Of Illinois At Chicago Team; Center For Advanced Radiation Sources, University Of Chicago Collaboration

    Polyethylene glycol (PEG) has been conjugated to phospholipids to form liposomes with longer blood circulation time, since PEG brushes prevent non-specific protein adsorption and help particles escape phagocytosis. Although PEG provides steric repulsions, it also affects lipid packing and liposome stability. We report here liposomes hydrolysis catalyzed by secreted phospholipase A2 (sPLA2), with an emphasis on revealing the contradictory effects of PEG. The kinetics of liposome hydrolysis were studied by dynamic light scattering. We measured the hydrolysis lag times of liposomes by monitoring the changes in size after mixing with different concentrations of sPLA2. The results followed two exponential functions, defining regimes of degradation kinetics. The effects of PEGylation on the packing of the phospholipid monolayers were studied using X-ray reflectivity and grazing incidence diffraction. The packing of phospholipid monolayers was just slightly disturbed with the inclusion of 5-10% PEGylation (PEG Mw 2000-5000). However, sPLA2 induced hydrolysis of liposomes with higher degrees of PEGylation appeared to be attenuated. In sum, the effects of PEGylation on the protection of lipid assemblies overcomes their disturbance on the lipid packing in the range of our experiments. Author 1-3, 6.

  14. Pegylated polystyrene particles as a model system for artificial cells

    NARCIS (Netherlands)

    Meng, Fenghua; Engbers, G.H.M.; Gessner, Andrea; Müller, Reiner H.; Feijen, Jan

    2004-01-01

    Pegylated polystyrene particles (PS-PEG) were prepared as a model system for artificial cells, by modification of carboxyl polystyrene particles (PS-COOH) with homo- and hetero-bifunctional polyethylene glycols (PEG, MW 1500, 3400, and 5000) containing an amino end group for immobilization and an

  15. Interferon alpha therapy for hepatitis C: treatment completion and response rates among patients with substance use disorders

    Directory of Open Access Journals (Sweden)

    Loftis Jennifer M

    2007-01-01

    Full Text Available Abstract Background Individuals with substance use disorders (SUDs are at increased risk for hepatitis C viral infection (HCV, and few studies have explored their treatment responses empirically. The objective of this study was to assess interferon alpha therapy (IFN completion and response rates among patients with HCV who had a history of comorbid SUDs. More data is needed to inform treatment strategies and guidelines for these patients. Using a medical record database, information was retrospectively collected on 307,437 veterans seen in the Veterans Integrated Service Network 20 (VISN 20 of the Veterans Healthcare Administration (VHA between 1998 and 2003. For patients treated with any type of IFN (including regular or pegylated IFN or combination therapy (IFN and ribavirin who had a known HCV genotype, IFN completion and response rates were compared among patients with a history of SUD (SUD+ Group and patients without a history of SUD (SUD- Group. Results Odds ratio analyses revealed that compared with the SUD- Group, the SUD+ Group was equally likely to complete IFN therapy if they had genotypes 2 and 3 (73.1% vs. 68.0%, and if they had genotypes 1 and 4 (39.5% vs. 39.9%. Within the sample of all patients who began IFN therapy, the SUD- and SUD+ groups were similarly likely to achieve an end of treatment response (genotypes 2 and 3, 52.8% vs. 54.3%; genotypes 1 and 4, 24.5% vs. 24.8% and a sustained viral response (genotypes 2 and 3, 42.6% vs. 41.1%; genotypes 1 and 4: 16.0% vs. 22.3%. Conclusion Individuals with and without a history of SUD responded to antiviral therapy for HCV at similar rates. Collectively, these findings suggest that patients who have co-morbid SUD and HCV diagnoses can successfully complete a course of antiviral therapy.

  16. Rhadinoviral interferon regulatory factor homologues.

    Science.gov (United States)

    Koch, Sandra; Schulz, Thomas F

    2017-07-26

    Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV8) is a gammaherpesvirus and the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman disease. The KSHV genome contains genes for a unique group of proteins with homology to cellular interferon regulatory factors, termed viral interferon regulatory factors (vIRFs). This review will give an overview over the oncogenic, antiapoptotic and immunomodulatory characteristics of KSHV and related vIRFs.

  17. PEGylated chitosan protected silver nanoparticles as water-borne coating for leather with antibacterial property.

    Science.gov (United States)

    Liu, Gongyan; Li, Kaijun; Luo, Quanqing; Wang, Haibo; Zhang, Zongcai

    2017-03-15

    Development of eco-labeled and effectively antibacterial coatings for final leather products has been desiderated both by industry and by consumers. Herein, PEGylated chitosan modified silver nanoparticles (PEG-g-CS@AgNPs) were prepared and characterized by UV-vis spectroscopy, transmission electron microscopy and dynamic light scattering. The antimicrobial activity of such silver nanoparticles was investigated against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus), exhibiting much lower minimum inhibitory concentration (MIC) than chitosan or PEG-g-CS. Water-borne coating was formed by immobilizing the PEG-g-CS@AgNPs onto the leather surface through the electrostatic interaction between amino groups of chitosan and carboxyl groups of leather collagen. Scanning electron microscopy and water contact angle were employed to study the coating's morphology and hydrophilicity, respectively. After coating, leather samples showed significantly high bactericidal efficiency with reusability after release of dead cells from the coating by simply water washing. The excellent antibacterial property of PEG-g-CS@AgNPs coating was ascribed to the combination of bacteria-resistance and bacteria-release by PEGylation, and dual bacteria-killing based on chitosan and Ag + release. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. A magnetic adsorbent-based process for semi-continuous PEGylation of proteins

    DEFF Research Database (Denmark)

    Ottow, Kim Ekelund; Maury, Trine Lütken; Hobley, Timothy John

    2011-01-01

    to minimize reagent consumption. Two streams containing (i) 1.2 g/L trypsin and (ii) 4 g/L magnetic adsorbents derivatized with the reversible affinity ligand benzamidine were pumped into a pipe reactor. At the exit, a third solution of activated PEG (0-40 g/L) was introduced and the solutions immediately fed......A semi-continuous magnetic particle-based process for the controlled attachment of PEG (PEGylation) to proteins is described for the first time. Trypsin and 2 kDa mono-activated PEG were used to systematically develop the steps in the process. Proof of concept was shown in a microfluidics system...... into a second reactor. Upon exiting, the mixture was combined in a third reactor with a fourth stream of free amine groups to stop the reaction (50 mM lysine). The mixture continued into a high-gradient magnetic separator where magnetic supports, with PEGylated trypsin still attached, were captured and washing...

  19. Formulation optimization of itraconazole loaded PEGylated liposomes for parenteral administration by using design of experiments.

    Science.gov (United States)

    Curić, Anamarija; Reul, Regina; Möschwitzer, Jan; Fricker, Gert

    2013-05-01

    The aim of this study was to systematically characterize and optimize the encapsulation process of itraconazole (ITZ) into the PEGylated liposomes. ITZ was used as a model compound for poorly soluble drugs. PEGylated liposomes were prepared using the film hydration method combined with sonication in order to produce small unilamellar vesicles (SUV). The concentration of encapsulated ITZ was measured by a reversed phase-high-performance liquid chromatography (RP-HPLC) method. Systematic characterization of encapsulation process was performed using the design of experiments (DoE) approach. The systematic screening of process parameters and well designed settings of parameter levels in optimization phase improved the ITZ encapsulation process. Optimization demonstrated that only minimal range of design space could be used to achieve the highest encapsulation efficiency (EE (%)), more precisely the EE of 90% was gained using 25mg/ml of lipid and drug loading of 0.3% (w/w). However, the desirable drug loading could be predicted and adjusted by using mathematical modeling behind the DoE approach. The entire encapsulation process was shown to be repeatable with high significance (pDoE plays an important role in optimization experiments leading to robust results supporting high quality. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Pegylated derivatives of recombinant human arginase (rhArg1 for sustained in vivo activity in cancer therapy: preparation, characterization and analysis of their pharmacodynamics in vivo and in vitro and action upon hepatocellular carcinoma cell (HCC

    Directory of Open Access Journals (Sweden)

    Wheatley Denys N

    2009-04-01

    Full Text Available Abstract Background Protein used in medicine, e.g. interferon, are immunogenic and quickly broken down by the body. Pegylation is a recognized way of preserving their integrity and reducing immune reactions, and works well with enzymes used to degrade amino acids, a recent focus of attention in controlling cancer growth. Of the two arginine-degrading enzymes being explored clinically, arginine deiminase is a decidedly foreign mycoplasm-derived enzyme, whereas human arginase 1 is a native liver enzyme. Both have been pegylated, the former with adjuncts of 20 kD, the latter with 5 kD PEG. Pegylation is done by several different methods, not all of which are satisfactory or desirable. Methods The preparation of novel polyethylene glycol (PEG derivatives for modifying proteins is described, but directed specifically at pegylation of recombinant human arginase 1 (rhArg1. rhArg1 expressed in Escherichia coli was purified and coupled in various ways with 5 different PEG molecules to compare their protective properties and the residual enzyme activity, using hepatocellular cell lines both in vitro and in vivo. Results Methoxypolyethylene glycol-succinimidyl propionate (mPEG-SPA 5,000 coupled with very high affinity under mild conditions. The resulting pegylated enzyme (rhArg1-peg5,000 mw had up to 6 PEG chains of 5K length which not only protected it from degradation and any residual immunogenicity, but most importantly let it retain >90% of its native catalytic activity. It remained efficacious in depleting arginine in rats after a single ip injection of 1,500 U of the conjugate as the native enzyme, plasma arginine falling to >0.05 μM from ~170 μM within 20 min and lasting 6 days. The conjugate had almost the same efficacy as unpegylated rhArg1 on 2 cultured human liver cancer (HCC cell lines. It was considerably more effective than 4 other pegylated conjugates prepared. Conclusion Valuable data on the optimization of the pegylation procedure and

  1. Hematologic toxicity associated with interferon-based hepatitis C therapy in HIV type 1-coinfected subjects.

    Science.gov (United States)

    Behler, Caroline M; Vittinghoff, Eric; Lin, Feng; Chung, Raymond T; Peters, Marion G; Robbins, Gregory K; Volberding, Paul A

    2007-05-15

    This study investigates whether dose modifications for adverse hematologic effects or the use of hematopoietic growth factors influenced the outcome of therapy for hepatitis C virus (HCV) infection in patients who were coinfected with HCV and human immunodeficiency virus (HIV) and who were participants in a randomized, controlled trial. Subjects were randomized to receive ribavirin plus interferon-alfa-2a (IFN-alfa-2a) or pegylated IFN-alfa-2a for a total of 48 weeks. Doses were modified for a number of adverse effects (including hematologic toxicity), and hematopoietic growth factors were administered at the discretion of the physician. Associations of dose modifications or initiation of hematopoietic growth factor support with treatment outcomes were determined by standard statistical methods. One hundred thirty-three subjects were included in this study. Subjects treated with pegylated IFN-alfa-2a were more likely to have had dose modifications (dose reduction or discontinuation) than were those treated with IFN-alfa-2a. By multivariate analysis, treatment with pegylated IFN-alfa-2a is associated with higher sustained virologic and/or histologic response. Dose modifications for nonhematologic toxicity are independently associated with lower sustained virologic and/or histologic responses. Although hematologic toxicity was not directly associated with clinical outcome in this analysis, use of hematopoietic growth factors was associated with an increased sustained virologic and/or histologic response. Dose modifications for anti-HCV therapy may adversely affect the outcome of treatment of HCV in individuals who are coinfected with HIV. The use of hematopoietic growth factor support may be associated with an improved clinical response to therapy.

  2. Kinetic and stoichiometric analysis of the modification process for N-terminal PEGylation of staphylokinase.

    Science.gov (United States)

    Wang, Jun; Hu, Tao; Liu, Yongdong; Zhang, Guifeng; Ma, Guanghui; Su, Zhiguo

    2011-05-01

    Staphylokinase (SAK) is a therapeutic protein with promise for thrombolytic therapy of acute myocardial infarction. In this study, polyethylene glycol (PEG) aldehyde was used for N-terminal PEGylation of SAK to improve the pharmacological profiles of SAK. Due to the presence of the competitive PEGylation between the N terminus and the Lys residues, kinetic and stoichiometric analysis was carried out to investigate the process for the N-terminal PEGylation of SAK. To achieve this objective, size exclusion chromatography and tryptic peptide mapping were used to measure the PEGylation extent of SAK molecule and its specific amino acid residues, respectively. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy.

    Directory of Open Access Journals (Sweden)

    Sheeja M Krishnan

    2011-02-01

    Full Text Available The current standard of care for hepatitis C virus (HCV infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in

  4. Stereocomplex-Reinforced PEGylated Polylactide Micelle for Optimized Drug Delivery

    OpenAIRE

    Chunsheng Feng; Meihua Piao; Di Li

    2016-01-01

    The instability of PEGylated polylactide micelles is a challenge for drug delivery. Stereocomplex interaction between racemic polylactide chains with different configurations provides an effective strategy to enhance the stability of micelles as the nanocarriers of drugs. In this work, a stereocomplex micelle (SCM) self-assembled from the amphiphilic triblock copolymers comprising poly(ethylene glycol) (PEG), and dextrorotatory and levorotatory polylactides (PDLA and PLLA) was applied for eff...

  5. Anti-diabetic drugs, insulin and metformin, have no direct interaction with hepatitis C virus infection or anti-viral interferon response

    Directory of Open Access Journals (Sweden)

    Mohamad S. Hakim

    2014-01-01

    Full Text Available Hepatitis C virus (HCV infection is associated with insulin resistance (IR and type 2 diabetes (T2D. Chronic HCV patients with IR and T2D appear to have a decreased response to the standard pegylated-interferon-alpha and ribavirin (PEG-IFN/RBV anti-viral therapy. Insulin and metformin are anti-diabetic drugs regularly used in the clinic. A previous in vitro study has shown a negative effect of insulin on interferon signaling. In the clinic, adding metformin to PEG-IFN/RBV therapy was reported to increase the response rate in chronic HCV patients and it has been suggested this effect derives from an improved anti-viral action of interferon. The goal of this study was to further investigate the molecular insight of insulin and metformin interaction with HCV infection and the anti-viral action of interferon. We used two cell culture models of HCV infection. One is a sub-genomic model that assays viral replication through luciferase reporter gene expression. The other one is a full-length infectious model derived from the JFH1 genotype 2a isolate. We found that both insulin and metformin do not affect HCV infection. Insulin and metformin also do not influence the anti-viral potency of interferon. In addition, there is no direct interaction between these two drugs and interferon signaling. Our results do not confirm the previous laboratory observation that insulin interferes with interferon signaling and suggest that classical nutritional signaling through mTOR may be not involved in HCV replication. If metformin indeed can increase the response rate to interferon therapy in patients, our data indicate that this could be mediated via an indirect mechanisms.

  6. PEGylated graphene oxide elicits strong immunological responses despite surface passivation

    Science.gov (United States)

    Luo, Nana; Weber, Jeffrey K.; Wang, Shuang; Luan, Binquan; Yue, Hua; Xi, Xiaobo; Du, Jing; Yang, Zaixing; Wei, Wei; Zhou, Ruhong; Ma, Guanghui

    2017-02-01

    Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is important to elucidate how synthetic nanomaterials interact with critical biological systems before such products can be safely utilized in humans. Past evidence suggests that polyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatible and elicit less dramatic immune responses than their pristine counterparts. We here report results that contradict these findings. We find that PEGylated graphene oxide nanosheets (nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite not being internalized. Atomistic molecular dynamics simulations support a mechanism by which nGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, thereby amplifying interactions with stimulatory surface receptors. Further experiments demonstrate that nGO-PEG indeed provokes cytokine secretion by enhancing integrin β8-related signalling pathways. The present results inform that surface passivation does not always prevent immunological reactions to 2D nanomaterials but also suggest applications for PEGylated nanomaterials wherein immune stimulation is desired.

  7. Synergistic effect of PEGylated resveratrol on delivery of anticancer drugs.

    Science.gov (United States)

    Wang, Wenlong; Zhang, Liang; Le, Yuan; Chen, Jian-Feng; Wang, Jiexin; Yun, Jimmy

    2016-02-10

    Resveratrol (RES) is a natural polyphenol which can be considered as a nutraceutical because of its benefits such as anticancer and antioxidant activity. In this paper, we designed polymer-RES conjugates as anticancer drug carrier for synergistic therapeutic effect in cancer treatment. Bicalutamide (BIC) was used as a model drug to investigate the drug release behaviors and in vitro anticancer performance. PEG-RES and PEG-Glycine-RES nanoparticles were prepared and characterized. The size of the prepared particles was around 50 nm with RES content of 17.2 and 16.3 wt% for PEG-RES and PEG-Glycine-RES, respectively, and BIC loading efficiency were of 81.6% and 84.5%, separately. Release rate of RES from conjugates depended on the stability of ester group against hydrolysis. BIC release was much faster than RES release. The anticancer activity of BIC loaded PEGylated RES nanoparticles was much better than that of free BIC, indicating the conjugates provided a synergetic cytotoxicity to cancer cells. Confocal laser scanning microscopy observation and flow cytometry analyses indicated that PEGylated RES conjugates were more efficiently internalized into cells, released drug into cytoplasm. These results suggest that PEGylated RES conjugates show great potential for cancer therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Pegylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Markman M

    2011-06-01

    Full Text Available Maurie MarkmanCancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USAAbstract: Pegylated liposomal doxorubicin (PLD has become a major component in the routine management of epithelial ovarian cancer. The drug is frequently employed as a single agent in the platinum-resistant setting, and recently reported data reveal the superiority of the combination of PLD plus carboplatin, compared with the platinum drug plus paclitaxel, in delaying the time to disease progression in women with recurrent (potentially platinum-sensitive disease. Current research efforts involving PLD in ovarian cancer are focusing on adding novel targeted drugs to this cytotoxic agent. The utility of such approaches in the platinum-resistant population, compared with the sequential administration of single agents active in this setting, remains to be determined.Keywords: PLD, carboplatin, paclitaxel, platinum-sensitive, platinum-resistant

  9. Surface analysis of PEGylated nano-shields on nanoparticles installed by hydrophobic anchors

    DEFF Research Database (Denmark)

    Ebbesen, M F; Whitehead, Bradley Joseph; Gonzalez, Borja Ballarin

    2013-01-01

    and cellular interactions. Methods: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared with a hydrophilic PEGylated "nano-shield" inserted at different levels by hydrophobic anchoring using either a phospholipid-PEG conjugate or the copolymer PLGA-block-PEG by an emulsification/diffusion method......Purpose: This work describes a method for functionalisation of nanoparticle surfaces with hydrophilic "nano-shields" and the application of advanced surface characterisation to determine PEG amount and accumulation at the outmost 10 nm surface that is the predominant factor in determining protein....... Surface and bulk analysis was performed including X-ray photoelectron spectroscopy (XPS), nuclear magnetic resonance spectroscopy (NMR) and zeta potential. Cellular uptake was investigated in RAW 264.7 macrophages by flow cytometry. Results: Sub-micron nanoparticles were formed and the combination of (NMR...

  10. Panitumumab and Pegylated Liposomal Doxorubicin in Platinum-Resistant Epithelial Ovarian Cancer With KRAS Wild-Type

    DEFF Research Database (Denmark)

    Steffensen, Karina Dahl; Waldstrøm, Marianne; Pallisgård, Niels

    2013-01-01

    cancer patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. PATIENTS AND METHODS: Major eligibility criteria were relapsed ovarian/fallopian/peritoneal cancer patients with platinum-resistant disease, measurable disease by GCIG CA125 criteria and KRAS wild......OBJECTIVE: The increasing number of negative trials for ovarian cancer treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may improve survival. The aim of this study was to investigate the response rate in platinum-resistant, KRAS wild-type ovarian...

  11. pH-Responsive Structural Change of PEGylated Amine-Bearing Nanogel Explored by Small Angle X-ray Scattering

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Goshu; Shinohara, Yuya; Amemiya, Yoshiyuki [Department of Advanced Materials Science, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561 (Japan); Akiba, Isamu; Sakurai, Kazuo [Department of Chemistry and Biochemistry, University of Kitakyushu (Japan); Tamura, Atsushi; Oishi, Motoi; Nagasaki, Yukio, E-mail: goshu@x-ray.k.u-tokyo.ac.jp [Department of Materials Science, Graduated School of Pure and Applied Science, University of Tsukuba (Japan)

    2011-01-01

    A PEGylated nanogel sphere containing cross-linked amino groups in its core undergoes dramatic volumetric changes upon pH-change. We measured small angle x-ray scattering from the nanogel and analyzed the data with a core-shell sphere model to determine the core size upon pH-change from 8.0 to 5.8. The protonation of the poly-amine core due to the pH-change increased the core volume by over 300%. Combining the obtained core volume and the absolute intensity, we estimated the change of the core electron density.

  12. CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.

    Science.gov (United States)

    Arnaud, Laurent; Hervier, Baptiste; Néel, Antoine; Hamidou, Mohamed A; Kahn, Jean-Emmanuel; Wechsler, Bertrand; Pérez-Pastor, Gemma; Blomberg, Bjørn; Fuzibet, Jean-Gabriel; Dubourguet, François; Marinho, António; Magnette, Catherine; Noel, Violaine; Pavic, Michel; Casper, Jochen; Beucher, Anne-Bérangère; Costedoat-Chalumeau, Nathalie; Aaron, Laurent; Salvatierra, Juan; Graux, Carlos; Cacoub, Patrice; Delcey, Véronique; Dechant, Claudia; Bindi, Pascal; Herbaut, Christiane; Graziani, Giorgio; Amoura, Zahir; Haroche, Julien

    2011-03-10

    Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis, with noncodified therapeutic management and high mortality. No treatment has yet been shown to improve survival in these patients. We conducted a multicenter prospective observational cohort study to assess whether extraskeletal manifestations and interferon-α treatment would influence survival in a large cohort of ECD patients. To achieve this goal, we thoroughly analyzed the clinical presentation of 53 patients with biopsy-proven ECD, and we performed a survival analysis using Cox proportional hazard model. Fifty-three patients (39 men and 14 women) with biopsy-proven ECD were followed up between November 1981 and November 2010. Forty-six patients (87%) received interferon-α and/or PEGylated interferon-α. Multivariate survival analysis using Cox proportional hazard model revealed that central nervous system involvement was an independent predictor of death (hazard ratio = 2.51; 95% confidence interval, 1.28-5.52; P = .006) in our cohort. Conversely, treatment with interferon-α was identified as an independent predictor of survival (hazard ratio = 0.32; 95% confidence interval, 0.14-0.70; P = .006). Although definitive confirmation would require a randomized controlled trial, these results suggest that interferon-α improves survival in ECD patients. This may be seen as a significant advance, as it is the first time a treatment is shown to improve survival in this multisystemic disease with high mortality.

  13. [Alpha-interferon and mental disorders].

    Science.gov (United States)

    Debien, C; De Chouly De Lenclave, M B; Foutrein, P; Bailly, D

    2001-01-01

    The interferon alpha stands as a reference both in oncology and virology. But its efficiency is limited by frequent somatic as well as neuropsychic side effects. As a matter of fact, the reduction or the ending of a chemotherapy treatment come chiefly from the psychiatric complications caused by the use of interferon. For about 30% of patients, various psychic disorders are noticed: personality disorders, mood disorders, anxiety states, suicidal tendencies, manic and psychotic symptoms. We thus propose a review which shall be completed by a discussion on wether the interferon is responsible or not of the appearance of the described mental disorders. We shall conclude with a synthesis of the proposed practical management when confronted with such disorders. Psychiatric complications under interferon-Alpha. The appearance of psychiatric complications caused by interferon has been the subject of many publications. They have also raised the question of the toxicity mechanism which is still misunderstood today. This toxicity appears to be dose-dependent with variations depending on the daily dose given, the mode of administration, the combination with other chemotherapy treatments, the concomitance with a cerebral radiotherapy or a medical history of psychiatric disorders. Most of these effects occur after three weeks of treatment but non specific neuropsychic symptoms can be observed earlier. Non specific symptoms. They appear early but are difficult to detect, though they bring together a whole lot of clinical signs: asthenia, irritability, psychomotor slowdown, depressive mood or even a real "subsyndromic" depressive syndrome, anorexia, decline of the libido, concentration and attention problems, dizzy spells and headaches. Some authors have described intense and fluctuating of personality, mixing anxiety, irritability and disorder of drive control. Depression. Depression is the most frequently found psychiatric pathology in studies but the real frequency of clear

  14. Effects of parental smoking on interferon gamma production in children.

    Science.gov (United States)

    Tebow, Gina; Sherrill, Duane L; Lohman, I Carla; Stern, Debra A; Wright, Anne L; Martinez, Fernando D; Halonen, Marilyn; Guerra, Stefano

    2008-06-01

    Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon gamma and interleukin 4 production at 11 years of age. We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon gamma and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured. Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon gamma production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon gamma production in the child. These dose-response relationships with interferon gamma remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production. Interferon gamma responses of school-aged children are impacted by parental smoking.

  15. In vitro Evaluation of PEGylated-Mucin Matrix as Carrier for Oral ...

    African Journals Online (AJOL)

    Method: Three different formulations of metformin hydrochloride (MTH) (PEG-M1, PEG-M2 and PEGM3) were prepared using PEGylation method. PEG-8000 and snail mucin, in a ratio of 1:3, were PEGylated together using solvent interaction principle. Loading of MTH into the matrix was by diffusion method and the ...

  16. Effects of PEG size on structure, function and stability of PEGylated BSA

    DEFF Research Database (Denmark)

    Plesner, Bitten; Fee, Conan J.; Westh, Peter

    2011-01-01

    . The unfolding temperature and the temperature of aggregation were both independent of the molecular weight of the PEG chain. Possible functional changes of BSA after PEGylation were measured by Isothermal Titration Calorimetry (ITC), where the binding of sodium dodecyl sulphate (SDS) to BSA and PEGylated BSA...

  17. Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

    Directory of Open Access Journals (Sweden)

    Hwankyu Lee

    2014-03-01

    Full Text Available Polyethylene glycol (PEG has been conjugated to many drugs or drug carriers to increase their solubility and circulating lifetime, and reduce toxicity. This has motivated many experimental studies to understand the effect of PEGylation on delivery efficiency. To complement the experimental findings and uncover the mechanism that cannot be captured by experiments, all-atom and coarse-grained molecular dynamics (MD simulations have been performed. This has become possible, due to recent advances in simulation methodologies and computational power. Simulations of PEGylated peptides show that PEG chains wrap antimicrobial peptides and weaken their binding interactions with lipid bilayers. PEGylation also influences the helical stability and tertiary structure of coiled-coil peptides. PEGylated dendrimers and single-walled carbon nanotubes (SWNTs were simulated, showing that the PEG size and grafting density significantly modulate the conformation and structure of the PEGylated complex, the interparticle aggregation, and the interaction with lipid bilayers. In particular, simulations predicted the structural transition between the dense core and dense shell of PEGylated dendrimers, the phase behavior of self-assembled complexes of lipids, PEGylated lipids, and SWNTs, which all favorably compared with experiments. Overall, these new findings indicate that simulations can now predict the experimentally observed structure and dynamics, as well as provide atomic-scale insights into the interactions of PEGylated complexes with other molecules.

  18. Human Leukocyte Antigen-G Is Frequently Expressed in a Multicentric Study on Glioblastoma and May Be Induced in Vitro by Combined 5-aza-2'-deoxycytidine and Interferon-γ Treatments

    DEFF Research Database (Denmark)

    Wastowski, Isabela J; Simões, Renata T; Yaghi, Layale

    2012-01-01

    Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly......-G protein expression was associated with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2'-deoxycytidine treatment and enhanced...... by interferon-γ. HLA-G protein expression was observed in U251MG cells only. These cells exhibited a permissive chromatin state at the HLA-G gene promoter and the highest levels of induced HLA-G transcriptional activity following 5-aza-2'-deoxycytidine treatment. Several antigen-presenting machinery components...

  19. Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

    Science.gov (United States)

    Lawrie, Theresa A; Bryant, Andrew; Cameron, Alison; Gray, Emma; Morrison, Jo

    2013-07-09

    Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs. To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC). We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer. Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software. We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC

  20. [Recent advances in the study of accelerated blood clearance phenomenon of PEGylated liposomes].

    Science.gov (United States)

    Xu, Huan; Wang, Kai-Qian; Huang, Wei-Wei; Deng, Yi-Hui; Chen, Da-Wei

    2010-06-01

    It is generally believed that liposomes modified with polyethylene glycol (PEG) have no or lower immunogenicity. However, based on many recent literatures, when the PEGylated liposomes were repeatedly applied to the same animal, the immune responses occurred. The first injection of PEGylated liposomes resulted in a reduction in the circulation time and an increase in hepatic and splenic accumulation of the second dose of PEGylated liposomes in a time-interval, which was called "accelerated blood clearance (ABC)" phenomenon. Such immunogenicity of PEGylated liposomes presents a barrier in the research of liposomal formulations and their use in the clinics. This review focused on the definition, the method of verification, the development of the reason for ABC phenomenon, influencing factors of ABC phenomenon, and discussed if other PEGylated nanocarriers also induce ABC phenomenon.

  1. Low affinity PEGylated hemoglobin from Trematomus bernacchii, a model for hemoglobin-based blood substitutes

    Science.gov (United States)

    2011-01-01

    Background Conjugation of human and animal hemoglobins with polyethylene glycol has been widely explored as a means to develop blood substitutes, a novel pharmaceutical class to be used in surgery or emergency medicine. However, PEGylation of human hemoglobin led to products with significantly different oxygen binding properties with respect to the unmodified tetramer and high NO dioxygenase reactivity, known causes of toxicity. These recent findings call for the biotechnological development of stable, low-affinity PEGylated hemoglobins with low NO dioxygenase reactivity. Results To investigate the effects of PEGylation on protein structure and function, we compared the PEGylation products of human hemoglobin and Trematomus bernacchii hemoglobin, a natural variant endowed with a remarkably low oxygen affinity and high tetramer stability. We show that extension arm facilitated PEGylation chemistry based on the reaction of T. bernacchii hemoglobin with 2-iminothiolane and maleimido-functionalyzed polyethylene glycol (MW 5000 Da) leads to a tetraPEGylated product, more homogeneous than the corresponding derivative of human hemoglobin. PEGylated T. bernacchii hemoglobin largely retains the low affinity of the unmodified tetramer, with a p50 50 times higher than PEGylated human hemoglobin. Moreover, it is still sensitive to protons and the allosteric effector ATP, indicating the retention of allosteric regulation. It is also 10-fold less reactive towards nitrogen monoxide than PEGylated human hemoglobin. Conclusions These results indicate that PEGylated hemoglobins, provided that a suitable starting hemoglobin variant is chosen, can cover a wide range of oxygen-binding properties, potentially meeting the functional requirements of blood substitutes in terms of oxygen affinity, tetramer stability and NO dioxygenase reactivity. PMID:22185675

  2. The Protein Corona of PEGylated PGMA-Based Nanoparticles is Preferentially Enriched with Specific Serum Proteins of Varied Biological Function.

    Science.gov (United States)

    Naidu, Priya S R; Norret, Marck; Smith, Nicole M; Dunlop, Sarah A; Taylor, Nicolas L; Fitzgerald, Melinda; Iyer, K Swaminathan

    2017-11-14

    The composition of the protein corona formed on poly(ethylene glycol)-functionalized (PEGylated) poly(glycidyl methacrylate) (PGMA) nanoparticles (NPs) was qualitatively and quantitatively compared to the protein corona on non-PEGylated PGMA NPs. Despite the reputation of PEGylated NPs for stealth functionality, we demonstrate the preferential enrichment of specific serum proteins of varied biological function in the protein corona on PEGylated NPs when compared to non-PEGylated NPs. Additionally, we suggest that the base material of polymeric NPs plays a role in the preferential enrichment of select serum proteins to the hard corona.

  3. Alfapeguinterferon-2a e ribavirina versus alfapeguinterferon-2b e ribavirina: avaliação custo-efetividade e do impacto orçamentário do tratamento do genótipo 1 da hepatite C crônica Alfa-pegylated interferons (2a and 2b and ribavirin for treatment chronic hepatitis C, genotype 1: a cost-effectiveness analysis

    Directory of Open Access Journals (Sweden)

    Gabriela Bittencourt Gonzalez Mosegui

    2011-01-01

    Full Text Available Foi realizada análise de custo-efetividade e do impacto orçamentário de tratamentos indicados para adultos infectados com genótipo 1 do vírus da hepatite C, comparando o não-tratamento com terapias combinadas de alfapeguinterferon-2a e 2b associados a ribavirina. O modelo de Markov desenvolvido projetou a evolução da hepatite C em coorte de 1.000 pacientes, por um período de 30 anos, para os vários estados do desenvolvimento da doença. As terapias combinadas da ribavirina com o alfapeguinterferon 2a ou 2b apresentam efetividades estatisticamente idênticas quando avaliadas em 30 anos de evolução da doença. Quanto ao impacto do tratamento nos anos de vida e nos anos de vida ajustados por qualidade de vida; os anos de vida ganhos por qualidade de vida em relação à evolução da doença sem tratamento foram de 1,67 e 1,63, respectivamente, para a terapia combinada com alfapeguinterferon 2a e 2b, aplicando-se 5% de desconto. A estratégia de tratamento com alfapeguinterferon 2a mais ribavirina se revelou mais custo-efetiva, dominando a outra alternativa de tratamento. Embora não haja diferenças significativas de efetividade entre os dois tipos de alfapeguinterferon, a diferença de preço entre os dois medicamentos faz com que a alternativa do uso do alfapeguinterferon 2a mais ribavirina seja mais eficiente. Quanto à estimativa do impacto orçamentário para o período de 2008 a 2017, a utilização do alfapeguinterferon 2a mais ribavirina resulta em redução nos gastos de aproximadamente 19%, caso todos os doentes fossem tratados utilizando-se os esquemas terapêuticos selecionados.A cost-effectiveness and budget impact of treatments given to adults infected with genotype 1 hepatitis C virus was performed by comparing the non-treatment with combined therapy alfapeguinterferon-2a and 2b and ribavirin. The Markov model developed engineered the development of hepatitis C in a cohort of 1,000 patients for a period of 30 years for

  4. Interferon-Mediated Regression of Fibrosis During Antiviral Therapy for Chronic Hepatitis C in Different Variants of IL28B Gene Polymorphism

    Directory of Open Access Journals (Sweden)

    D.Ye. Telegin

    2014-02-01

    Full Text Available The article considers the relationship between the degree of reduction of HCV-induced liver fibrosis by the end of antiviral therapy (AVT for chronic hepatitis C (CHC and the main variants of IL28b gene polymorphism. Materials and Methods. Retrospectively we analyzed the outcomes of treatment of 324 patients who received standard antiviral therapy (a combination of pegylated interferons PegIFN-alpha2b or PegIFN-alpha2a and ribavirin for CHC genotype 1b. The total duration of treatment was 12 months. We evaluated three types of virologic response: rapid (RVR, 4th week of AVT, early (EVR, 12th week of AVT and sustained (SVR, 24th week after the AVT. Results and Discussion. All types of detected changes of fibrosis stages by the end of antiviral treatment in comparison with baseline values were distributed into the following groups : 1 — a significant reduction of fibrosis (25 % of treated patients, 2 — moderate decrease in fibrosis (64 % patients, 3 — unchanged degree of fibrosis (7.6 %, increased fibrosis (3.4 %. A comparison of fibrosis dynamics during antiviral therapy was carried out in the two groups of patients: without (N = 110 and with (N = 214 T-allele of the gene IL28b. The most significant decrease in the degree of fibrosis detected among patients with favorable CC gene IL28b variant, because exactly in this group of patients the frequency of SVR was highest. Among those who have reached sustained aviremia, the lowest degree of reduction of fibrosis was found in T-allele carriers of the gene IL28b. Conclusions. The findings suggest that not all patients with CHC who achieved sustained virologic response escape the risks associated with the effects of viral persistence of HCV.

  5. Interferon-based anti-viral therapy for hepatitis C virus infection after renal transplantation: an updated meta-analysis.

    Directory of Open Access Journals (Sweden)

    Fang Wei

    Full Text Available BACKGROUND: Hepatitis C virus (HCV infection is highly prevalent in renal transplant (RT recipients. Currently, interferon-based (IFN-based antiviral therapies are the standard approach to control HCV infection. In a post-transplantation setting, however, IFN-based therapies appear to have limited efficacy and their use remains controversial. The present study aimed to evaluate the efficacy and safety of IFN-based therapies for HCV infection post RT. METHODS: We searched Pubmed, Embase, Web of Knowledge, and The Cochrane Library (1997-2013 for clinical trials in which transplant patients were given Interferon (IFN, pegylated interferon (PEG, interferon plus ribavirin (IFN-RIB, or pegylated interferon plus ribavirin (PEG-RIB. The Sustained Virological Response (SVR and/or drop-out rates were the primary outcomes. Summary estimates were calculated using the random-effects model of DerSimonian and Laird, with heterogeneity and sensitivity analysis. RESULTS: We identified 12 clinical trials (140 patients in total. The summary estimate for SVR rate, drop-out rate and graft rejection rate was 26.6% (95%CI, 15.0-38.1%, 21.1% (95% CI, 10.9-31.2% and 4% (95%CI: 0.8%-7.1%, respectively. The overall SVR rate in PEG-based and standard IFN-based therapy was 40.6% (24/59 and 20.9% (17/81, respectively. The most frequent side-effect requiring discontinuation of treatment was graft dysfunction (14 cases, 45.1%. Meta-regression analysis showed the covariates included contribute to the heterogeneity in the SVR logit rate, but not in the drop-out logit rate. The sensitivity analyses by the random model yielded very similar results to the fixed-effects model. CONCLUSIONS: IFN-based therapy for HCV infection post RT has poor efficacy and limited safety. PEG-based therapy is a more effective approach for treating HCV infection post-RT than standard IFN-based therapy. Future research is required to develop novel strategies to improve therapeutic efficacy and

  6. Interferon-based therapy decreases risks of hepatocellular carcinoma and complications of cirrhosis in chronic hepatitis C patients.

    Directory of Open Access Journals (Sweden)

    Ching-Sheng Hsu

    Full Text Available Interferon-based therapy (IBT has been the standard of care for hepatitis C virus (HCV infection. However, conflicting results exist regarding the effects of IBT on risk of developing hepatocellular carcinoma (HCC and cirrhosis-associated complications, and most included highly selected patients.This 8-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000 consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance enrollees in 2000 (>23.7 million. Patients with newly detected HCV infections (n=11,264 were classified based on treatment and clinical outcomes. IBTs were defined as regimens that included interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months. The Cox proportional hazards models were used to estimate the hazard ratio (HR and associated confidence interval (CI of HCC and cirrhosis-associated complications for IBT.The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among those who did not. The HCC-free survival rate was significantly higher among patients receiving IBT during the 8-year period than their counterpart (adjusted HR, 0.50; 95% CI, 0.31-0.81; P= .004. Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95% CI, 0.22-0.91; P= .026, hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.21-0.69; P= .001, ascites (adjusted HR, 0.28; 95% CI, 0.14-0.57; P<.001, and cirrhosis (adjusted HR, 0.63; 95% CI, 0.44-0.91; P= .013 were significantly higher among patients who received IBT than those who did not, after adjustment for associated factors.Treatment with interferon may reduce the 8-year risk of HCC and cirrhosis-associated complications in patients with chronic HCV infection.

  7. Effect of PEGylation on Drug Entry into Lipid Bilayer

    DEFF Research Database (Denmark)

    Rissanen, S.; Kumorek, M.; Martinez-Seara, H.

    2014-01-01

    Poly(ethylene glycol) (PEG) is a polymer commonly used for functionalization of drug molecules to increase their bloodstream lifetime, hence efficacy. However, the interactions between the PEGylated drugs and biomembranes are not clearly understood. In this study, we employed atomic-scale molecular...... dynamics (MD) simulations to consider the behavior of two drug molecules functionalized with PEG (tetraphenylporphyrin used in cancer phototherapy and biochanin A belonging to the isoflavone family) in the presence of a lipid bilayer. The commonly held view is that functionalization of a drug molecule...

  8. Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C.

    Science.gov (United States)

    Nanba, Shintaro; Ikeda, Fusao; Baba, Nobuyuki; Takaguchi, Koichi; Senoh, Tomonori; Nagano, Takuya; Seki, Hiroyuki; Takeuchi, Yasuto; Moritou, Yuki; Yasunaka, Tetsuya; Ohnishi, Hideki; Miyake, Yasuhiro; Takaki, Akinobu; Nouso, Kazuhiro; Iwasaki, Yoshiaki; Yamamoto, Kazuhide

    2016-03-01

    Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established. We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera. Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (poxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients. UMIN 000001031. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. Fluorescent proteins as efficient tools for evaluating the surface PEGylation of silica nanoparticles

    Science.gov (United States)

    Zhang, Wei; Ma, Minyan; Zhang, Xiao-ai; Zhang, Ze-yu; Saleh, Sayed M.; Wang, Xu-dong

    2017-06-01

    Surface PEGylation is essential for preventing non-specific binding of biomolecules when silica nanoparticles are utilized for in vivo applications. Methods for installing poly(ethylene glycol) on a silica surface have been widely explored but varies from study to study. Because there is a lack of a satisfactory method for evaluating the properties of silica surface after PEGylation, the prepared nanoparticles are not fully characterized before use. In some cases, even non-PEGylated silica nanoparticles were produced, which is unfortunately not recognized by the end-user. In this work, a fluorescent protein was employed, which acts as a sensitive material for evaluating the surface protein adsorption properties of silica nanoparticles. Eleven different methods were systematically investigated for their reaction efficiency towards surface PEGylation. Results showed that both reaction conditions (including pH, catalyst) and surface functional groups of parent silica nanoparticles play critical roles in producing fully PEGylated silica nanoparticles. Great care needs to be taken in choosing the proper coupling chemistry for surface PEGylation. The data and method shown here will guarantee high-quality PEGylated silica nanoparticles to be produced and guide their applications in biology, chemistry, industry and medicine.

  10. PEGylation enhancement of pH stability of uricase via inhibitive tetramer dissociation.

    Science.gov (United States)

    Tian, Hong; Guo, Yuan; Gao, Xiangdong; Yao, Wenbing

    2013-01-01

    Previously, PEGylated uricase was demonstrated to maintain catalytic activity at pH 5.8, the isoelectric point of uricase, where native uricase ceases to function. To find out whether PEGylation could enhance pH stability of uricase, the enzyme activity to pH curve was completely characterized. Complete characterization of the enzyme activity to pH curve, indicating an inverted bell-shaped relationship not previously documented, is presented. PEGylation enhancement of uricase stability at a pH lower than that commonly found in the liver, can be explored by dynamic dissociation of uricase using ultrafiltration and size-exclusion chromatography. The results suggest the role of PEGylation in enhanced pH stability is via inhibition of subunit disintegration. The mechanism of this effect is characterized by the wrapping of PEG chains around uricase, providing a flexible shell preventing subunit disintegration. The presence of notable PEGylation-induced changes in uricase supports this mechanism and include improved enzyme-substrate affinity and elevated thermal stability. Characterization of PEGylated uricase provides a basis for the rational design of therapeutic PEGylated proteins. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  11. Oxidative Modification of Blood Serum Proteins in Multiple Sclerosis after Interferon Beta and Melatonin Treatment

    Directory of Open Access Journals (Sweden)

    Monika Adamczyk-Sowa

    2017-01-01

    Full Text Available Multiple sclerosis (MS is a disease involving oxidative stress (OS. This study was aimed at examination of the effect of melatonin supplementation on OS parameters, especially oxidative protein modifications of blood serum proteins, in MS patients. The study included 11 control subjects, 14 de novo diagnosed MS patients with the relapsing-remitting form of MS (RRMS, 36 patients with RRMS receiving interferon beta-1b (250 μg every other day, and 25 RRMS patients receiving interferon beta-1b plus melatonin (5 mg daily. The levels of N′-formylkynurenine, kynurenine, dityrosine, carbonyl groups, advanced glycation products (AGEs, advanced oxidation protein products (AOPP, and malondialdehyde were elevated in nontreated RRSM patients. N′-Formylkynurenine, kynurenine, AGEs, and carbonyl contents were decreased only in the group treated with interferon beta plus melatonin, while dityrosine and AOPP contents were decreased both in the group of patients treated with interferon beta and in the group treated with interferon beta-1b plus melatonin. These results demonstrate that melatonin ameliorates OS in MS patients supporting the view that combined administration of interferon beta-1b and melatonin can be more effective in reducing OS in MS patients than interferon beta-1b alone.

  12. DMPD: Type I interferon [corrected] gene induction by the interferon regulatory factorfamily of transcription factors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16979567 Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...ng) (.svg) (.html) (.csml) Show Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...orrected] gene induction by the interferon regulatory factorfamily of transcription factors. Authors Honda K

  13. PEGylated cationic polylactides for hybrid biosynthetic gene delivery.

    Science.gov (United States)

    Jones, Charles H; Chen, Chih-Kuang; Chen, Mingfu; Ravikrishnan, Anitha; Zhang, Hanguang; Gollakota, Akhila; Chung, Taichun; Cheng, Chong; Pfeifer, Blaine A

    2015-03-02

    Genetic vaccination is predicated on the underlying principle that diseases can be prevented by the controlled introduction of genetic material encoding antigenic proteins from pathogenic organisms to elicit the formation of protective immune responses. Driving this process is the choice of carrier that is responsible for navigating the obstacles associated with gene delivery. In this work, we expand upon a novel class of hybrid biosynthetic gene delivery vectors that are composed of a biomaterial outer coating and a bacterial (Escherichia coli) inner core. Specifically, a series of newly developed biodegradable cationic polylactides (CPLAs) and their PEGylated variants were selected to investigate the role of low polydispersity index (PDI), charge density, and PEGylation upon hybrid vector assembly and gene delivery efficacy. Upon assembly, hybrid vectors mediated increased gene delivery beyond that of the individual bacterial vector in isolation, including assays with increasing medium protein content to highlight shielding properties afforded by the PEG-functionalized CPLA component. Furthermore, after extensive characterization of surface deposition of the polymer, results prompted a new model for describing hybrid vector assembly that includes cellular coating and penetration of the CPLA component. In summary, these results provide new options and insight toward the assembly and application of next-generation hybrid biosynthetic gene delivery vectors.

  14. Increased cellular uptake of peptide-modified PEGylated gold nanoparticles.

    Science.gov (United States)

    He, Bo; Yang, Dan; Qin, Mengmeng; Zhang, Yuan; He, Bing; Dai, Wenbing; Wang, Xueqing; Zhang, Qiang; Zhang, Hua; Yin, Changcheng

    2017-12-09

    Gold nanoparticles are promising drug delivery vehicles for nucleic acids, small molecules, and proteins, allowing various modifications on the particle surface. However, the instability and low bioavailability of gold nanoparticles compromise their clinical application. Here, we functionalized gold nanoparticles with CPP fragments (CALNNPFVYLI, CALRRRRRRRR) through sulfhydryl PEG to increase their stability and bioavailability. The resulting gold nanoparticles were characterized with transmission electron microscopy (TEM), dynamic light scattering (DLS), UV-visible spectrometry and X-ray photoelectron spectroscopy (XPS), and the stability in biological solutions was evaluated. Comparing to PEGylated gold nanoparticles, CPP (CALNNPFVYLI, CALRRRRRRRR)-modified gold nanoparticles showed 46 folds increase in cellular uptake in A549 and B16 cell lines, as evidenced by the inductively coupled plasma atomic emission spectroscopy (ICP-AES). The interactions between gold nanoparticles and liposomes indicated CPP-modified gold nanoparticles bind to cell membrane more effectively than PEGylated gold nanoparticles. Surface plasmon resonance (SPR) was used to measure interactions between nanoparticles and the membrane. TEM and uptake inhibitor experiments indicated that the cellular entry of gold nanoparticles was mediated by clathrin and macropinocytosis. Other energy independent endocytosis pathways were also identified. Our work revealed a new strategy to modify gold nanoparticles with CPP and illustrated the cellular uptake pathway of CPP-modified gold nanoparticles. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Pharmacological properties of granulocytic colony-stimulating factor pegylated using electron beam synthesis nanotechnologies.

    Science.gov (United States)

    Dygai, A M; Zyuz'kov, G N; Zhdanov, V V; Madonov, P G; Udut, E V; Miroshnichenko, L A; Khrichkova, T Yu; Simanina, E V; Stavrova, L A; Artamonov, A V; Bekarev, A A; Kinsht, D N; Chaikovskiy, A V; Markova, T S; Gurto, R V

    2011-11-01

    Granulocytic CSF pegylated using electron-beam synthesis nanotechnology exhibits pronounced granulomonocytopoiesis-stimulating and SC-mobilizing activity. More potent stimulation of committed precursors against the background of less pronounced activation of polypotent hemopoietic cells is a peculiarity of hemostimulating action of pegylated using electron-beam synthesis nanotechnology granulocytic CSF in comparison with its non-modified analog. The mobilizing effect of pegylated using electron-beam synthesis nanotechnology granulocytic CSF on early progenitor elements surpasses that of non-conjugated cytokine.

  16. The unexpected effect of PEGylated gold nanoparticles on the primary function of erythrocytes

    Science.gov (United States)

    He, Zeng; Liu, Jiaxin; Du, Libo

    2014-07-01

    Polyethylene glycol-functionalized gold nanoparticles (PEGylated AuNPs) have been widely used as nanocarriers for the delivery of various drugs. However, little attention has been paid to whether the PEGylated AuNPs could affect the primary function of human erythrocytes, which is the main cellular component in the blood. In the current study, we show that both the deformability and oxygen-delivering ability of erythrocytes are decreased when treated with PEGyalted AuNPs of various sizes, which can be attributed to the interaction between PEGylated AuNPs and erythrocyte membranes. It is observed that the PEGylated AuNPs could also induce the aggregation of band-3 and the ATP decrease of erythrocytes. In addition, the PEGylated AuNPs can accelerate the loss of CD47 on erythrocyte membranes, possibly enhancing the senescent process of erythrocytes and the following clearance by SIRPα-expressing leukocytes in bloodstream. The results suggested that PEGylated AuNPs have the potential to affect the primary function of human erythrocytes, which should be considered when using them as drug carriers.Polyethylene glycol-functionalized gold nanoparticles (PEGylated AuNPs) have been widely used as nanocarriers for the delivery of various drugs. However, little attention has been paid to whether the PEGylated AuNPs could affect the primary function of human erythrocytes, which is the main cellular component in the blood. In the current study, we show that both the deformability and oxygen-delivering ability of erythrocytes are decreased when treated with PEGyalted AuNPs of various sizes, which can be attributed to the interaction between PEGylated AuNPs and erythrocyte membranes. It is observed that the PEGylated AuNPs could also induce the aggregation of band-3 and the ATP decrease of erythrocytes. In addition, the PEGylated AuNPs can accelerate the loss of CD47 on erythrocyte membranes, possibly enhancing the senescent process of erythrocytes and the following clearance by

  17. HBcrAg Identifies Patients Failing to Achieve HBeAg Seroconversion Treated with Pegylated Interferon Alfa-2b

    Directory of Open Access Journals (Sweden)

    Hui Ma

    2016-01-01

    Conclusions: Effective antiviral treatment can decrease HBcrAg levels in the serum. The NPVs of HBcrAg for predicting HBeAg seroconversion at 24-week follow-up was 100%, but the PPVs were not satisfactory (all <31%. The serum HBcrAg levels of the patients with HBeAg seroconversion at the end of the 24-week follow-up steadily declined or even became undetectable during the LTFU.

  18. A PILOT AND FEASIBILITY CLINICAL TRIAL EVALUATING IMMUNO-GENE THERAPY OF MALIGNANT PLEURAL MESOTHELIOMA (MPM) USING INTRAPLEURAL DELIVERY OF ADENOVIRUS- INTERFERON-ALPHA (Ad.hIFN-α2b) IN COMBINATION WITH HIGH-DOSE CELECOXIB AND SYSTEMIC CHEMOTHERAPY

    Science.gov (United States)

    Sterman, Daniel H; Alley, Evan; Stevenson, James; Friedberg, Joseph; Metzger, Susan; Recio, Adri; Moon, Edmund; Haas, Andrew R; Vachani, Anil; Katz, Sharyn I; Sun, Jing; Heitjan, Daniel F; Hwang, Wei-Ting; Litzky, Leslie; Yearley, Jennifer H; Tan, Kay See; Papasavvas, Emmanouil; Kennedy, Paul; Montaner, Luis J.; Cengel, Keith; Simone, Charles B; Culligan, Melissa; Langer, Corey J; Albelda, Steven M

    2016-01-01

    Purpose “In situ vaccination” using immuno-gene therapy has the ability to induce polyclonal anti-tumor responses directed by the patient’s immune system. Experimental Design Patients with unresectable MPM received two intrapleural doses of a replication-defective adenoviral vector containing the human interferon-alpha2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Bio-correlates on blood and tumor were measured. Results Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n=7) or gemcitabine (n=15). Treatment was generally well tolerated. The overall response rate was 25% and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with non-epithelial histology. MOS in the first-line cohort was 12.5 months, while MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of interferon-α in blood or pleural fluid, induction of anti-tumor antibodies, nor an immune-gene signature in pretreatment biopsies. Conclusions The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. Overall survival rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. PMID:26968202

  19. Ledipasvir/sofosbuvir fixed-dose combination tablet in Taiwanese patients with chronic genotype 1 hepatitis C virus.

    Science.gov (United States)

    Chuang, Wan-Long; Chien, Rong-Nan; Peng, Cheng-Yuan; Chang, Ting-Tsung; Lo, Gin-Ho; Sheen, I-Shyan; Wang, Horng-Yuan; Chen, Jyh-Jou; Yang, Jenny C; Knox, Steven J; Gao, Bing; Garrison, Kimberly L; Mo, Hongmei; Pang, Phillip S; Hsu, Yu-Chun; Hu, Tsung-Hui; Chu, Chi-Jen; Kao, Jia-Horng

    2016-07-01

    Pegylated-interferon-alpha plus ribavirin is the current standard-of-care regimen for treating chronic hepatitis C virus (HCV) infection in Taiwan; however, interferon-based regimens can be poorly tolerated. The interferon-free, two-drug, fixed-dose combination tablet ledipasvir/sofosbuvir is approved in Europe, the USA, and Japan for treating chronic genotype 1 HCV infection. Little is known about its efficacy/safety in Taiwanese patients. In this multicenter, open-label, phase 3b (NCT02021656) study, 85 Taiwanese patients (n = 42, treatment-naïve; n = 43, treatment-experienced) with chronic genotype 1 HCV infection (±compensated cirrhosis) received 12 weeks of ledipasvir/sofosbuvir fixed-dose combination tablet. The primary efficacy end point was the proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were collected. The overall SVR12 rate was 98% (83/85), with 100% (42/42) and 95% (41/43) of treatment-naïve and treatment-experienced patients, respectively, achieving SVR12. There were no on-treatment virologic failures. One patient relapsed after treatment discontinuation; one patient withdrew consent on day 2. The most common treatment-emergent adverse event (AE) was headache (14%, 12/85). There was one grade 3 AE (small cell lung cancer unrelated to ledipasvir/sofosbuvir), no grade 4 AEs, and four grade 3-4 laboratory abnormalities. Only the patient with small cell lung cancer prematurely discontinued treatment. Two patients reported three serious AEs; none was considered related to ledipasvir/sofosbuvir. Data from this phase 3b study suggest that 12 weeks of once-daily treatment with the interferon-free, ribavirin-free regimen ledipasvir/sofosbuvir is effective and well-tolerated in Taiwanese patients with chronic genotype 1 HCV infection, irrespective of treatment history. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons

  20. Nanostructured aqueous dispersions of citrem interacting with lipids and PEGylated lipids

    DEFF Research Database (Denmark)

    Hedegaard, S.F.; Nilsson, Christa; Laurinmäki, P.

    2013-01-01

    -PEGylated dispersions of citrem. Citrem can be easily dispersed in water in the absence of other surfactant-like lipids without applying high-energy input. However, to investigate the stability and to characterize the internal structure of dispersions with a narrow size distribution, ultrasonication was applied...... for the emulsification of citrem or its binary mixture with PEGylated lipids of poly (ethylene glycol) monooleate with M ∼ 460 (MO-PEG) or M ∼ 860 (MO-PEG) and non-PEGylated lipids (monoolein (MO) or phytantriol (PHYT)). We obtained stable dispersions (>4 months) consisting of particles with highly negative zeta...... X-ray scattering (SAXS), where the effect of partial replacement of citrem by two PEGylated lipids or other well-known lipids (MO and PHYT) was investigated. In addition, cryogenic transmission electron microscopy (cryo-TEM) was applied to characterize the morphology and the internal structure...

  1. Design and characterization of anionic PEGylated liposomal formulation loaded with paclitax for ovarian cancer

    Directory of Open Access Journals (Sweden)

    K Makwana

    2012-01-01

    Full Text Available Despite its strong antitumor activity, paclitaxel (Taxol® has limited clinical applications due to its low aqueous solubility and hypersensitivity caused by cremophor EL and ethanol which is the vehicle used in the current commercial product. In an attempt to develop a pharmaceutically acceptable formulation that could replace Taxol® , we have prepared PEGylated liposomes containing paclitaxel to improve its solubility and physicochemical stability. Its percent drug entrapment (PDE, mean particle size, zeta potential and in vitro release profile were determined. The optimized PEGylated liposomes provided high percent entrapment efficiency (64.29% and mean particle size of 228.6 nm. The electroflocculation method showed 5 mol% of DSPE-mPEG2000 was required to obtain maximum stability for PEGylated liposome. In vitro release data showed its long circulating characteristic. Paclitaxel loaded PEGylated liposomes can be considered a promising long circulating paclitaxel delivery with absence of side effects related to Taxol® .

  2. The Safety of Pegylated Liposomal Doxorubicin Plus Irinotecan in Recurrent Ovarian Cancer Patients: A Phase I Trial.

    Science.gov (United States)

    Miyahara, Daisuke; Ueda, Taeko; Katsuda, Takahiro; Maehara, Miyako; Fukagawa, Satoshi; Miyata, Kohei; Nam, Sung Ouk; Kondo, Haruhiko; Miyamoto, Shingo

    2015-08-01

    The study was designed to evaluate the safety of combined chemotherapy with pegylated liposomal doxorubicin (PLD) and irinotecan (CPT-11) in patients with recurrent ovarian cancer. Six patients with platinum-resistant and taxane-pretreated ovarian cancer were enrolled in the study based on the traditional 3-plus-3 design. PLD was administered intravenously on day 1 and CPT-11 on days 1 and 8 of each 28-day course. Initial doses were 30 mg/m(2) PLD and 50 mg/m(2) CPT-11. Hematotoxicity was the principal toxicity (1 patient developed grade 3 neutropenia and 2 developed grade 3 leukocytopenia); hand-foot syndrome was not observed. Furthermore, 1 patient achieved complete response, whereas 2 patients achieved partial response. The combined PLD and CPT-11 regimen was well-tolerated indicating its potential clinical benefit for ovarian cancer patients. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  3. Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer

    OpenAIRE

    Carmela Pisano; Sabrina Chiara Cecere; Marilena Di Napoli; Carla Cavaliere; Rosa Tambaro; Gaetano Facchini; Cono Scaffa; Simona Losito; Antonio Pizzolorusso; Sandro Pignata

    2013-01-01

    Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then rece...

  4. Interferon-γ Inhibits Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  5. High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment

    DEFF Research Database (Denmark)

    Gonzalez, Veronica D; Falconer, Karolin; Blom, Kim G

    2009-01-01

    Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs......, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic...

  6. PEGylated chitosan complexes DNA while improving polyplex colloidal stability and gene transfection efficiency.

    Science.gov (United States)

    Maurstad, Gjertrud; Stokke, Bjørn T; Vårum, Kjell M; Strand, Sabina P

    2013-04-15

    Chitosan is widely explored as a gene delivery vehicle due to its ability to condense DNA, facilitate transport, and subsequent release allowing gene expression, as well as protecting the DNA. Here, we investigate the enhancement of chitosan-DNA dispersion stability while maintaining transfection efficacy by PEGylation of chitosan. Molecular properties of fully deacetylated chitosans and degree of PEGylation were investigated with respect to compaction of DNA, stability and transfection efficacy. Each of the three chitosan samples with varying chain lengths was PEGylated at three different degrees. The chitosans with degree of PEGylation from 0.6 to 1.9% made polyplexes with DNA. PBS induced colloidal aggregation of polyplexes with initial radius of about 100 nm observed for nonPEGylated chitosans was suppressed for 1.9% PEGylated chitosans. The observed increase in transfection efficacy coinciding with increased polyplex colloidal stability suggests that aggregation of gene-delivery packages may reduce the transfection efficacy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. A tale of the two PEGylated liposomal doxorubicins

    Directory of Open Access Journals (Sweden)

    Chou HH

    2015-07-01

    Full Text Available Hunghsueh Chou,1,4 Hao Lin,2,4 Jacqueline M Liu31Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, Linkou, Taiwan; 2Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Linkou, Taiwan; 3TTY Oncology Translational Research Center, TTY Biopharm, Taipei, Taiwan; 4Chang Gung University College of Medicine, Linkou, TaiwanWe are writing this letter in response to the article "Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era" by Berger et al and published in August 2014.1 This paper is one of the earliest reports of the outcome of using Lipodox® available in the Western medical literature.View original paper by Berger et alCorrigendum for this article has been published

  8. PEGylated IL-10 Activates Kupffer Cells to Control Hypercholesterolemia.

    Directory of Open Access Journals (Sweden)

    Ivan H Chan

    Full Text Available Interleukin-10 (IL-10 is a multifunctional cytokine that exerts potent context specific immunostimulatory and immunosuppressive effects. We have investigated the mechanism by which PEGylated rIL-10 regulates plasma cholesterol in mice and humans. In agreement with previous work on rIL-10, we report that PEGylated rIL-10 harnesses the myeloid immune system to control total plasma cholesterol levels. We have discovered that PEG-rMuIL-10's dramatic lowering of plasma cholesterol is dependent on phagocytotic cells. In particular, PEG-rHuIL-10 enhances cholesterol uptake by Kupffer cells. In addition, removal of phagocytotic cells dramatically increases plasma cholesterol levels, suggesting for the first time that immunological cells are implicitly involved in regulating total cholesterol levels. These data suggest that treatment with PEG-rIL-10 potentiates endogenous cholesterol regulating cell populations not currently targeted by standard of care therapeutics. Furthermore, we show that IL-10's increase of Kupffer cell cholesterol phagocytosis is concomitant with decreases in liver cholesterol and triglycerides. This leads to the reversal of early periportal liver fibrosis and facilitates the restoration of liver health. These data recommend PEG-rIL-10 for evaluation in the treatment of fatty liver disease and preventing its progression to non-alcoholic steatohepatitis. In direct confirmation of our in vivo findings in the treatment of hypercholesterolemic mice with PEG-rMuIL-10, we report that treatment of hypercholesterolemic cancer patients with PEG-rHuIL-10 lowers total plasma cholesterol by up to 50%. Taken together these data suggest that PEG-rIL-10's cholesterol regulating biology is consistent between mice and humans.

  9. Synthesis and biological evaluation of PEGylated CuO nanoparticles.

    Science.gov (United States)

    Giannousi, K; Hatzivassiliou, E; Mourdikoudis, S; Vourlias, G; Pantazaki, A; Dendrinou-Samara, C

    2016-11-01

    There is a growing field of research into the physicochemical properties of metal oxide nanoparticles (NPs) and their potential use against tumor formation, development and progression. Coated NPs with biocompatible surfactants can be incorporated into the natural metabolic pathway of the body and specifically favor delivery to the targeted cancerous cells versus normal cells. Polyethylene glycol (PEG) is an FDA approved, biocompatible synthetic polymer and PEGylated NPs are regarded as "stealth" nanoparticles, which are not recognized by the immune system. Herein, PEGylated cupric oxide nanoparticles (CuO NPs) with either PEG 1000 or PEG 8000 were hydrothermally prepared upon properly adjusting the reaction conditions. Depending on the reaction time CuO NPs in the range of core sizes 11-20nm were formed, while hydrodynamic sizes substantially varied (330-1120nm) with improved colloidal stability in PBS. The anticancer activity of the NPs was evaluated on human cervical carcinoma HeLa cells by using human immortalized embryonic kidney 293 FT cells as a control. Viability assays (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) revealed that CuO NPs could selectively reduce viability of tumor cells (IC50 values 11.91-25.78μg/mL). Reactive oxygen species (ROS) production, cell membrane damage and apoptotic DNA laddering were also evident by nitroblue tetrazolium (NBT) reduction, lactate dehydrogenase (LDH) release assays and DNA electrophoresis, respectively. CuO NPs strongly inhibited lipoxygenase (LOX) enzymatic activity with IC50 values 4-5.9μg/mL, highlighting in that manner their anti-inflammatory activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Cure of hepatitis C virus infection without interferon alfa: scientific basis and current clinical evidence.

    Science.gov (United States)

    Thomas, David L

    2014-01-01

    Cure of hepatitis C virus (HCV) infection is achievable without interferon alfa through the use of new direct-acting antiviral (DAA) drugs. In this era of interferon alfa-sparing therapy, however, interferon alfa sensitivity still matters, even as it turns out, if interferon alfa is not used. Inclusion of ribavirin in the treatment regimen remains a factor in treatment response, as does duration of treatment. HCV genotype and subtype remain relevant considerations in choosing a treatment regimen, and viral resistance may emerge when treatment fails. The potency and barrier to resistance of new DAAs and the use of appropriately designed interferon alfa-sparing combinations can overcome obstacles to cure posed by HCV resistance, interferon alfa resistance, and differences in response based on HCV genotype and subtype. Studies demonstrating the use of new DAAs to overcome these obstacles are discussed. This article summarizes a presentation by David L. Thomas, MD, MPH, at the IAS-USA continuing education program held in New York, New York, in June 2013.

  11. Trisomy 21 consistently activates the interferon response

    Science.gov (United States)

    Sullivan, Kelly D; Lewis, Hannah C; Hill, Amanda A; Pandey, Ahwan; Jackson, Leisa P; Cabral, Joseph M; Smith, Keith P; Liggett, L Alexander; Gomez, Eliana B; Galbraith, Matthew D; DeGregori, James; Espinosa, Joaquín M

    2016-01-01

    Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits. DOI: http://dx.doi.org/10.7554/eLife.16220.001 PMID:27472900

  12. Computational and nonglycosylated systems: a simpler approach for development of nanosized PEGylated proteins

    Directory of Open Access Journals (Sweden)

    Mirzaei H

    2016-03-01

    Full Text Available Hadi Mirzaei,1 Bahram Kazemi,1 Mojgan Bandehpour,1 Alireza Shoari,2 Vahid Asgary,2 Mehdi Shafiee Ardestani,3 Armin Madadkar-Sobhani,4 Reza Ahangari Cohan2 1Department of Biotechnology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Pilot Nanobiotechnology, Pasteur Institute of Iran, Tehran, Iran; 3Department of Radiopharmacy, Pharmacy Faculty, Tehran University of Medical Sciences, Tehran, Iran; 4Faculty of Science, University of Ontario Institute of Technology, Oshawa, Canada Abstract: Cysteine PEGylation includes several steps, and is difficult to manage in practice. In the current investigation, the cysteine PEGylation of erythropoietin analogs was examined using computational and nonglycosylated systems to define a simpler approach for specific PEGylation. Two model analogs (E31C and E89C were selected for PEGylation based on lowest structural deviation from the native form, accessibility, and nucleophilicity of the free thiol group. The selected analogs were cloned and the expression was assessed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and Western blot using Coomassie blue staining and anti-His monoclonal antibody, respectively. PEGylation with 20 kDa mPEG-maleimide resulted in 79% and 82% conjugation yield for E31C and E89C nonglycosylated erythropoietin (ngEPO analogs, respectively. The size distribution and charge analysis showed an increase in size and negative charge of the PEGylated forms compared with nonconjugated ones. Biological assay revealed that E31C and E89C mutations and subsequent PEGylation of ngEPO analogs have no deleterious effects on in vitro biological activity when compared to CHO-derived recombinant human erythropoietin. In addition, PEG-conjugated ngEPOs showed a significant increase in plasma half-lives after injection into rats when compared to nonconjugated ones. The development of the cysteine-PEGylated proteins using nonglycosylated

  13. Production of interferon in respiratory syncytial virus bronchiolitis.

    OpenAIRE

    Isaacs, D

    1989-01-01

    Production of interferon alfa in vitro was significantly reduced during acute respiratory syncytial virus bronchiolitis but subsequently returned to normal. Nasopharyngeal and endotracheal interferon alfa were detected intermittently and in low concentrations. The degree of impairment of in vitro production and poor in vivo production of interferon alfa suggest the need for a therapeutic trial of nebulised or systemic interferon in acute bronchiolitis.

  14. Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection

    DEFF Research Database (Denmark)

    Stylianou, E; Aukrust, P; Bendtzen, K

    2000-01-01

    Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV...... seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-alpha in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART....

  15. PEGylation of carbon nanotubes via mussel inspired chemistry: Preparation, characterization and biocompatibility evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xiaoyong; Zeng, Guangjian; Tian, Jianwen; Wan, Qing; Huang, Qiang [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Wang, Ke; Zhang, Qingsong [Department of Chemistry and the Tsinghua Center for Frontier Polymer Research, Tsinghua University, Beijing 100084 (China); Liu, Meiying; Deng, Fengjie [Department of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang 330031 (China); Wei, Yen, E-mail: xiaoyongzhang1980@gmail.com [Department of Chemistry and the Tsinghua Center for Frontier Polymer Research, Tsinghua University, Beijing 100084 (China)

    2015-10-01

    Graphical abstract: Water dispersible and biocompatible PEGylated carbon nanotubes were prepared via a novel mussel inspired strategy for the first time. - Highlights: • Surface modification of CNTs via bioinspired chemistry. • CNTs with high water dispersibility and excellent biocompatibility. • PEGytion of CNTs via Michael addition reaction. • Preparation of aminated PEG molecules via chain transfer polymerization. - Abstract: A novel strategy for surface modification of multi-walled carbon nanotubes (MWCNT) was developed via combination of mussel inspired chemistry and Michael addition reaction. In this procedure, pristine MWCNT were first coated with polydopamine (PDA) through self polymerization of dopamine. The PDA functionalized CNT (CNT-PDA) were further functionalized with amino-terminated polymers (polyPEGMA), which were synthesized via free radical polymerization using cysteamine hydrochloride as the chain transfer agent and poly(ethylene glycol) monomethyl ether methacylate as the monomer. The successful modification of CNT was ascertained by a series of characterization techniques including transmission electron microscopy, Fourier transform infrared spectroscopy, thermal gravimetric analysis and X-ray photoelectron spectrometry. The polymer modified CNT showed enhanced dispersibility in aqueous and organic solution. Cytotoxicity evaluation of polymers modified CNT showed that these modified CNT are biocompatible with cells. Finally, due to the universal adhesive of PDA and chain transfer free radical polymerization, this strategy developed in this work can also be extended for surface modification of many other nanomaterials with different functional polymers.

  16. Versatile Route to Synthesize Heterobifunctional Poly(ethylene glycol of Variable Functionality for Subsequent Pegylation

    Directory of Open Access Journals (Sweden)

    Redouan Mahou

    2012-02-01

    Full Text Available Pegylation using heterotelechelic poly(ethylene glycol (PEG offers many possibilities to create high-performance molecules and materials. A versatile route is proposed to synthesize heterobifunctional PEG containing diverse combinations of azide, amine, thioacetate, thiol, pyridyl disulfide, as well as activated hydroxyl end groups. Asymmetric activation of one hydroxyl end group enables the heterobifunctionalization while applying selective monotosylation of linear, symmetrical PEG as a key step. The azide function is introduced by reacting monotosyl PEG with sodium azide. A thiol end group is obtained by reaction with sodium hydrosulfide. The activation of the hydroxyl end group and subsequent reaction with potassium carbonate/thioacetic acid yields a thioacetate end group. The hydrolysis of the thioester end group by ammonia in presence of 2,2′-dipyridyl disulfide provides PEG pyridyl disulfide. Amine terminated PEG is prepared either by reduction of the azide or by nucleophilic substitution of mesylate terminated PEG using ammonia. In all cases, >95% functionalization of the PEG end groups is achieved. The PEG derivatives particularly support the development of materials for biomedical applications. For example, grafting up to 13% of the Na-alg monomer units with α-amine-ω-thiol PEG maintains the gelling capacity in presence of calcium ions but simultaneous, spontaneous disulfide bond formation reinforces the initial physical hydrogel.

  17. Pegylated Liposomal Doxorubicin-Induced Acute Transient Encephalopathy in a Patient with Breast Cancer: A Case Report

    Directory of Open Access Journals (Sweden)

    Michelle Baker

    2014-03-01

    Full Text Available Background: Pegylated liposomal doxorubicin (PLD has a unique pharmacokinetic profile and is widely used to treat a variety of malignancies, alone or in combination with other agents. Case Report: A 57-year-old female patient with metastatic breast cancer developed dural metastases to the brain and underwent craniotomy and whole-brain radiation. She continued to receive chemotherapy with carboplatin without any serious complications. Four months later, there was evidence of progression leading to the institution of PLD. During the first course of PLD, there was evidence of acute encephalopathy which resolved after 18 h with discontinuation of this agent. Interestingly, she did well when she was rechallenged with conventional doxorubicin in the following cycles. Conclusion: We hereby report, to the best of our knowledge, the first case of acute transient encephalopathy induced by PLD. We postulate that partial disruption of the blood-brain barrier may have been responsible for PLD-induced encephalopathy.

  18. When nonplatinum is the answer: the role of trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer.

    Science.gov (United States)

    Colombo, Nicoletta

    2017-10-01

    Trabectedin + pegylated liposomal doxorubicin (PLD) offers a well tolerated and effective nonplatinum, nontaxane alternative for treatment of ovarian cancer patients with a treatment-free interval after platinum beyond 6 months, especially for those relapsing between 6 and 12 months and those who are not candidates to receive platinum-based therapy. Using the nonplatinum trabectedin + PLD combination gives patients time to recover from platinum-related toxicities and may restore platinum sensitivity in tumor cells. The sequence effect, by which intercalation of trabectedin + PLD between platinum regimens may enhance the activity of next platinum and improve survival, is currently under investigation in the Phase III prospective INternational OVArian cancer patients Trial with YONdelis.

  19. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha2b in patients with recurrent epithelial ovarian cancer

    NARCIS (Netherlands)

    Dijkgraaf, E.M.; Santegoets, S.J.; Reyners, A.K.; Goedemans, R.; Wouters, M.C.; Kenter, G.G.; Erkel, A.R. van; Poelgeest, M.I.E. van; Nijman, H.W.; Hoeven, J.J.M. van der; Welters, M.J.; Burg, S.H. van der; Kroep, J.R.

    2015-01-01

    BACKGROUND: The immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R;

  20. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha 2b in patients with recurrent epithelial ovarian cancer

    NARCIS (Netherlands)

    Dijkgraaf, E. M.; Santegoets, S. J. A. M.; Reyners, A. K. L.; Goedemans, R.; Wouters, M. C. A.; Kenter, G. G.; van Erkel, A. R.; van Poelgeest, M. I. E.; Nijman, H. W.; van der Hoeven, J. J. M.; Welters, M. J. P.; van der Burg, S. H.; Kroep, J. R.

    2015-01-01

    Background: The immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R;

  1. Management of chronic hepatitis C treatment failures: role of consensus interferon

    Directory of Open Access Journals (Sweden)

    Stevan A Gonzalez

    2009-03-01

    Full Text Available Stevan A Gonzalez1, Emmet B Keeffe21Division of Hepatology, Baylor Regional Transplant Institute, Baylor All Saints Medical Center, Fort Worth and Baylor University Medical Center, Dallas, TX, USA; 2Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USAAbstract: A significant proportion of patients with chronic hepatitis C virus (HCV infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR. Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferonbased therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients.Keywords: consensus interferon, hepatitis C, interferon, nonresponder, relapser

  2. Clinical observation of trabeculectomy with mitomycin and interferon therapy on neovascular glaucoma

    Directory of Open Access Journals (Sweden)

    Dao-Hong Wan

    2015-01-01

    Full Text Available AIM:To understand the clinical effect of trabeculectomy with mitomycin and interferon therapy on neovascular glaucoma.METHODS:Neovascular glaucoma patients in our hospital from January 2011 to January 2013 were sampled, from them, 57 cases(57 eyeswere randomly divided into two groups, control group received routine trabeculectomy for treatment, the experimental group accepted combination therapy of trabeculectomy + mitomycin + interferon. The clinical efficacy of two groups were observed. RESULTS:The total effective rate(96%in experimental group was significantly better than that in the control group(76%, and the visual acuity, filtering bleb and postoperative 1wk, 1a of intraocular pressure changes were better than those of the control group, there was a statistically significant difference(PP>0.05.CONCLUSION:Trabeculectomy combined mitomycin and interferon treatment of neovascular glaucoma has exact clinical effect, and is worthy of clinical popularization and application.

  3. Positional effect of phosphorylation sites 266 and 267 in the cytoplasmic domain of the E2 protein of hepatitis C virus 3a genotype: Interferon Resistance analysis via Sequence Alignment

    Directory of Open Access Journals (Sweden)

    Ur Rehman Irshad

    2011-05-01

    Full Text Available Abstract Background Interferon is well thought-out as the key defence against all infections including HCV. The only treatment for HCV infection is pegylated interferon alpha (IFN-α but unluckily more than half of the infected individuals do not act in response to the cure and become chronic HCV carriers. The mechanism how HCV induce interferon resistance is still elusive. It is recently reported that HCV envelope protein 2 interacts with PKR which is the interferon-inducible protein kinase and which in turn blocks the activity of its target molecule called eukaryotic initiation factor elF2. Sequence analysis of Envelope protein reveals it contains a domain homologous to phosphorylation sites of PKR andthe translation initiation factor eIF2alpha. Envelope protein competes for phosphorylation with PKR. Inhibition of kinase activity of PKR is postulated as a mechanism of to interferon (IFN resistance. Results Present study involves the insilico investigation of possible role of potential phosphorylation in envelope 2 protein of 3a genotype in interferon resistance. Envelope protein coding genes were isolated from local HCV isolates, cloned and sequenced. Phylogenetic analysis was done and tertiary structure of envelope gene was predicted. Visualization of phosphorylation in tertiary structure reveals that residue 266 and 267 of envelope gene 2 are surface exposed and their phosphorylation may compete with the phosphorylation of PKR protein and possibly involved in mediating Interferon Resistance. Conclusion A hybrid in-silico and wet laboratory approach of motif prediction, evolutionary and structural analysis has pointed out serine 266 and 267 of the HCV E2 gene as a hopeful claimant for the serine phosphorylation. Recognition of these nucleotide variations may assist to propose genotype precise therapy to avoid and resolve HCV infections.

  4. A Phase II clinical trial of pegylated liposomal doxorubicin and carboplatin in Japanese patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer.

    Science.gov (United States)

    Nakanishi, Toru; Aoki, Daisuke; Watanabe, Yoh; Ando, Yuichi; Tomotsugu, Naoki; Sato, Yuji; Saito, Toshiaki

    2015-05-01

    This single-arm Phase II trial was designed to assess the safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer. Patients with a histological diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, who were relapse-free at least 6 months after completion of first-line platinum-based chemotherapy, and who had measurable disease and gave consent to participate in this study received infusions of pegylated liposomal doxorubicin (30 mg/m(2)) at 1 mg/min, followed by carboplatin (AUC 5 mg min/ml) over 30 min every 28 days. Thirty-three of 35 enrolled patients were eligible for efficacy analysis. One patient (3.0%) achieved a complete response, while 16 (48.5%) achieved a partial response, with an overall objective response rate of 51.5% (95% confidence interval, 34.5-68.6%). Among the 22 patients who had evaluable CA125 levels at entry, responses were observed in 18 patients, with a response rate of 81.8% (95% confidence interval, 65.3-98.3%). The median progression-free survival and overall survival rates for all 35 patients were 10.7 months (95% confidence interval, 8.1-13.2 months) and 38.8 months (95% confidence interval, 31.0-46.7 months), respectively. The most frequent Grade 3-4 toxicities, regardless of cause, were neutropenia (82.9%), thrombocytopenia (51.4%), leukopenia (45.7%) and anemia (17.1%). The safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer were confirmed. Although there were concerns of severe hematological toxicity with this therapy, this potential complication was safely managed through adequate monitoring of bone marrow function. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Minghui; Qian, Junmin, E-mail: jmqian@mail.xjtu.edu.cn; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid “burst” release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)–doxorubicin (PEG–DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG–DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG–DOX prodrug were confirmed by {sup 1}H NMR analysis. The PEG–DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG–DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy. - Highlights: • A novel stimuli-responsive PEGylated prodrugs is synthesized. • PEGylated prodrugs can self-assemble into spherical nanoparticles (140 nm

  6. Folate-decorated PEGylated triblock copolymer as a pH/reduction dual-responsive nanovehicle for targeted intracellular co-delivery of doxorubicin and Bcl-2 siRNA.

    Science.gov (United States)

    Suo, Aili; Qian, Junmin; Xu, Minghui; Xu, Weijun; Zhang, Yaping; Yao, Yu

    2017-07-01

    Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanovehicle has emerged as a promising combination therapy approach to treating cancers because of their synergistic effect. Nanocarrier delivery systems with low cytotoxicity and high efficiency are needed for such a purpose. In this study, a novel folate-conjugated PEGylated cationic triblock copolymer, poly(acrylhydrazine)-block-poly(3-dimethylaminopropyl methacrylamide)-block-poly(acrylhydrazine) (PAH-b-PDMAPMA-b-PAH), was synthesized and evaluated as a stimuli-sensitive vehicle for the targeted co-delivery of doxorubicin (DOX) and Bcl-2 siRNA into breast cancer MCF-7 cells. The synthetic process of the PEGylated triblock copolymer involved sequential reversible addition-fragmentation chain transfer polymerization, PEGylation and removal of tert-butoxy carbamate protecting groups. Folate-conjugated and/or -unconjugated poly(ethylene glycol) segments were grafted onto PAH-b-PDMAPMA-b-PAH via a reduction-sensitive disulfide linkage. The synthetic polymers were characterized by 1 H NMR and gel permeation chromatography. The PEGylated triblock copolymer could chemically conjugate DOX onto PAH blocks via pH-responsive hydrazone bonds and simultaneously complex negatively charged Bcl-2 siRNA with cationic PDMAPMA blocks through electrostatic interactions at N/P ratios≥32:1 to form multifunctional nanomicelleplexes. The nanomicelleplexes exhibited spherical shape, possessed a positively charged surface with a zeta potential of +22.5mV and had a desirable and uniform particle size of 187nm. In vitro release studies revealed that the nanomicelleplexes could release DOX and Bcl-2 siRNA in a reduction and pH dual-sensitive manner and the payload release was significantly enhanced in a reductive acidic environment mimicking the endosomes/lysosomes of cancer cells compared to under physiology conditions. Furthermore, the release of both DOX and siRNA was found to follow Higuchi kinetic

  7. The efficacy and safety of adjuvant interferon-alfa therapy in the evolving treatment landscape for resected high-risk melanoma.

    Science.gov (United States)

    Trinh, Van Anh; Zobniw, Chrystia; Hwu, Wen-Jen

    2017-08-01

    Patients with resected stage II or III melanoma are at high risk of recurrence, with 5-year mortality rate of 40-60%. Adjuvant interferon-alfa has demonstrated a small RFS and OS benefit versus observation in this patient population. However, the adjuvant treatment landscape is evolving rapidly. Areas covered: This review aims to summarize the safety and efficacy profiles of adjuvant IFNα/PEG-IFNα, revisit the controversy surrounding its application, and reappraise its position in the rapidly changing treatment landscape of resected melanoma. A literature search using PubMed database was undertaken using search words melanoma, interferon-alfa, pegylated interferon-alfa, adjuvant therapy. Expert opinion: Currently, there is no international consensus regarding the optimal dosing schedule for adjuvant IFNα, but HD IFNα-2b remains the most widely used regimen. The AEs of HD IFNα-2b are substantial; however, toxicity management experience amassed over the past 2 decades has significantly improved safety. Many exciting studies are ongoing to examine the roles of immune checkpoint inhibitors and BRAF-targeted therapies in the adjuvant setting and will further delineate the role of adjuvant IFNα.

  8. Stereocomplex-Reinforced PEGylated Polylactide Micelle for Optimized Drug Delivery

    Directory of Open Access Journals (Sweden)

    Chunsheng Feng

    2016-04-01

    Full Text Available The instability of PEGylated polylactide micelles is a challenge for drug delivery. Stereocomplex interaction between racemic polylactide chains with different configurations provides an effective strategy to enhance the stability of micelles as the nanocarriers of drugs. In this work, a stereocomplex micelle (SCM self-assembled from the amphiphilic triblock copolymers comprising poly(ethylene glycol (PEG, and dextrorotatory and levorotatory polylactides (PDLA and PLLA was applied for efficient drug delivery. The spherical SCM showed the smallest scale and the lowest critical micelle concentration (CMC than the micelles with single components attributed to the stereocomplex interaction between PDLA and PLLA. 10-Hydroxycamptothecin (HCPT as a model antitumor drug was loaded into micelles. Compared with the loading micelles from individual PDLA and PLLA, the HCPT-loaded SCM exhibited the highest drug loading efficiency (DLE and the slowest drug release in phosphate-buffered saline (PBS at pH 7.4, indicating its enhanced stability in circulation. More fascinatingly, the laden SCM was demonstrated to have the highest cellular uptake of HCPT and suppress malignant cells most effectively in comparison to the HCPT-loaded micelles from single copolymer. In summary, the stereocomplex-enhanced PLA–PEG–PLA micelle may be promising for optimized drug delivery in the clinic.

  9. A new class of pegylated plasmonic liposomes: synthesis and characterization.

    Science.gov (United States)

    Stiufiuc, Rares; Iacovita, Cristian; Stiufiuc, Gabriela; Florea, Adrian; Achim, Marcela; Lucaciu, Constantin M

    2015-01-01

    The multifunctional nanoobjects that can be controlled, manipulated and triggered using external stimuli represent very promising candidates for nanoscale therapeutic and diagnostic applications. In this study we report the successful synthesis and characterization of a new class of very stable multifunctional nanoobjects, containing cationic liposomes decorated with PEGylated gold nanoparticles (PEGAuNPs). The multifunctional hybrid nanoobjects (mHyNp) were prepared by taking advantage of the electrostatic interactions between small unilamelar cationic liposomes and negatively charged gold nanoparticles. The mHyNps have been investigated by UV-VIS absorption spectroscopy, Dynamic Light Scattering (DLS), Zeta Potential Measurements and Transmission Electron Microscopy (TEM). The TEM images clearly revealed the attachment of individual gold nanoparticles onto the spherical outer surface of the cationic liposomes which was also confirmed by DLS and UV-VIS data. Furthermore, the plasmonic properties of the hybrid complexes have been evaluated by using the Surface Enhanced Raman Spectroscopy (SERS) technique. It is shown that PEG mediated interaction between the liposomes and the gold nanoparticles enabled the recording of the SER spectra of the liposomes in aqueous environment, thus demonstrating the plasmonic properties of the hybrids. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy

    Science.gov (United States)

    Su, Yu-Cheng; Burnouf, Pierre-Alain; Chuang, Kuo-Hsiang; Chen, Bing-Mae; Cheng, Tian-Lu; Roffler, Steve R.

    2017-06-01

    Triple-negative breast cancer (TNBC) lacks effective treatment options due to the absence of traditional therapeutic targets. The epidermal growth factor receptor (EGFR) has emerged as a promising target for TNBC therapy because it is overexpressed in about 50% of TNBC patients. Here we describe a PEG engager that simultaneously binds polyethylene glycol and EGFR to deliver PEGylated nanomedicines to EGFR+ TNBC. The PEG engager displays conditional internalization by remaining on the surface of TNBC cells until contact with PEGylated nanocarriers triggers rapid engulfment of nanocargos. PEG engager enhances the anti-proliferative activity of PEG-liposomal doxorubicin to EGFR+ TNBC cells by up to 100-fold with potency dependent on EGFR expression levels. The PEG engager significantly increases retention of fluorescent PEG probes and enhances the antitumour activity of PEGylated liposomal doxorubicin in human TNBC xenografts. PEG engagers with specificity for EGFR are promising for improved treatment of EGFR+ TNBC patients.

  11. PEGYLATION OF αα-Hb USING SUCCINIMIDYL PROPIONIC ACID PEG 5K

    Science.gov (United States)

    Meng, Fantao; Tsai, Amy G.; Intaglietta, Marcos; Acharya, Seetharama A.

    2014-01-01

    PEGylation of intramolecularly crosslinked Hb has been studied here to overcome the limitation of dissociation of Hb tetramers. New hexa and deca PEGylated low oxygen affi nity PEG-αα-Hbs have been generated. Infl uence of PEG conjugation chemistry and the PEG shell structure on the functional properties as well as PEGylation induced plasma expander like properties of the protein has been delineated. The results have established that in the design of PEG-Hbs as oxygen therapeutics, the infl uence of conjugation chemistry and the PEG shell structure on the oxygen affi nity of Hb needs to be optimized independently besides optimizing the PEG shell structure for inducing resuscitation fluid like properties. PMID:24597567

  12. PEGylated versus non-PEGylated magnetic nanoparticles as camptothecin delivery system

    Directory of Open Access Journals (Sweden)

    Paula M. Castillo

    2014-08-01

    Full Text Available Camptothecin (CPT; (S-(+-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H-dione is a highly cytotoxic natural alkaloid that has not yet found use as chemotherapeutic agent due to its poor water-solubility and chemical instability and, as a consequence, no effective administration means have been designed. In this work, camptothecin has been successfully loaded into iron oxide superparamagnetic nanoparticles with an average size of 14 nm. It was found that surface modification of the nanoparticles by polyethylene glycol enables loading a large amount of camptothecin. While the unloaded nanoparticles do not induce apoptosis in the H460 lung cancer cell line, the camptothecin-loaded nanoparticle formulations exhibit remarkable pro-apoptotic activity. These results indicate that camptothecin retains its biological activity after loading onto the magnetic nanoparticles. The proposed materials represent novel materials based on naturally occurring bioactive molecules loaded onto nanoparticles to be used as chemotherapeutic formulations. The procedure seems apt to be extended to other active molecules extracted from natural products. In addition, these materials offer the potential of being further implemented for combined imaging and therapeutics, as magnetic nanoparticles are known to be multifunctional tools for biomedicine.

  13. Modelling of electrokinetic phenomena for capture of PEGylated ribonuclease A in a microdevice with insulating structures

    Science.gov (United States)

    Mata-Gomez, Marco A.; Rito-Palomares, Marco

    2016-01-01

    Synthesis of PEGylated proteins results in a mixture of protein-polyethylene glycol (PEG) conjugates and the unreacted native protein. From a ribonuclease A (RNase A) PEGylation reaction, mono-PEGylated RNase A (mono-PEG RNase A) has proven therapeutic effects against cancer, reason for which there is an interest in isolating it from the rest of the reaction products. Experimental trapping of PEGylated RNase A inside an electrokinetically driven microfluidic device has been previously demonstrated. Now, from a theoretical point of view, we have studied the electrokinetic phenomena involved in the dielectrophoretic streaming of the native RNase A protein and the trapping of the mono-PEG RNase A inside a microfluidic channel. To accomplish this, we used two 3D computational models, a sphere and an ellipse, adapted to each protein. The effect of temperature on parameters related to trapping was also studied. A temperature increase showed to rise the electric and thermal conductivities of the suspending solution, hindering dielectrophoretic trapping. In contrast, the dynamic viscosity of the suspending solution decreased as the temperature rose, favoring the dielectrophoretic manipulation of the proteins. Also, our models were able to predict the magnitude and direction of the velocity of both proteins indicating trapping for the PEGylated conjugate or no trapping for the native protein. In addition, a parametric sweep study revealed the effect of the protein zeta potential on the electrokinetic response of the protein. We believe this work will serve as a tool to improve the design of electrokinetically driven microfluidic channels for the separation and recovery of PEGylated proteins in one single step. PMID:27375815

  14. Fluorouracil continuous infusion plus alfa interferon plus oral folinic acid in advanced colorectal cancer

    NARCIS (Netherlands)

    Punt, C. J.; de Mulder, P. H.; Burghouts, J. T.; Wagener, D. J.

    1992-01-01

    Several reports on fluorouracil (5-FU) and alfa interferon (IFN-alpha) combination therapy in patients with advanced colorectal cancer have been published. In our study high-dose continuous infusion 5-FU (60 mg/kg per 48 hours), oral folinic acid (FA) (8 x 90 mg during 5-FU), and IFN-alpha three

  15. Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer.

    Science.gov (United States)

    Pérez-López, María Eva; Curiel, Teresa; Gómez, Jesús García; Jorge, Mónica

    2007-06-01

    The most significant factor predicting response to second-line chemotherapy is the time interval elapsed from the end of chemotherapy to relapse occurrence. Two types of situations may be considered: patients with platinum-sensitive relapse (relapse-free interval longer than 6 months) and patients with platinum-refractory relapse (progression during treatment or relapse-free interval under 6 months). Pegylated liposomal doxorubicin is a doxorubicin formulation. Encapsulation in liposomes confers it different pharmacokinetic characteristics and a more favorable toxicity profile. The following review examines the efficacy and safety of pegylated liposomal doxorubicin for the treatment of relapsing epithelial ovarian cancer.

  16. Preparation and evaluation of PEGylated phospholipid membrane coated layered double hydroxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Mina Yan

    2016-06-01

    Full Text Available The aim of the present study was to develop layered double hydroxide (LDH nanoparticles coated with PEGylated phospholipid membrane. By comparing the size distribution and zeta potential, the weight ratio of LDH to lipid materials which constitute the outside membrane was identified as 2:1. Transmission electron microscopy photographs confirmed the core-shell structure of PEGylated phospholipid membrane coated LDH (PEG-PLDH nanoparticles, and cell cytotoxicity assay showed their good cell viability on Hela and BALB/C-3T3 cells over the concentration range from 0.5 to 50 μg/mL.

  17. The Effect of Protein PEGylation on Physical Stability in Liquid Formulation

    DEFF Research Database (Denmark)

    Holm, Louise Stenstrup; Mcumber, Aaron; Rasmussen, Jakob Ewald

    2014-01-01

    The presence of micron aggregates in protein formulations has recently attracted increased interest from regulatory authorities, industry, and academia because of the potential undesired side effects of their presence. In this study, we characterized the micron aggregate formation of hen egg......-white lysozyme (Lyz) and its diPEGylated (5 kDa) analog as a result of typical handling stress conditions. Both proteins were subjected to mechanical stress in the absence and presence of silicone oil (SO), elevated temperatures, and freeze-thaw cycles. Flow imaging microscopy showed that PEGylated Lyz formed...... typical handling stresses....

  18. Acquired haemophilia complicated with gastrointestinal bleeding and spontaneous iliopsoas muscle haematoma in a woman with chronic C hepatitis under treatment with pegylated IFN alpha 2a and ribavirin.

    Science.gov (United States)

    Boţianu, Ana-Maria; Demian, Smaranda; Macarie, Ioan; Georgescu, Dan; Oltean, Galafteon; Băţagă, Simona

    2012-03-01

    Acquired haemophilia A is a very rare (1-2 cases per million people) but often life-threatening haemorrhagic disorder characterized by antibodies directed against coagulation factor VIII. We report the case of a 55-year old woman under treatment with Pegylated alpha 2a interferon (IFN) and Ribavirin for chronic viral C hepatitis, who developed a progressive severe haemorrhagic syndrome diagnosed as acquired haemophilia based on supplementary laboratory data (prolonged activated partial thromboplastin time, extremely low factor VIII level - 1%, high titre of factor VIII inhibitor - 30 Bethesda U/ml).The onset was insidious, about three months before presenting to our unit. Antiviral therapy had been stopped three weeks before current admission. Emergency intensive treatment included: haemostatic agents - rFVII (Novoseven), FEIBA (Factor VIII Inhibitor Bypassing Activity), vitamin K, adrenostazin, cryoprecipitate, fresh frozen plasma, as well as immunosuppressive therapy (high dose corticotherapy and cyclophoshamide), immunoglobulins (Humaglobin), prophylactic PPI and antibiotics. The evolution was slowly favourable with the remission of the haemorrhagic syndrome and regression of the iliopsoas muscle haematoma. Clinicians should be aware that acquired forms of haemophilia do exist, representing a rare diagnosis and a therapeutic challenge. To our knowledge, this is the first reported case of acquired haemophilia in Romania, in a patient with chronic viral C hepatitis under antiviral treatment.

  19. Antibody-Hapten Recognition at the Surface of Functionalized Liposomes Studied by SPR: Steric Hindrance of Pegylated Phospholipids in Stealth Liposomes Prepared for Targeted Radionuclide Delivery

    Directory of Open Access Journals (Sweden)

    Eliot. P. Botosoa

    2011-01-01

    Full Text Available Targeted PEGylated liposomes could increase the amount of drugs or radionuclides delivered to tumor cells. They show favorable stability and pharmacokinetics, but steric hindrance of the PEG chains can block the binding of the targeting moiety. Here, specific interactions between an antihapten antibody (clone 734, specific for the DTPA-indium complex and DTPA-indium-tagged liposomes were characterized by surface plasmon resonance (SPR. Non-PEGylated liposomes fused on CM5 chips whereas PEGylated liposomes did not. By contrast, both PEGylated and non-PEGylated liposomes attached to L1 chips without fusion. SPR binding kinetics showed that, in the absence of PEG, the antibody binds the hapten at the surface of lipid bilayers with the affinity of the soluble hapten. The incorporation of PEGylated lipids hinders antibody binding to extents depending on PEGylated lipid fraction and PEG molecular weight. SPR on immobilized liposomes thus appears as a useful technique to optimize formulations of liposomes for targeted therapy.

  20. Interferon-induced depression: prevalence and management.

    Science.gov (United States)

    Scalori, A; Pozzi, M; Bellia, V; Apale, P; Santamaria, G; Bordoni, T; Redaelli, A; Avolio, A; Parravicini, P; Pioltelli, P; Roffi, L

    2005-02-01

    Interferon-induced depression ranges from 0 to 50%. Interferon schedule and a history of psychiatric illnesses are not enough to predict who will develop symptoms and who will not. To assess the prevalence of depression during interferon therapy; to test whether Minnesota Multiphasic Personality Inventory is useful in clinical practice for the early identification of patients at risk of depression; whether and how the depression can be cured. One hundred and eighty-five patients treated with interferon and ribavirin for chronic hepatitis C. Before therapy, all patients underwent a Minnesota Multiphasic Personality Inventory and a clinical examination, specifically for the identification of depressive symptoms. Thirty-one patients developed a psychiatric disorder, 11 of them requiring treatment with anti-depressant drugs. Among the 18 patients with Minnesota Multiphasic Personality Inventory positive tests, 16 developed a psychiatric disorder, 8 of them a severe disorder (sensitivity of 0.58; 0.73 for severe disorders). Among the 154 who did not develop psychiatric side effects, 152 had a negative Minnesota Multiphasic Personality Inventory (specificity: 0.99). Severe psychiatric disorders were successfully treated with anti-depressant drugs. Psychiatric side effects are easy to see during interferon therapy. A psychiatric evaluation should be considered on all patients before treatment. If depression develops, it should be treated aggressively, and selective serotonin re-uptake inhibitors are the anti-depressants of choice.

  1. The evolution of interferon-tau.

    Science.gov (United States)

    Ealy, Alan D; Wooldridge, Lydia K

    2017-11-01

    Thirty years ago, a novel type I interferon (IFN) was identified by molecular cloning of cDNA libraries constructed from RNA extracted from ovine and bovine pre-implantation embryos. This protein was eventually designated as IFN-tau (IFNT) to highlight its trophoblast-dependent expression. IFNT function is not immune related. Instead, it interacts with the maternal system to initiate the establishment and maintenance of pregnancy. This activity is indispensable for the continuation of pregnancy. Our review will describe how IFNT evolved from other type I IFNs to function in this new capacity. IFNT genes have only been identified in pecoran ruminants within the Artiodactyla order (e.g. cattle, sheep, goats, deer, antelope, giraffe). The ancestral IFNT gene emerged approximately 36 million years ago most likely from rearrangement and/or insertion events that combined an ancestral IFN-omega (IFNW) gene with a trophoblast-specifying promoter/enhancer. Since then, IFNT genes have duplicated, likely through conversion events, and mutations have allowed them to adapt to their new function in concert with the emergence of different species. Multiple IFNT polymorphisms have been identified in cattle, sheep and goats. These genes and gene alleles encode proteins that do not display identical antiviral, antiproliferative and antiluteolytic activities. The need for multiple IFNT genes, numerous alleles and distinct activities remains debatable, but the consensus is that this complexity in IFNT expression and biological activity must be needed to provide the best opportunity for pregnancy to be recognized by the maternal system so that gestation may continue. © 2017 Society for Reproduction and Fertility.

  2. Interferon alfa with or without ribavirin for chronic hepatitis C

    DEFF Research Database (Denmark)

    Kjaergard, L L; Krogsgaard, K; Gluud, C

    2001-01-01

    To assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C.......To assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C....

  3. Interferon-alfa treatment of facial infantile haemangiomas

    DEFF Research Database (Denmark)

    Fledelius, Hans C.; Illum, N.; Jensen, H.

    2001-01-01

    ophthalmology, haemangiomas of the face, infancy, Interferon alfa, eye at risk, amblyopia, induced refractive change, ultrasound imaging......ophthalmology, haemangiomas of the face, infancy, Interferon alfa, eye at risk, amblyopia, induced refractive change, ultrasound imaging...

  4. Site-specific PEGylation of hemoglobin at Cys-93(beta): correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain.

    Science.gov (United States)

    Manjula, B N; Tsai, A; Upadhya, R; Perumalsamy, K; Smith, P K; Malavalli, A; Vandegriff, K; Winslow, R M; Intaglietta, M; Prabhakaran, M; Friedman, J M; Acharya, A S

    2003-01-01

    Increasing the molecular size of acellular hemoglobin (Hb) has been proposed as an approach to reduce its undesirable vasoactive properties. The finding that bovine Hb surface decorated with about 10 copies of PEG5K per tetramer is vasoactive provides support for this concept. The PEGylated bovine Hb has a strikingly larger molecular radius than HbA (1). The colligative properties of the PEGylated bovine Hb are distinct from those of HbA and even polymerized Hb, suggesting a role for the colligative properties of PEGylated Hb in neutralizing the vasoactivity of acellular Hb. To correlate the colligative properties of surface-decorated Hb with the mass of the PEG attached and also its vasoactivity, we have developed a new maleimide-based protocol for the site-specific conjugation of PEG to Hb, taking advantage of the unusually high reactivity of Cys-93(beta) of oxy HbA and the high reactivity of the maleimide to protein thiols. PEG chains of 5, 10, and 20 kDa have been functionalized at one of their hydroxyl groups with a maleidophenyl moiety through a carbamate linkage and used to conjugate the PEG chains at the beta-93 Cys of HbA to generate PEGylated Hbs carrying two copies of PEG (of varying chain length) per tetramer. Homogeneous preparations of (SP-PEG5K)(2)-HbA, (SP-PEG10K)(2)-HbA, and (SP-PEG20K)(2)-HbA have been isolated by ion exchange chromatography. The oxygen affinity of Hb is increased slightly on PEGylation, but the length of the PEG-chain had very little additional influence on the O(2) affinity. Both the hydrodynamic volume and the molecular radius of the Hb increased on surface decoration with PEG and exhibited a linear correlation with the mass of the PEG chain attached. On the other hand, both the viscosity and the colloidal osmotic pressure (COP) of the PEGylated Hbs exhibited an exponential increase with the increase in PEG chain length. In contrast to the molecular volume, viscosity, and COP, the vasoactivity of the PEGylated Hbs was not a

  5. Peginterferon alfa-2b and ribavirin in thalassaemia/chronic hepatitis C virus-co-infected non-responder to standard interferon-based.

    Science.gov (United States)

    Hamidah, A; Thambidorai, C R; Jamal, R

    2005-10-01

    We describe a patient with HbE-beta thalassaemia and chronic hepatitis C virus infection (genotype 1a) who was treated successfully with peginterferon alfa-2b and ribavirin, following failure to respond to standard interferon and ribavirin therapy. She had sustained virological response for nearly 24 months after completing peginterferon alfa-2b and ribavirin therapy. Transfusion requirements were significantly increased during combination therapy due to ribavirin-induced haemolysis. The adverse effects of interferon were well tolerated. Combination therapy with peginterferon alfa-2b and ribavirin maybe a feasible treatment option for a subset of thalassaemia/HCV infected non-responders to standard interferon-based therapy.

  6. General Information about Chronic Myeloproliferative Neoplasms

    Science.gov (United States)

    ... of treatment is also called biotherapy or immunotherapy. Interferon alfa and pegylated interferon alpha are biologic agents commonly ... Chemotherapy with or without phlebotomy. Biologic therapy using interferon alfa or pegylated interferon alpha . Low- dose aspirin . Use ...

  7. Treatment Option Overview (Chronic Myeloproliferative Neoplasms)

    Science.gov (United States)

    ... of treatment is also called biotherapy or immunotherapy. Interferon alfa and pegylated interferon alpha are biologic agents commonly ... Chemotherapy with or without phlebotomy. Biologic therapy using interferon alfa or pegylated interferon alpha . Low- dose aspirin . Use ...

  8. Essential Thrombocythemia

    Science.gov (United States)

    ... of treatment is also called biotherapy or immunotherapy. Interferon alfa and pegylated interferon alpha are biologic agents commonly ... Chemotherapy with or without phlebotomy. Biologic therapy using interferon alfa or pegylated interferon alpha . Low- dose aspirin . Use ...

  9. Primary Myelofibrosis

    Science.gov (United States)

    ... of treatment is also called biotherapy or immunotherapy. Interferon alfa and pegylated interferon alpha are biologic agents commonly ... Chemotherapy with or without phlebotomy. Biologic therapy using interferon alfa or pegylated interferon alpha . Low- dose aspirin . Use ...

  10. Chronic Myeloproliferative Neoplasms Treatment

    Science.gov (United States)

    ... of treatment is also called biotherapy or immunotherapy. Interferon alfa and pegylated interferon alpha are biologic agents commonly ... Chemotherapy with or without phlebotomy. Biologic therapy using interferon alfa or pegylated interferon alpha . Low- dose aspirin . Use ...

  11. Treatment Options for Chronic Myeloproliferative Neoplasms

    Science.gov (United States)

    ... of treatment is also called biotherapy or immunotherapy. Interferon alfa and pegylated interferon alpha are biologic agents commonly ... Chemotherapy with or without phlebotomy. Biologic therapy using interferon alfa or pegylated interferon alpha . Low- dose aspirin . Use ...

  12. PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation

    DEFF Research Database (Denmark)

    Brambilla, Davide; Verpillot, Romain; Le Droumaguet, Benjamin

    2012-01-01

    We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the int...

  13. PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs.

    Science.gov (United States)

    Turecek, Peter L; Bossard, Mary J; Schoetens, Freddy; Ivens, Inge A

    2016-02-01

    Modification of biopharmaceutical molecules by covalent conjugation of polyethylene glycol (PEG) molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules and has been used successfully in 12 approved drugs. Both linear and branched-chain PEG reagents with molecular sizes of up to 40 kDa have been used with a variety of different PEG derivatives with different linker chemistries. This review describes the properties of PEG itself, the history and evolution of PEGylation chemistry, and provides examples of PEGylated drugs with an established medical history. A trend toward the use of complex PEG architectures and larger PEG polymers, but with very pure and well-characterized PEG reagents is described. Nonclinical toxicology findings related to PEG in approved PEGylated biopharmaceuticals are summarized. The effect attributed to the PEG part of the molecules as observed in 5 of the 12 marketed products was cellular vacuolation seen microscopically mainly in phagocytic cells which is likely related to their biological function to absorb and remove particles and macromolecules from blood and tissues. Experience with marketed PEGylated products indicates that adverse effects in toxicology studies are usually related to the active part of the drug but not to the PEG moiety. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  14. Hybrid liposomal PEGylated calix[4]arene systems as drug delivery platforms for curcumin

    OpenAIRE

    Drakalska, Elena; Momekova, Denitsa; Manolova, Yana; Budurova, Desislava; Momekov, Georgi; Genova, Margarita; Antonov, Liudmil; Lambov, Nikolay; Rangelov, Stanislav

    2014-01-01

    The tremendous therapeutic potential of curcumin as a chemopreventive, antineoplastic and chemosensitizing agent has failed to progress towards clinical development and commercialization due to its unfavorable physicochemical properties, low aqueous solubility, chemical instability, and pharmacokinetics. The present contribution is focused on the feasibility of using PEGylated calixarene, in particular polyoxyethylene-derivatized tert-butylcalix[4]arene, to prepare various platforms for deliv...

  15. Non-pegylated liposomal doxorubicin for patients with recurrent ovarian cancer: A multicentric phase II trial.

    Science.gov (United States)

    Brucker, Janina; Mayer, Christine; Gebauer, Gerhard; Mallmann, Peter; Belau, Antje Kristina; Schneeweiss, Andreas; Sohn, Christof; Eichbaum, Michael

    2016-08-01

    Patients with non-platinum-sensitive recurrent ovarian cancer have a poor prognosis. Non-pegylated liposomal doxorubicin (Myocet(®)) is a promising drug that may be able to improve treatment for such patients. In the current study, patients with recurrent ovarian cancer relapsing within 12 months after primary treatment received non-pegylated liposomal doxorubicin at 75 mg/m(2) d1q22 and 60 mg/m(2) d1q22 after study dose modification, respectively. There were 29 patients enrolled in the trial, and 124 cycles of non-pegylated liposomal doxorubicin were administered in total. All 29 patients were evaluable for toxicity. The clinical benefit rate (defined as the proportion of patients with either complete remission or partial remission, or with stable disease for >6 months) was 50%. The predominant non-hematological toxicity was nausea and vomiting (18 patients, grade I/II), whilst no palmar plantar erythrodysesthesia was observed. In 3 patients, a grade III hematological toxicity occurred, and the treatment schedule was consequently modified to 60 mg/m(2) d1q22. The findings suggest that non-pegylated liposomal doxorubicin administered in a schedule of 60 mg/m(2) d1q22 is well-manageable and is associated with tolerable non-hematological toxicities (predominantly nausea).

  16. Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Henriksen, Louise Tram; Nersting, Jacob; Raja, Raheel A

    2014-01-01

    . The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m(2) i.m. every second week, and to correlate CSF asparagine concentration with serum L-asparaginase enzyme activity. Danish children (1-17 years) with ALL, treated according...

  17. "Inside-Out" PEGylation of Bovine β-Cross-Linked Hemoglobin.

    Science.gov (United States)

    Webster, Kyle D; Dahhan, Dana; Otto, Abigail M; Frosti, Cheyanne L; Dean, William L; Chaires, Jonathan B; Olsen, Kenneth W

    2017-04-01

    The development of a blood substitute is urgent due to blood shortages and potential communicable diseases. A novel method, inside-out PEGylation, has been used here to conjugate a multiarm maleimide-PEG (Mal-PEG) to β-cross-linked (βXL-Hb) hemoglobin (Hb) tetramers through the Cys β93 residues. This method produces a polymer with a single PEG backbone that is surrounded by multiple proteins, rather than coating a single protein with multiple PEG chains. Electrophoresis under denaturing conditions showed a large molecular weight species. Gel filtration chromatography and analytical ultracentrifugation determined the most prevalent species had three βXL-Hb to one Mal-PEG. Thermal denaturation studies showed that the cross-linked and PEGylated species were more stable than native Hb. Cross-linking under oxy-conditions produced a high oxygen affinity Hb species (P50  = 9.18 Torr), but the oxygen affinity was not significantly altered by PEGylation (P50  = 9.67 Torr). Inside-out PEGylation can be used to produce a hemoglobin-based oxygen carrier and potentially for other multiprotein complexes. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  18. Disulfide bond-conjugated dual PEGylated siRNAs for prolonged multiple gene silencing.

    Science.gov (United States)

    Liao, Zi-Xian; Hsiao, Chun-Wen; Ho, Yi-Cheng; Chen, Hsin-Lung; Sung, Hsing-Wen

    2013-09-01

    Many human diseases carry at least two independent gene mutations, further exacerbating clinical disorders. In this work, disulfide bond-conjugated dual PEGylated siRNAs were synthesized, capable of specifically targeting and silencing two genes simultaneously. To achieve efficient delivery, the conjugated siRNAs were formulated with the cationic chitosan together with an anionic polymer, poly(γ-glutamic acid) (γPGA), to form a ternary complex. Experimental results indicate that the incorporated γPGA could significantly enhance their intracellular delivery efficiency, allowing for reduction of the disulfide bond-conjugated PEGylated siRNAs delivered to the PEGylated siRNAs in the reductive cytoplasmic environment. The PEGylated siRNAs could more significantly increase their enzymatic tolerability, effectively silence multiple genes, and prolong the duration of their gene silencing capability than the unmodified siRNAs could. Silencing of different genes simultaneously significantly contributes to the efforts to treat multiple gene disorders, and prolonged duration of gene silencing can reduce the need for frequent administrations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Cyclodextrin as membrane protectant in spray-drying and freeze-drying of PEGylated liposomes

    NARCIS (Netherlands)

    van den Hoven, J.M.; Metselaar, Josbert Maarten; Storm, Gerrit; Beijnen, J.H.; Nuijen, B.

    2012-01-01

    Abstract In this study it was investigated whether hydroxypropyl-β-cyclodextrin (HPβCD) is able to stabilize the liposomal membranes during drying of long circulating polyethylene glycol (PEG) coated liposomes, as compared to the disaccharides trehalose and sucrose. PEGylated liposomes loaded with

  20. Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin

    Directory of Open Access Journals (Sweden)

    Maximilian Richter

    2015-01-01

    Full Text Available A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1 that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.

  1. Activity and safety of pegylated liposomal doxorubicin, 5-fluorouracil and folinic acid in inoperable hepatocellular carcinoma: A phase II study

    Science.gov (United States)

    Lorenzo, Giuseppe Di; Rea, Antonio; Carlomagno, Chiara; Pepe, Stefano; Palmieri, Giovannella; Labianca, Roberto; Chirianni, Antonio; Stefano, Alfonso De; Esposito, Vincenzo; Placido, Sabino De; Montesarchio, Vincenzo

    2007-01-01

    AIM: To improve the results of New therapeutic strategies in hepatocellular carcinoma (HCC). We have conducted a phase II study with pegylated liposomal doxorubicin (PLD), 5-fluorouracil (5FU) and folinic acid (FA). METHODS: Thirty-one patients with hystologically-confirmed, inoperable HCC, received combination chemotherapy with PLD 25 mg/mq on d 1, 5FU 1200 mg/mq in 48 h continuous infusion, and oral FA 30 mg on d 1 and 2 every 3 wk until disease progression or intolerable toxicity. RESULTS: The median age was 65 years (range 41-82) and 28 patients were hepatitis C virus seropositive (90%). The majority of patients were Child-Pugh Class B (55%). Two patients showed a partial response (PR), and 16 had stable disease (SD). With a median follow-up of 14 mo, the median time to progression of all evaluable patients was 4 mo (95% CI 1.7-7). Median overall survival was 9 mo (95% CI 3-24 mo). After 1 year, 9 of 18 PR/SD patients were alive. Chemotherapy was well tolerated. CONCLUSION: PLD/FU/FA combination seems capable of achieving durable stabilization of HCC. The manageable toxicity supports a role for combination with other anticancer agents. PMID:18161926

  2. Laboratory evaluation of commercial interferon preparations

    African Journals Online (AJOL)

    The antiviral, antiproliferative and natural killer-cell. (NKC) stimulatory activities of four commercial the- rapeutic interferon preparations were assayed in our laboratory. The antiviral and antiproliferative activities of each preparation were relatively similar, but an unexpectedly high NKC stimulatory activity was foupd in one ...

  3. Neuropsychiatric Complications Associated with Interferon - Alpha ...

    African Journals Online (AJOL)

    Adelaide and Meath Hospital, Tallaght, Ireland. Abstract. Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man.

  4. Laboratory evaluation of commercial interferon preparations

    African Journals Online (AJOL)

    Antiviral radio-immunoassay. This technique has been described in greater detail else- where. 7 The test is based on the quantitation by radio-immuno- assay of the reduction of growth of challenge Sindbis virus due to the protection of cells by the interferon samples. Briefly, confluent monolayers of Vero cells were grown in.

  5. Interferons in the central nervous system

    DEFF Research Database (Denmark)

    Owens, Trevor; Khorooshi, Reza M. H.; Wlodarczyk, Agnieszka

    2014-01-01

    Interferons (IFNs) are implicated as an important component of the innate immune system influencing viral infections, inflammation, and immune surveillance. We review here the complex biological activity of IFNs in the central nervous system (CNS) and associated glial–immune interactions...

  6. Quantification of interferon signaling in avian cells

    NARCIS (Netherlands)

    Kint, Joeri; Forlenza, Maria

    2015-01-01

    Activation of the type I interferon (IFN) response is an essential defense mechanism against invading pathogens such as viruses. This chapter describes two protocols to quantify activation of the chicken IFN response through analysis of gene expression by real-time quantitative PCR and by

  7. Neuropsychiatric Complications Associated with Interferon - Alpha ...

    African Journals Online (AJOL)

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant ...

  8. PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery.

    Science.gov (United States)

    Luong, Duy; Kesharwani, Prashant; Deshmukh, Rahul; Mohd Amin, Mohd Cairul Iqbal; Gupta, Umesh; Greish, Khaled; Iyer, Arun K

    2016-10-01

    Poly(amidoamine) dendrimers (PAMAM) are well-defined, highly branched, nanoscale macromolecules with numerous active amine groups on the surface. PAMAM dendrimer can enhance the solubility of hydrophobic drugs, and with numerous reactive groups on the surface PAMAM dendrimer can be engineered with various functional groups for specific targeting ability. However, in physiological conditions, these amine groups are toxic to cells and limit the application of PAMAM. In the recent years, polyethylene glycol (PEG) conjugation has been the most widely used approach to reduce the toxicity of the active group on dendrimer surface. PEG molecules are known to be inert, non-immunogenic, and non-antigenic with a significant water solubility. PEGylated PAMAM-mediated delivery could not only overcome the limitations of dendrimer such as drug leakage, immunogenicity, hemolytic toxicity, systemic cytotoxicity but they also have the ability to enhance the solubilization of hydrophobic drugs and facilitates the potential for DNA transfection, siRNA delivery and tumor targeting. This review focuses on the recent developments on the application and influence of PEGylation on various biopharmaceutical properties of PAMAM dendrimers. It is well established that dendrimers have demonstrated promising potentials for drug delivery. However, the inherent toxicity poses challenges for its clinical translation. In this regard, PEGylation has helped mitigate some of the toxicity concerns of dendrimers and have paved the way forward for testing its translational potentials. The review is a collection of articles demonstrating the utility of PEGylation of the most studied PAMAM dendrimers. To our knowledge, this is a first such attempt to draw reader's attention, specifically, towards PEGylated PAMAM dendrimers. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  9. Glycosylation site-targeted PEGylation of glucose oxidase retains native enzymatic activity.

    Science.gov (United States)

    Ritter, Dustin W; Roberts, Jason R; McShane, Michael J

    2013-04-10

    Targeted PEGylation of glucose oxidase at its glycosylation sites was investigated to determine the effect on enzymatic activity, as well as the bioconjugate's potential in an optical biosensing assay. Methoxy-poly(ethylene glycol)-hydrazide (4.5kDa) was covalently coupled to periodate-oxidized glycosylation sites of glucose oxidase from Aspergillus niger. The bioconjugate was characterized using gel electrophoresis, liquid chromatography, mass spectrometry, and dynamic light scattering. Gel electrophoresis data showed that the PEGylation protocol resulted in a drastic increase (ca. 100kDa) in the apparent molecular mass of the protein subunit, with complete conversion to the bioconjugate; liquid chromatography data corroborated this large increase in molecular size. Mass spectrometry data proved that the extent of PEGylation was six poly(ethylene glycol) chains per glucose oxidase dimer. Dynamic light scattering data indicated the absence of higher-order oligomers in the PEGylated GOx sample. To assess stability, enzymatic activity assays were performed in triplicate at multiple time points over the course of 29 days in the absence of glucose, as well as before and after exposure to 5% w/v glucose for 24h. At a confidence level of 95%, the bioconjugate's performance was statistically equivalent to native glucose oxidase in terms of activity retention over the 29 day time period, as well as following the 24h glucose exposure. Finally, the bioconjugate was entrapped within a poly(2-hydroxyethyl methacrylate) hydrogel containing an oxygen-sensitive phosphor, and the construct was shown to respond approximately linearly with a 220±73% signal change (n=4, 95% confidence interval) over the physiologically-relevant glucose range (i.e., 0-400mg/dL); to our knowledge, this represents the first demonstration of PEGylated glucose oxidase incorporated into an optical biosensing assay. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Literature systematic review on the ophthalmological side effects of interferons

    Directory of Open Access Journals (Sweden)

    Yara Dadalti Fragoso

    2011-08-01

    Full Text Available Interferons alpha and beta have been used worldwide for a few decades, altering the natural history of several severe diseases including hepatitis C, cancer and immune-mediated conditions such as multiple sclerosis. The adverse events profile of interferons is well established, but only isolated reports of ophthalmological complications of interferon therapy have been published. The objective of this study was to carry out a literature systematic review on the subject, bringing to light the need for careful ophthalmological monitoring of patients undergoing interferon treatment. Nearly 500 cases of ophthalmological complications related to interferon have been reported. The most frequent findings were soft exudates, hemorrhages and retina ischemia.

  11. Interferon-alpha in the treatment of multiple myeloma

    DEFF Research Database (Denmark)

    Khoo, T.L.; Joshua, D.; Gibson, J.

    2011-01-01

    in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs" - thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment......Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the hematological malignancy multiple myeloma. Interferon has been used...... of multiple myeloma or will interferon be resigned to the history books remains to be seen....

  12. Interleukins, interferons, and establishment of pregnancy in pigs.

    Science.gov (United States)

    Mathew, Daniel J; Lucy, Matthew C; D Geisert, Rodney

    2016-06-01

    Early pregnancy in mammals requires complex and highly orchestrated cellular and molecular interactions between specialized cells within the endometrium and the conceptus. Proinflammatory cytokines are small signaling proteins released by leukocytes that augment innate and adaptive immune responses. They are also released by the mammalian trophectoderm as the conceptus apposes the uterine surface for implantation. On approximately day 12 of development in pigs, the conceptus undergoes a rapid morphological transformation referred to as elongation while simultaneously releasing estrogens and a novel conceptus form of interleukin-1 beta (IL1β). Following elongation, pig conceptuses express interferon gamma (IFNγ) and, in lesser amounts, interferon delta (IFNδ). Significant IFN signaling takes place within the endometrium between day 14 and 18 of pregnancy as the conceptus intimately associates with the uterine epithelium. Based on studies carried out in pigs and other mammals, the combined spacio-temporal activities of conceptus estrogens, IL1β, and IFN set in motion a series of coordinated events that promote establishment of pregnancy. This is achieved through enhancement of conceptus development, uterine receptivity, maternal-fetal hemotropic exchange, and endometrial leukocyte function. These events require activation of specific signaling pathways within the uterine luminal epithelium, glandular epithelium, and stroma. Here, we review proinflammatory cytokine expression by pig conceptuses and the hypothesized actions of these molecules during establishment of pregnancy. © 2016 Society for Reproduction and Fertility.

  13. Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.

    Science.gov (United States)

    Trott, Josephine F; Kim, Jeffrey; Abu Aboud, Omran; Wettersten, Hiromi; Stewart, Benjamin; Berryhill, Grace; Uzal, Francisco; Hovey, Russell C; Chen, Ching-Hsien; Anderson, Katie; Graef, Ashley; Sarver, Aaron L; Modiano, Jaime F; Weiss, Robert H

    2016-10-11

    Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC.

  14. Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon

    Directory of Open Access Journals (Sweden)

    Patrícia Alessandra Dastoli

    2011-02-01

    Full Text Available OBJECTIVE: To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD: Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS: Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60% and the bigger reduction was 98.37%. Eleven patients had a reduction greater than 90%. Five patients had a tumor reduction between 75 and 90% and in three patients the tumors were reduced by less than 75%. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION: The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

  15. Binding of human serum albumin to PEGylated liposomes: insights into binding numbers and dynamics by fluorescence correlation spectroscopy

    DEFF Research Database (Denmark)

    Kristensen, Kasper; Urquhart, Andrew; Thormann, Esben

    2016-01-01

    Liposomes for medical applications are often administered by intravenous injection. Once in the bloodstream, the liposomes are covered with a "protein corona", which impacts the behavior and eventual fate of the liposomes. Currently, many aspects of the liposomal protein corona are not well...... used FCS to investigate the binding of human serum albumin (HSA) to standard types of PEGylated fluid-phase liposomes (consisting of DOPC and DOPE-PEG2k) and PEGylated gel-phase liposomes (consisting of DSPC and DSPE-PEG2k) with various PEG chain surface densities. We detected no significant binding...... of HSA to the PEGylated fluid-phase liposomes. In contrast, we found that HSA bound tightly to the PEGylated gel-phase liposomes, although only a low number of HSA molecules could be accommodated per liposome. Overall, we believe that our data provides a useful benchmark for other researchers interested...

  16. A phase I study of irinotecan and pegylated liposomal doxorubicin in recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study).

    Science.gov (United States)

    Shoji, Tadahiro; Takatori, Eriko; Kaido, Yoshitaka; Omi, Hideo; Yokoyama, Yoshihito; Mizunuma, Hideki; Kaiho, Michiko; Otsuki, Takeo; Takano, Tadao; Yaegashi, Nobuo; Nishiyama, Hiroshi; Fujimori, Keiya; Sugiyama, Toru

    2014-05-01

    A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer. Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m(2). CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m(2) on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m(2) (level 1, 50 mg/m(2); level 2, 60 mg/m(2); level 3, 70 mg/m(2); level 4, 80 mg/m(2)) to determine MTD and RD. During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m(2)) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m(2). The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m(2) of CPT-11 and 30 mg/m(2

  17. PEGylated and Functionalized Aliphatic Polycarbonate Polyplex Nanoparticles for Intravenous Administration of HDAC5 siRNA in Cancer Therapy.

    Science.gov (United States)

    Frère, Antoine; Baroni, Alexandra; Hendrick, Elodie; Delvigne, Anne-Sophie; Orange, François; Peulen, Olivier; Dakwar, George R; Diricq, Jérôme; Dubois, Philippe; Evrard, Brigitte; Remaut, Katrien; Braeckmans, Kevin; De Smedt, Stefaan C; Laloy, Julie; Dogné, Jean-Michel; Feller, Georges; Mespouille, Laetitia; Mottet, Denis; Piel, Géraldine

    2017-01-25

    Guanidine and morpholine functionalized aliphatic polycarbonate polymers are able to deliver efficiently histone deacetylase 5 (HDAC5) siRNA into the cytoplasm of cancer cells in vitro leading to a decrease of cell proliferation were previously developed. To allow these biodegradable and biocompatible polyplex nanoparticles to overcome the extracellular barriers and be effective in vivo after an intravenous injection, polyethylene glycol chains (PEG750 or PEG2000) were grafted on the polymer structure. These nanoparticles showed an average size of about 150 nm and a slightly positive ζ-potential with complete siRNA complexation. Behavior of PEGylated and non-PEGylated polyplexes were investigated in the presence of serum, in terms of siRNA complexation (fluorescence correlation spectroscopy), size (dynamic light scattering and single-particle tracking), interaction with proteins (isothermal titration calorimetry) and cellular uptake. Surprisingly, both PEGylated and non-PEGylated formulations presented relatively good behavior in the presence of fetal bovine serum (FBS). Hemocompatibility tests showed no effect of these polyplexes on hemolysis and coagulation. In vivo biodistribution in mice was performed and showed a better siRNA accumulation at the tumor site for PEGylated polyplexes. However, cellular uptake in protein-rich conditions showed that PEGylated polyplex lost their ability to interact with biological membranes and enter into cells, showing the importance to perform in vitro investigations in physiological conditions closed to in vivo situation. In vitro, the efficiency of PEGylated nanoparticles decreases compared to non-PEGylated particles, leading to the loss of the antiproliferative effect on cancer cells.

  18. The effect of GlycoPEGylation on the physical stability of human rFVIIa with increasing calcium chloride concentration

    DEFF Research Database (Denmark)

    Plesner, Bitten; Westh, Peter; Hvidt, Søren

    2011-01-01

    FVIIa, whereas the concentration of CaCl(2) has to be raised to 100mM in order to see the same effect on the GlycoPEGylated rFVIIa compounds. The temperature of aggregation of rFVIIa, T(agg), increased as the CaCl(2) concentration increased from 35 mM to 100 mM, while T(agg) for the GlycoPEGylated r...

  19. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study.

    Science.gov (United States)

    Omrani, Ali S; Saad, Mustafa M; Baig, Kamran; Bahloul, Abdelkarim; Abdul-Matin, Mohammed; Alaidaroos, Amal Y; Almakhlafi, Ghaleb A; Albarrak, Mohammed M; Memish, Ziad A; Albarrak, Ali M

    2014-11-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with high mortality and has no approved antiviral therapy. We aimed to compare ribavirin and interferon alfa-2a treatment for patients with severe MERS-CoV infection with a supportive therapy only. In this retrospective cohort study, we included adults (aged ≥16 years) with laboratory-confirmed MERS-CoV infection and pneumonia needing ventilation support, diagnosed between Oct 23, 2012, and May 1, 2014, at the Prince Sultan Military Medical City (Riyadh, Saudi Arabia). All patients received appropriate supportive care and regular clinical and laboratory monitoring, but patients diagnosed after Sept 16, 2013, were also given oral ribavirin (dose based on calculated creatinine clearance, for 8-10 days) and subcutaneous pegylated interferon alfa-2a (180 μg per week for 2 weeks). The primary endpoint was 14-day and 28-day survival from the date of MERS-CoV infection diagnosis. We used χ(2) and Fischer's exact test to analyse categorical variables and the t test to analyse continuous variables. We analysed 20 patients who received ribavirin and interferon (treatment group; initiated a median of 3 days [range 0-8] after diagnosis) and 24 who did not (comparator group). Baseline clinical and laboratory characteristics were similar between groups, apart from baseline absolute neutrophil count, which was significantly lower in the comparator group (5·88 × 10(9)/L [SD 3·95] vs 9·88 × 10(9)/L [6·63]; p=0·023). 14 (70%) of 20 patients in the treatment group had survived after 14 days, compared with seven (29%) of 24 in the comparator group (p=0·004). After 28 days, six (30%) of 20 and four (17%) of 24, respectively, had survived (p=0·54). Adverse effects were similar between groups, apart from reduction in haemoglobin, which was significantly greater in the treatment group than in the comparator group (4·32 g/L [SD 2·47] vs 2·14 g/L [1·90]; p=0·002). In patients with

  20. Preparation and characterization of PEGylated multiwall carbon nanotubes as covalently conjugated and non-covalent drug carrier: A comparative study.

    Science.gov (United States)

    Habibizadeh, Mina; Rostamizadeh, Kobra; Dalali, Naser; Ramazani, Ali

    2017-05-01

    In this study, PEGylated multiwall carbon nanotubes (MWNTs)-based drug delivery system was developed. Ibuprofen as a model drug was loaded by physical and chemical method. The surface functionalization of nanotubes was carried out by enrichment of acylated groups. In order to synthesis PEGylated MWNTs, hydrophilic diamino-polyethylene glycol was covalently linked to the MWNTs surface via amidation reaction. Finally, ibuprofen was chemically and physically loaded on the PEGylated MWNTs. The resultants were characterized by FTIR, AFM, and DLS techniques. Cytotoxicity of PEGylated MWNTs were examined by MTT assay and the results revealed that PEG functionalized nanotubes did not show significant detrimental effects on the viability of L929 Cells. The percent of drug loading for chemically and physically drug payload carrier were determined to be 52.5% and 38%, respectively. The release of ibuprofen from covalently conjugated and non-covalent drug loaded PEGylated MWNTs at pH=7.4, and 5.3 were investigated, as well. From the results, it was found that chemically loaded MWNTs showed much sustained release behavior compared to the physically loaded one, especially at pH=5.3. The kinetic of drug release was also investigated. The results strongly suggest that the chemically conjugated PEGylated MWNTs could be used as controlled release system for various drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Two cholesterol derivative-based PEGylated liposomes as drug delivery system, study on pharmacokinetics and drug delivery to retina

    Science.gov (United States)

    Geng, Shengyong; Yang, Bin; Wang, Guowu; Qin, Geng; Wada, Satoshi; Wang, Jin-Ye

    2014-07-01

    In this study, two cholesterol derivatives, (4-cholesterocarbonyl-4‧-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and 4-cholesterocarbonyl-4‧-(N,N-diethylamine butyloxyl) azobenzene (ACB), one of which is positively charged while the other is neutral, were synthesized and incorporated with phospholipids and cholesterol to form doxorubicin (DOX)-loaded liposomes. PEGylation was achieved by including 1,2-distearoyl-sn-glycero-3-phosphatiylethanol-amine-N-[methoxy-(polyethylene glycol)-2000 (DSPE-PEG2000). Our results showed that PEGylated liposomes displayed significantly improved stability and the drug leakage was decreased compared to the non-PEGylated ones in vitro. The in vivo study with rats also revealed that the pharmacokinetics and circulation half-life of DOX were significantly improved when liposomes were PEGylated (p derivative ACB played some role in improving liposomes’ stability in systemic circulation compared to the conventional PC liposome and the positively charged CAB liposome, with or without PEGylation. In addition, in the case of local drug delivery, the positively charged PEG-liposome not only delivered much more of the drug into the rats’ retinas (p < 0.001), but also maintained much longer drug retention time compared to the neutral PEGylated liposomes.

  2. Raised interferon-β, type 3 interferon and interferon-stimulated genes - evidence of innate immune activation in neutrophilic asthma.

    Science.gov (United States)

    da Silva, J; Hilzendeger, C; Moermans, C; Schleich, F; Henket, M; Kebadze, T; Mallia, P; Edwards, M R; Johnston, S L; Louis, R

    2017-03-01

    Interferons play an important role in innate immunity. Previous studies report deficiency in virus induction of interferon (IFN)-α, IFN-β and IFN-λ in bronchial epithelial and bronchial lavage cells in atopic asthmatics. It is now recognized that asthma is a heterogeneous disease comprising different inflammatory phenotypes, some of which may involve innate immune activation in the absence of overt infection. The aim of this study was to investigate whether the severity of asthma or a specific cellular sputum pattern may be linked to evidence of innate immune activation. Here we investigate the expression of IFN-β, IFN-λ1 (IL-29), IFN-λ2/3 (IL-28A/B) and the interferon-stimulated genes (ISGs) such as myxovirus resistance 1 (Mx1), oligoadenylate synthetase (OAS) and viperin in unstimulated sputum cells in 57 asthmatics (including 16 mild, 19 moderate and 22 severe asthma patients) and compared them with 19 healthy subjects. We observed increased expression of IFN-β, IFN-λ1/IL-29, OAS and viperin in asthmatics compared with healthy subjects, while IL-28 was not expressed in any group. The overexpression was restricted to neutrophilic asthmatics (sputum neutrophils ≥ 76%), while eosinophilic asthmatics (sputum eosinophils ≥ 3%) did not differ from healthy subjects or even showed a lower expression of Mx1. No difference in interferon or ISG expression was observed according to clinical asthma severity. Neutrophilic, but not eosinophilic, asthmatics display overexpression of IFN-β, IFN-λ1/IL-29 and ISGs in their sputum cells that may reflect ongoing innate immune activation. © 2016 John Wiley & Sons Ltd.

  3. A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study

    Directory of Open Access Journals (Sweden)

    Briasoulis Evangelos

    2010-01-01

    Full Text Available Abstract Background Platinum-based combinations are the standard second-line treatment for platinum-sensitive ovarian cancer (OC. This randomized phase II study was undertaken in order to compare the combination of carboplatin and pegylated liposomal doxorubicin (LD with carboplatin and paclitaxel (CP in this setting. Methods Patients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21 or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28. Results A total of 189 eligible patients (CP 96, CLD 93, with a median age of 63 years, median Performance Status (PS 0 and a median platinum free interval (PFI of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016. The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23% and there was no statistical difference in time-to-progression (TTP or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454. No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%. More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016, skin toxicity and Palmar-plantar erythrodysesthesia (PPE grade 1-2 (38% versus 9%, PP = 0.029, 20% versus 5%, P = 0.003. PS and PFI were independent prognostic factors for TTP and OS. Conclusions The combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients. Trial Registration Australian New Zealand Clinical Trials Registry: ACTRN12609000436279

  4. Oromucosal Administration of Interferon to Humans

    Directory of Open Access Journals (Sweden)

    Manfred W. Beilharz

    2010-01-01

    Full Text Available The prevailing dogma is that, to be systemically effective, interferon-alpha (IFNα must be administered in sufficiently high doses to yield functional blood concentrations. Such an approach to IFNa therapy has proven effective in some instances, but high-dose parenteral IFNα therapy has the disadvantage of causing significant adverse events. Mounting evidence suggests that IFNα delivered into the oral cavity in low doses interacts with the oral mucosa in a unique manner to induce systemic host defense mechanisms without IFNα actually entering the circulation, thus reducing the potential for toxic side effects. A better understanding of the applications and potential benefits of this treatment modality are under active investigation. This paper provides a review of the relevant literature on the clinical use of the oromucosal route of administration of interferon, with an emphasis on the treatment of influenza.

  5. Type I Interferon in Chronic Virus Infection and Cancer.

    Science.gov (United States)

    Snell, Laura M; McGaha, Tracy L; Brooks, David G

    2017-08-01

    Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN-I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C.

    Directory of Open Access Journals (Sweden)

    Christian M Lange

    Full Text Available To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C.Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012 and the response to treatment with pegylated interferon-α (PEG-IFN-α and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D(3 (25[OH]D(3 and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061-2.188, but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D(3<20 ng/mL during all seasons, but 25(OHD(3 serum levels were not associated with treatment outcome.Our study suggests a role of bioactive vitamin D (1,25[OH](2D(3, calcitriol in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OHD(3 is not a suitable predictor of treatment outcome.

  7. PEGylation of {sup 99m}Tc-labeled bombesin analogues improves their pharmacokinetic properties

    Energy Technology Data Exchange (ETDEWEB)

    Daepp, Simone; Garayoa, Elisa Garcia [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, CH-5232 Villigen-PSI (Switzerland); Maes, Veronique; Brans, Luc; Tourwe, Dirk A. [Department of Organic Chemistry, Vrije Universiteit Brussel, 1050 Brussels (Belgium); Mueller, Cristina [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, CH-5232 Villigen-PSI (Switzerland); Schibli, Roger, E-mail: roger.schibli@psi.ch [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, CH-5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

    2011-10-15

    Introduction: Radiolabeled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumors in which BN{sub 2}/gastrin-releasing peptide (GRP) receptors are overexpressed. However, the low in vivo stability of BN conjugates may limit their clinical application. In an attempt to improve their pharmacokinetics and counteract their rapid enzymatic degradation, we prepared a series of polyethylene glycol (PEG)-ylated BN(7-14) analogues for radiolabeling with {sup 99m}Tc(CO){sub 3} and evaluated them in vitro and in vivo. Methods: Derivatization of a stabilized (N{sup {alpha}H}is)Ac-BN(7-14)[Cha{sup 13},Nle{sup 14}] analogue with linear PEG molecules of various sizes [5 kDa (PEG{sub 5}), 10 kDa (PEG{sub 10}) and 20 kDa (PEG{sub 20})] was performed by PEGylation of the {epsilon}-amino group of a {beta}{sup 3}hLys-{beta}Ala-{beta}Ala spacer between the stabilized BN sequence and the (N{sup {alpha}H}is)Ac chelator. The analogues were then radiolabeled by employing the {sup 99m}Tc-tricarbonyl technique. Binding affinity and internalization/externalization studies were performed in vitro in human prostate carcinoma PC-3 cells. Stability was investigated in vitro in human plasma and in vivo in Balb/c mice. Finally, single photon emission computed tomography (SPECT)/X-ray computed tomography studies were performed in nude mice bearing PC-3 tumor xenografts. Results: PEGylation did not affect the binding affinity of BN analogues, as the binding affinity for BN{sub 2}/GRP receptors remained high (K{sub d}<0.9 nM). However, in vitro binding kinetics of the PEGylated analogues were slower. Steady-state condition was reached after 4 h, and the total cell binding was 10 times lower than that for the non-PEGylated counterpart. Besides, PEGylation improved the stability of BN conjugates in vitro and in vivo. The BN derivative conjugated with a PEG{sub 5} molecule showed the best pharmacokinetics in vivo, i.e., faster blood clearance and

  8. Highly stable monodisperse PEGylated iron oxide nanoparticle aqueous suspensions: a nontoxic tracer for homogeneous magnetic bioassays

    Science.gov (United States)

    Lak, Aidin; Dieckhoff, Jan; Ludwig, Frank; Scholtyssek, Jan M.; Goldmann, Oliver; Lünsdorf, Heinrich; Eberbeck, Dietmar; Kornowski, Andreas; Kraken, Mathias; Litterst, F. J.; Fiege, Kathrin; Mischnick, Petra; Schilling, Meinhard

    2013-11-01

    Uniformly sized and shaped iron oxide nanoparticles with a mean size of 25 nm were synthesized via decomposition of iron-oleate. High resolution transmission electron microscopy and Mössbauer spectroscopy investigations revealed that the particles are spheres primarily composed of Fe3O4 with a small fraction of FeO. From Mössbauer and static magnetization measurements, it was deduced that the particles are superparamagnetic at room temperature. The hydrophobic particles were successfully transferred into water via PEGylation using nitrodopamine as an anchoring group. IR spectroscopy and thermogravimetric analysis showed the success and efficiency of the phase transfer reaction. After PEGylation, the particles retained monodispersity and their magnetic core remained intact as proven by photon cross-correlation spectroscopy, ac susceptibility, and transmission electron microscopy. The particle aqueous suspensions revealed excellent water stability over a month of monitoring and also against temperature up to 40 °C. The particles exhibited a moderate cytotoxic effect on in vitro cultured bone marrow-derived macrophages and no release of inflammatory or anti-inflammatory cytokines. The PEGylated particles were functionalized with Herceptin antibodies via a conjugation chemistry, their response to a rotating magnetic field was studied using a fluxgate-based setup and was compared with the one recorded for hydrophobic and PEGylated particles. The particle phase lag rose after labeling with Herceptin, indicating the successful conjugation of Herceptin antibodies to the particles.Uniformly sized and shaped iron oxide nanoparticles with a mean size of 25 nm were synthesized via decomposition of iron-oleate. High resolution transmission electron microscopy and Mössbauer spectroscopy investigations revealed that the particles are spheres primarily composed of Fe3O4 with a small fraction of FeO. From Mössbauer and static magnetization measurements, it was deduced that the

  9. Effects of adding ribavirin to interferon to treat chronic hepatitis C infection

    DEFF Research Database (Denmark)

    Brok, Jesper; Gluud, Lise L; Gluud, Christian

    2005-01-01

    vs interferon alone for treatment of patients with chronic hepatitis C infection. Randomized trials were included irrespective of blinding, language, or publication status. Trials were identified through the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Library, MEDLINE...... events. Previous antiviral therapy (treatment-naive patients, relapsers, or nonresponders), patient characteristics, treatment regimen, methodological quality, and duration of follow-up were extracted. We included 72 trials with a total of 9991 enrolled patients. Treatment with ribavirin plus interferon......, 0.89; 95% CI, 0.84-0.94). Combination therapy also significantly improved liver histologic response. The effects on quality of life are unclear. However, combination therapy significantly increased the risk of hematological, dermatological, gastrointestinal, and several other types of adverse events...

  10. Thrombotic microangiopathy associated with use of interferon-beta

    Directory of Open Access Journals (Sweden)

    Robles A

    2012-06-01

    Full Text Available Teresa Olea,1 Raquel Díaz-Mancebo,1 Maria-Luz Picazo,2 Jorge Martínez-Ara,1 Angel Robles,3 Rafael Selgas,11Departments of Nephrology, 2Pathology, 3Internal Medicine, Hospital Universitario La Paz, Madrid, SpainAbstract: Interferon-beta is widely used for the treatment of relapsing multiple sclerosis. The drug is usually well tolerated, but autoimmune adverse effects, including kidney disease, have been reported. Only a few cases of hemolytic uremic syndrome-thrombotic microangiopathy associated interferon-alpha have been described so far, and even fewer with beta-interferon. We report a patient who developed thrombotic microangiopathy during treatment with interferon-beta and improved after discontinuation and steroid therapy. Complement cascade and antiphospholipid antibodies are investigated. The spectrum of renal diseases associated with interferon-beta treatment is also reviewed.Keywords: thrombotic microangiopathy hemolytic uremic syndrome, multiple sclerosis, interferon-beta

  11. Efficacy and toxicity profile of pegylated liposomal doxorubicin in patients with advanced ovarian cancer.

    Science.gov (United States)

    Mayer, Christine; Brucker, Janina; Schuetz, Florian; Domschke, Christoph; Bechstein, Sarah; Heil, Jörg; Golatta, Michael; Wallwiener, Markus; Sohn, Christof; Schneeweiss, Andreas; Rom, Joachim

    2016-07-01

    The prognosis of patients with non-platinum-sensitive recurrent ovarian cancer is poor. There is a need for salvage therapies with anti-tumor activity and acceptable toxicity for maintaining quality of life. Pegylated liposomal doxorubicin (PLD, Caelyx(®)) is a promising drug fulfilling these demands. We present retrospective data of patients with advanced epithelial ovarian cancer (EOC) who were treated with pegylated liposomal doxorubicin at the University of Heidelberg between 2007 and 2009. Eligible patients for this retrospective study had advanced ovarian cancer and were treated in a palliative setting with PLD at the university hospital of Heidelberg, Germany. Primary objectives were toxicity and efficacy of PLD. 34 patients were included in this study between November 2007 and December 2009; one patient received PLD twice as palliative treatment. The median age of the 34 patients enrolled in this study was 59.9 years (range 27-77 years). The median weight of the patients was 69 kg (range 47-109 kg), the median height 164 cm (range 140-176 cm). Pegylated liposomal doxorubicin was administered every 4 weeks with a dosage of 40 mg/m(2) body surface. PLD was administered for three cycles in median (range 1-9 cycles). Dose reduction was necessary in only four patients. In our study time to progression and overall survival was 8.74 and 14.23 months. In conclusion, this retrospective study showed the efficacy and low toxicity of pegylated liposomal doxorubicin in patients with advanced EOC. Further observations are needed to confirm these preliminary experiences on a larger number of patients.

  12. PEGylation of lipoplexes: The right balance between cytotoxicity and siRNA effectiveness.

    Science.gov (United States)

    Lechanteur, Anna; Furst, Tania; Evrard, Brigitte; Delvenne, Philippe; Hubert, Pascale; Piel, Géraldine

    2016-10-10

    The delivery of small interfering RNA (siRNA) is an attractive therapeutic approach to treat several pathologies, such as viral infections or cancers. However, the stability and the efficacy of these biotherapies are still a major obstacle to their use. Cationic liposomes (DOTAP/Chol/DOPE 1/0.75/0.5M ratio) have been complexed to siRNA (lipoplexes) in order to be administrated by the vaginal route, in the context of HPV16 induced cervical preneoplastic lesions. To overcome the constraint of the cervico-vaginal mucus, PEGylation is required to allow the diffusion of lipoplexes through it. Thereby, PEGylated lipoplexes coated with three types of polyethylene glycol (PEG) as DSPE-PEG2000, DSPE-PEG750 or C8-PEG2000-Ceramide (Ceramide-PEG2000) at different densities have been developed and characterized. PEGylated lipoplexes were successfully prepared and showed a hydrodynamic diameter around 200nm, appropriate for vaginal application. In vitro assays on HPV16 positive cell lines revealed that a positive charge of PEGylated lipoplexes allows a higher mRNA knockdown by siRNA. However, the cationic property is also associated to cytotoxicity. The addition of a high percentage of PEG prevented this toxicity but seemed also to reduce siRNA endosomal escape, probably by steric hindrance. The decreasing of PEG density of Ceramide-PEG2000 to 20% allows the release of siRNA and in consequence, biological activities, contrarily to DSPE-PEG. These results suggest that Ceramide-PEG is more appropriate for siRNA delivery compared to DSPE-PEG. In conclusion, the right balance between cytotoxicity and siRNA effectiveness has been found with the transfection of lipoplexes coated with 20% of Ceramide-PEG2000. This new nanovector could have a high potential against multiple mucosal diseases, such as human papillomavirus-induced genital lesions. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Synthesis and evaluation of anticancer activity in cells of novel stoichiometric pegylated fullerene-doxorubicin conjugates.

    Science.gov (United States)

    Magoulas, George E; Bantzi, Marina; Messari, Danai; Voulgari, Efstathia; Gialeli, Chrisostomi; Barbouri, Despoina; Giannis, Athanassios; Karamanos, Nikos K; Papaioannou, Dionissios; Avgoustakis, Konstantinos

    2015-05-01

    To synthesize pegylated stoichiometrically and structurally well-defined conjugates of fullerene (C60) with doxorubicin (DOX) and investigate their antiproliferative effect against cancer cell lines. Stoichiometric (1:1 and 1:2) pegylated conjugates of C60 with DOX were synthesized using the Prato reaction to create fulleropyrrolidines equipped with a carboxyl function for anchoring a polyethylene glycol (PEG) moiety and either a hydroxyl group for attaching one molecule of DOX or a terminal alkyne group for attaching two molecules of DOX through a click reaction. In both conjugates, the DOX moieties are held through a urethane-type bond. Drug release was studied in phosphate buffer (PBS, pH 7.4) and MCF-7 cancer cells lysate. The uptake of the conjugates by MCF-7 cancer cells and their intracellular localization were studied with fluorescence microscopy. The antiproliferative activity of the conjugates was investigated using the WST-1 test. One or two DOX molecules were anchored on pegylated C60 particles to form DOX-C60-PEG conjugates. Drug liberation from the conjugates was significantly accelerated in the presence of tumor cell lysate compared to PBS. The conjugates could be internalized by MCF-7 cells. DOX from the conjugates exhibited much delayed, compared to free DOX, localization in the nucleus and antiproliferative activity. Pegylated DOX-C60 conjugates (1:1) and (2:1) with well-defined structure were successfully synthesized and found to exhibit comparable, but with a delayed onset, antiproliferative activity with free DOX against MCF-7 cancer cells. The results obtained justify further investigation of the potential of these conjugates as anticancer nanomedicines.

  14. Experience with trabectedin + pegylated liposomal doxorubicin for recurrent platinum-sensitive ovarian cancer unsuited to platinum rechallenge.

    Science.gov (United States)

    Colombo, Nicoletta; Hardy-Bessard, Anne-Claire; Ferrandina, Gabriella; Marth, Christian; Romero, Ignacio

    2016-11-01

    As most patients with ovarian cancer experience multiple remissions and relapses, oncologists must prepare ahead for long-term treatment. While platinum-based regimens are standard of care for platinum-sensitive recurrence, there are circumstances in which platinum rechallenge is not the best approach. These situations include patients with limited sensitivity to platinum; patients with residual toxicity from previous platinum therapy; and patients at risk of developing hypersensitivity reactions. An alternative regimen for these patients is the non-platinum combination of trabectedin + pegylated liposomal doxorubicin (PLD). Areas covered: In this review, case studies are presented to illustrate how careful strategic planning, in terms of therapeutic choices and optimal sequencing, can achieve good outcomes in difficult-to-treat patients. Expert commentary: Advantages with use of trabectedin + PLD in selected patients with platinum-sensitive recurrent ovarian cancer include additional time to recover from platinum-related toxicities, avoidance of hypersensitivity reactions, and the 'sequence effect' by which trabectedin may enhance response to next platinum and prolong survival.

  15. PEG-Interferon-α ribavirin-induced HCV viral clearance: a pharmacogenetic multicenter Spanish study

    Directory of Open Access Journals (Sweden)

    Javier Milara

    2015-01-01

    Full Text Available Objective: Dual PEGylated interferon-(PEG-IFN and ribavirin therapy has been the main hepatitis C virus (HCV treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR to dual PEG-IFN and ribavirin therapy in a representative Spanish population. Methods: Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors. Results: IL-28B (rs12979860, rs7248668, rs8105790, rs8099917 and TNFRSF1B (rs1061622 genotypes, as well as TNFRSF1B/IL-10/TNF(-308 non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3. Conclusions: IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population

  16. Decline in pulmonary function during chronic hepatitis C virus therapy with modified interferon alfa and ribavirin.

    Science.gov (United States)

    Foster, G R; Zeuzem, S; Pianko, S; Sarin, S K; Piratvisuth, T; Shah, S; Andreone, P; Sood, A; Chuang, W-L; Lee, C-M; George, J; Gould, M; Flisiak, R; Jacobson, I M; Komolmit, P; Thongsawat, S; Tanwandee, T; Rasenack, J; Sola, R; Messina, I; Yin, Y; Cammarata, S; Feutren, G; Brown, K K

    2013-04-01

    Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 μg q4wk or Peg-IFNα-2a 180 μg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 μg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research. © 2013 Blackwell Publishing Ltd.

  17. Effects of PEGylated paclitaxel nanocrystals on breast cancer and its lung metastasis

    Science.gov (United States)

    Zhang, Hua; Hu, Hongxiang; Zhang, Haoran; Dai, Wenbing; Wang, Xinglin; Wang, Xueqing; Zhang, Qiang

    2015-06-01

    As an attractive strategy developed rapidly in recent years, nanocrystals are used to deliver insoluble drugs. PEGylation may further prolong the circulation time of nanoparticles and improve the therapeutic outcome of drugs. In this study, paclitaxel (PTX) nanocrystals (PTX-NCs) and PEGylated PTX nanocrystals (PEG-PTX-NCs) were prepared using antisolvent precipitation augmented by probe sonication. The characteristics and antitumor efficacy of nanocrystals were investigated. The results indicated that the nanocrystals showed rod-like morphology, and the average particle size was 240 nm and 330 nm for PTX-NCs and PEG-PTX-NCs, respectively. The PEG molecules covered the surface of nanocrystals with an 11.54 nm fixed aqueous layer thickness (FALT), much higher than that of PTX-NCs (0.2 nm). PEG-PTX-NCs showed higher stability than PTX-NCs under both storage and physiological conditions. In breast cancer xenografted mice, PEG-PTX-NCs showed significantly better tumor inhibition compared to saline (p < 0.001) and PTX-NC groups (p < 0.05) after intravenous administration. In a model of lung tumor metastasis quantified by the luciferase activity, the PEG-PTX-NCs group showed higher anticancer efficacy not only than saline and PTX-NCs groups, but also than Taxol®, achieving an 82% reduction at the end of the experiment. These studies suggested the potential advantages of PEGylated PTX nanocrystals as alternative drug delivery systems for anticancer therapy.

  18. Transferrin-appended PEGylated nanoparticles for temozolomide delivery to brain: in vitro characterisation.

    Science.gov (United States)

    Jain, Aviral; Chasoo, Gousia; Singh, Shashank K; Saxena, Ajit K; Jain, Sanjay K

    2011-01-01

    Polymer-based nanotechnologies are proposed to be an alternative for drug administration, delivery and targeting to those of conventional formulations. The blood brain barrier is frequently a rate-limiting factor in determining permeation of a drug into brain. In this study, the surface-engineered long-circulating PLGA nanoparticles (NPs) were assessed for brain-specific delivery. Long circulating NPs of PLGA- and PEG-synthesised copolymer were prepared by emulsification solvent evaporation method. Further, the surface of PEGylated NPs was modified by anchoring transferrin (Tf) ligand for receptor-mediated targeting to brain. NPs were characterised for shape and size, zeta potential, entrapment efficiency and in vitro drug release. In vitro cytotoxicity studies were performed on human cancer cell lines. Confocal Laser Scanning Microscopy studies show the enhanced uptake of Tf-appended PEGylated NPs and their localisation in the brain tissues. Hence, the specific role of Tf ligand on PEGylated NPs for brain delivery was confirmed.

  19. PEGylation of Vesicular Stomatitis Virus Extends Virus Persistence in Blood Circulation of Passively Immunized Mice

    Science.gov (United States)

    Tesfay, Mulu Z.; Kirk, Amber C.; Hadac, Elizabeth M.; Griesmann, Guy E.; Federspiel, Mark J.; Barber, Glen N.; Henry, Stephen M.; Peng, Kah-Whye

    2013-01-01

    We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)–PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma. PMID:23325695

  20. Evaluation and mechanism studies of PEGylated dendrigraft poly-L-lysines as novel gene delivery vectors

    Energy Technology Data Exchange (ETDEWEB)

    Huang Rongqin; Liu Shuhuan; Shao Kun; Han Liang; Ke Weilun; Liu Yang; Li Jianfeng; Huang Shixian; Jiang Chen, E-mail: jiangchen@shmu.edu.cn [Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203 (China)

    2010-07-02

    Dendrimers have attracted great interest in the field of gene delivery due to their synthetic controllability and excellent gene transfection efficiency. In this work, dendrigraft poly-L-lysines (DGLs) were evaluated as a novel gene vector for the first time. Derivatives of DGLs (generation 2 and 3) with different extents of PEGylation were successfully synthesized and used to compact pDNA as complexes. The result of gel retardation assay showed that pDNA could be effectively packed by all the vectors at a DGLs to pDNA weight ratio greater than 2. An increase in the PEGylation extent of vectors resulted in a decrease in the incorporation efficiency and cytotoxicity of complexes in 293 cells, which also decreased the zeta potential a little but did not affect the mean diameter of complexes. Higher generation of DGLs could mediate higher gene transfection in vitro. Confocal microscopy and cellular uptake inhibition studies demonstrated that caveolae-mediated process and macropinocytosis were involved in the cellular uptake of DGLs-based complexes. Also the results indicate that proper PEGylated DGLs could mediate efficient gene transfection, showing their potential as an alternate biodegradable vector in the field of nonviral gene delivery.

  1. Evaluation and mechanism studies of PEGylated dendrigraft poly-L-lysines as novel gene delivery vectors

    Science.gov (United States)

    Huang, Rongqin; Liu, Shuhuan; Shao, Kun; Han, Liang; Ke, Weilun; Liu, Yang; Li, Jianfeng; Huang, Shixian; Jiang, Chen

    2010-07-01

    Dendrimers have attracted great interest in the field of gene delivery due to their synthetic controllability and excellent gene transfection efficiency. In this work, dendrigraft poly-L-lysines (DGLs) were evaluated as a novel gene vector for the first time. Derivatives of DGLs (generation 2 and 3) with different extents of PEGylation were successfully synthesized and used to compact pDNA as complexes. The result of gel retardation assay showed that pDNA could be effectively packed by all the vectors at a DGLs to pDNA weight ratio greater than 2. An increase in the PEGylation extent of vectors resulted in a decrease in the incorporation efficiency and cytotoxicity of complexes in 293 cells, which also decreased the zeta potential a little but did not affect the mean diameter of complexes. Higher generation of DGLs could mediate higher gene transfection in vitro. Confocal microscopy and cellular uptake inhibition studies demonstrated that caveolae-mediated process and macropinocytosis were involved in the cellular uptake of DGLs-based complexes. Also the results indicate that proper PEGylated DGLs could mediate efficient gene transfection, showing their potential as an alternate biodegradable vector in the field of nonviral gene delivery.

  2. The molar hydrodynamic volume changes of factor VIIa due to GlycoPEGylation

    DEFF Research Database (Denmark)

    Plesner, Bitten; Westh, Peter; Hvidt, Søren

    2011-01-01

    The effects of GlycoPEGylation on the molar hydrodynamic volume of recombinant human rFVIIa were investigated using rFVIIa and two GlycoPEGylated recombinant human FVIIa derivatives, a linear 10 kDa PEG and a branched 40 kDa PEG, respectively. Molar hydrodynamic volumes were determined by capillary...... viscometry and mass spectrometry. The intrinsic viscosities of rFVIIa, its two GlycoPEGylated compounds, and of linear 8 kDa, 10 kDa, 20 kDa and branched 40 kDa PEG polymers were determined. The measured intrinsic viscosity of rFVIIa is 6.0 mL/g, while the intrinsic viscosities of 10 kDa PEG-rFVIIa and 40 k......Da PEG-rFVIIa are 29.5 mL/g and 79.0 mL/g, respectively. The intrinsic viscosities of the linear PEG polymers are 20, 22.6 and 41.4 mL/g for 8, 10, and 20 kDa, respectively, and 61.1 mL/g for the branched 40 kDa PEG. From the results of the intrinsic viscosity and MALDI–TOF measurements it is evident...

  3. Antiviral effects of bovine interferons on bovine respiratory tract viruses.

    OpenAIRE

    Fulton, R W; Downing, M M; Cummins, J M

    1984-01-01

    The antiviral effects of bovine interferons on the replication of bovine respiratory tract viruses were studied. Bovine turbinate monolayer cultures were treated with bovine interferons and challenged with several bovine herpesvirus 1 strains, bovine viral diarrhea virus, parainfluenza type 3 virus, goat respiratory syncytial virus, bovine respiratory syncytial virus, bovine adenovirus type 7, or vesicular stomatitis virus. Treatment with bovine interferons reduced viral yield for each of the...

  4. Minocycline added to subcutaneous interferon β-1a in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, P S; Sellebjerg, F; Lycke, J

    2016-01-01

    BACKGROUND AND PURPOSE: Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) β-1a therapy. METHODS: This was a double...... of adverse events with minocycline versus placebo. CONCLUSION: Minocycline showed no statistically significant beneficial effect when added to sc IFN β-1a therapy....

  5. Peripheral Blood Mononuclear Cell Gene Expression Remains Broadly Altered Years after Successful Interferon-Based Hepatitis C Virus Treatment

    Directory of Open Access Journals (Sweden)

    Paul Ravi Waldron

    2015-01-01

    Full Text Available Background. Inflammatory gene expression in peripheral blood mononuclear cells (PBMCs is altered in chronic Hepatitis C Virus (HCV infection. Duration of changes after pegylated interferon- (peg-IFN- based HCV treatment is unclear. Methods. PBMC mRNA expression of 184 inflammatory response genes was analyzed (nCounter GX Human Inflammation Kit, Nanostring from peg-IFN treatment nonresponders (NR, n=18, sustained virologic responders (SVR, n=22, and spontaneous clearers (SC, n=15. Logistic regression was used for comparison. Results. Median time from last treatment was 2 and 2.7 years in SVR and NR, respectively (p = NS. Mean mRNA counts were significantly different for 42 and 29 genes comparing SVR to SC patients and NR to SC, respectively, and no genes comparing SVR to NR. Differential expression of 24 genes was significantly different in both SVR and NR groups compared to SC. Among these 24 acute and chronic inflammatory cascade genes, significant upregulation was noted for proinflammatory transcription regulators Fos, CEBPB, and MyD88 in SVR and NR compared to SC. HDAC4 was significantly downregulated in SVR and NR compared to the SC group. Conclusions. PBMC inflammatory gene expression patterns in SVR resemble NR more than SC patients. A generalized inflammatory response persists in PBMCs long after successful peg-IFN treatment for HCV infection.

  6. Interferon-Free Hepatitis C Treatment before and after Liver Transplantation: The Role of HCV Drug Resistance

    Directory of Open Access Journals (Sweden)

    Bruno Roche

    2015-09-01

    Full Text Available Hepatitis C virus (HCV infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN and ribavirin (RBV was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs, boceprevir (BOC or telaprevir (TVR, associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.