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PubMed2003

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].

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 until 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 x 10(6) 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 monotherapy (p = 0.76). End of treatment WBC was significantly lower in patients treated with combination therapy, compared to ribavirin (p < 0.01) as well as for patients treated with ribavirin monotherapy compared to placebo (p < 0.01). DISCUSSION: This belated report on the only placebo controlled study of interferon ribavirin combination therapy in non responders to standard doses of interferon monotherapy documents the effectiveness, be it limited, of this approach as well as the dynamics of the effects on blood counts.

Adult↗

PubMed1986

Differential effects of hyperthermia on human leukocyte production of interferon-alpha and interferon-gamma.

Hyperthermia is being used clinically in the treatment of neoplasms. However, there are insufficient data regarding effects of hyperthermia on leukocyte functions potentially important in antitumor immunity. In order to provide such data, human mononuclear leukocytes were exposed to moderate (40.7 degrees C) and marked (42.7 degrees C) hyperthermia for 2 hr. Leukocyte viability, measured by dye exclusion, was not altered by such exposures. Exposure of the cells to moderate hyperthermia did not alter leukocyte production of interferon-alpha in response to influenza virus or interferon-gamma in response to the mitogen phytohemagglutinin. Exposure of the cells to marked hyperthermia significantly depressed production of interferon-alpha. In contrast, production of interferon-gamma was not altered by exposure of the leukocytes to marked hyperthermia. Many studies support a role for interferons (alpha as well as gamma) in antitumor immunity. The current and other data suggest that marked hyperthermia in cancer therapy should be applied locally whenever possible, rather than to the whole body, in order to limit adverse effects on immunity. The data suggest further that interferon-gamma may be a heat shock (stress) protein for human leukocytes.

Adult↗

PubMedDate not supplied

Synergistic antitumour effect of a combination of toremifene and interferon-alpha on ZR-75-1 human breast cancer cells: dependence on interferon-alpha subtype.

We investigated the effect of toremifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination for their effect on the growth of ZR-75-1 human breast cancer cells. Median effect analysis was used to determine synergistic or additive effects. Anti-proliferative studies showed that the growth of ZR-75-1 cells was inhibited to a greater extent by combination treatment with toremifene plus interferon-alpha2a, resulting in a synergistic interaction (CI <1) for all concentrations tested. A combination of toremifene plus interferon-alpha2b resulted in a synergistic interaction (CI <1) for the two highest concentrations of toremifene (10(-6) and 10(-7) M) and an additive effect (CI approximately equal to 1) for the lower concentrations (10(-8) to 10(-10) M). When toremifene was combined with interferon-alpha2c no additive or synergistic interaction was determined.

Antineoplastic Agents, Hormonal↗

PubMedDate not supplied

Combination of interferon alfa-2a and amantadine does not improve the efficacy of interferon therapy in patients with chronic hepatitis C.

BACKGROUND/AIMS: A recent pilot study suggested that 18% of patients with hepatitis C viral infection achieved a sustained response to a 6-month course of 200 mg of oral amantadine alone with disappearance of serum hepatitis C virus ribonucleic acid. We prospectively studied 30 naive patients with chronic hepatitis C viral infection for the possible role of amantadine in improving the efficiency of interferon for the treatment of chronic hepatitis C. METHODOLOGY: Patients were assigned into two groups on a double-blind and randomized controlled basis. Placebo group received 4.5 MU of interferon alfa-2a thrice weekly and oral placebo daily for 24 weeks. Amantadine group received a combination of the interferon and 200 mg of oral amantadine daily for 24 weeks. Patients were observed and tested for blood chemistry every week for the initial 4 weeks and every 2 weeks thereafter during the treatment until 24 weeks. After the end of treatment, patients were followed up at 4-week intervals for an additional 12 months. RESULTS: At the end of treatment, 5 (33.3%) patients responded to the combination therapy, and 7 (46.7%) patients responded to interferon therapy alone. Twelve months after cessation of the treatment, 3 (21.4%) patients had a sustained complete response to the combination therapy, and 3 (20.0%) patients had a sustained complete response to interferon alone (P = 0.64). CONCLUSION: Amantadine does not increase the efficacy of interferon in the treatment of chronic hepatitis C.

Adult↗

PubMed2005

Cutaneous mucinosis and skin necrosis complicates interferon alfacon-1 (consensus interferon) treatment of chronic hepatitis C.

A 59-year-old Caucasian suffering from chronic hepatitis C started daily subcutaneous self-injections of interferon alfacon-1 (consensus interferon) according to the protocol of a randomised multicentre study. At week 10, he developed painful erythematous lesions at two injection sites. Consensus interferon dosage was reduced, and eventually, the lesions healed with small areas of scarring due to central necrosis. At week 51, again large areas of erythematous thickened skin arose at two other injection sites followed by substantial ulceration and central necrosis. Skin biopsy revealed excessive dermal mucin deposition so that cutaneous mucinosis was diagnosed. After 3-6 months, the lesions healed with central scarring. Due to a persistently negative HCV-PCR from serum (from week 12 onwards), consensus interferon treatment was not stopped but continued until week 60 according to the study protocol. - Cutaneous mucinosis has not been previously reported to complicate treatment with consensus interferon in patients with chronic hepatitis C and should therefore be added to the list of dermatological side-effects associated with interferon alfacon-1 therapy.

Antiviral Agents↗

PubMed2006

Daily consensus interferon (CIFN) monotherapy in non-responders or relapsers to a previous interferon regime: one year follow-up after 48 weeks of treatment.

BACKGROUND/AIMS: Data suggests on the basis of thrice a week therapy, efficacy of mono consensus interferon is comparable to other alpha interferons. One-year follow-up after 12-month daily consensus interferon monotherapy for chronic hepatitis C among non-responders or relapsers to previous consensus interferon monotherapy is investigated. METHODS: Between February and August 1998, 11 non-cirrhotic patients with previous consensus interferon failure were treated. Six were relapsers and five non-responders. Serum HCV-RNA was tested at the 12th and 48th weeks of treatment and followed for one year thereafter. RESULTS: Eight (72%) were HCV-RNA negative at both 12th and 48th weeks. Of these, 60% (3/5) were among previous non-responders and 83% (5/6) were among previous relapsers. One year sustained virological response was 55%. Of this, 40% (2/5) were among non-responders and 66% (4/6) previous relapsers. CONCLUSIONS: These findings suggest that daily consensus interferon needs to be further investigated as an alternative to pegylated formulations, especially with the addition of ribavirin.

Adult↗

PubMed1985

[The state of hyporeactivity in interferon production: localization and partial purification of the factor repressing the interferon production].

The hyporeactivity factor in interferon production by L-929 cells designated IRP (interferon repressing protein) has been studied. In particular, its localization and methods of its purification have been studied. The kinetics of IRP accumulation by producing cells correlate with the development of hyporeactivity condition. Most of IRP is localized in cell sap and in ribosomal fraction in evidence to regulatory role of repressor at the level of interferon mRNA translation. A 100-fold increase in repressor activity was achieved by IRP concentration by ammonium sulfate precipitation. IRP as well as interferon have been shown to possess high affinity to polyU sepharose. The preparations of IRP and interferon concentrated by ammonium sulfate precipitation were subsequently purified by fractioning in a polyI sepharose column. A 10,000-fold (6 x 10(4) U/mg) purification was achieved for IRP and 250-fold (10(4) U/mg) for interferon.

Animals↗

PubMed1977

Swine cell systems as interferon producers. IV. Comparative studies on the correlation between virulence of different Newcastle disease virus strains and their potency as interferon inducers.

Comparative studies concerning a correlation between virulence of various Newcastle virus strains and their interferon-inducing potency confirmed that such a correlation existed. The nearly avirulent La Sota strain of NDV was the poorest interferon inducer, the virulent Hertfordshire strain manifested a very good inducing potency. However, the most virulent J.B. strain virus was a poorer interferon inducer than the Hertfordshire strain. This should not be viewed as contradictory to the conclusion of the correlation between virulence and interferon-inducing ability of NDV since the highly virulent strain might destroy faster the interferon-producing cells, before the latter produced the maximum interferon quantity which they potentially could produce.

Animals↗

PubMedDate not supplied

Effect of interferon alpha, interferon gamma and tumor necrosis factor on the procoagulant activity of human cancer cells.

BACKGROUND: It is not known whether the different cytokines may influence the procoagulant activity of cancer cells; the purpose of this study was to investigate the effect of interferon alpha, interferon gamma and tumor necrosis factor on the procoagulation capacity of human cancer cells cultured "in vitro" or isolated from tumor tissues. METHODS: "In vitro" cultured tumor cell lines were derived from a patient with malignant mesothelioma and a patient with lung adenocarcinoma. Cells isolated from 6 carcinomas of different origin were also investigated. The procoagulant activity of the cells before and after treatment with the cytokines was expressed as RBT U/10(5) cells or RVV U/10(5) cells. RESULTS: Short-term incubation of tumor cells cultured "in vitro" with cytokines did not modify their procoagulant activity; after longer incubation however, interferon alpha induced a significant increase in the procoagulant activity of mesothelioma cells, while interferon gamma induced and increase in the procoagulant activity of lung adenocarcinoma cells. Furthermore, short-term incubation of cells isolated from tumor tissues with interferon gamma or tumor necrosis factor resulted in a significant increase of procoagulant activity, while interferon alpha had no effect. CONCLUSIONS: Altogether, these data demonstrate that the cytokines may influence the expression of the different procoagulant activities of tumor cells.

Blood Coagulation↗

PubMed1998

[Dynamics of interferon induction in albino mice by interferon inducer ridostin administered by various routes].

The time dependence of interferon production in blood, tissues of the respiratory tract, brain and olfactory tract of mice BALB/c was investigated after administration of the interferon inductor ridostin by various routes. Intraperitoneal injection of ridostin in a dose of 5 mg/kg induced intensive accumulation of interferon in the blood serum with the peak in 8 hours (2560 U/0.2 ml) while no interferon was detected in the tissues of the respiratory tract and brain of the animals. Intracerebral injection of ridostin in the same dose induced accumulation of interferon in both the tissues of the brain (maximum 160 U/0.2 ml in 24 hours) and the blood serum (maximum 1280 U/0.2 ml in 8 hours). After respiratory administration of ridostin interferon was detected only in the site of the administration in the tissues of the upper respiratory tract and lungs of the mice.

Administration, Inhalation↗

PubMed1998

Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group.

BACKGROUND: Previous trials of interferon beta in multiple sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known. We undertook a double-blind, placebo-controlled study in relapsing/remitting MS to investigate the effects of subcutaneous interferon beta-1a. METHODS: 560 patients with Kurtzke expanded disability status scale (EDSS) scores of 0-5.0, from 22 centres in nine countries, were randomly assigned subcutaneous recombinant interferon beta-1a 22 microg (n=189), or 44 microg (n=184), or placebo (n=187) three times a week for 2 years. Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat. FINDINGS: Clinical data on 533 (95%) patients were available at 2 years. The relapse rate was significantly lower at 1 and 2 years with both doses of interferon beta-1a than with placebo (mean number per patient 1.82 for 22 microg group, 1.73 for 44 microg group vs 2.56 for placebo group: risk reductions 27% [95% CI 14-39] and 33 [21-44]). Time to first relapse was prolonged by 3 and 5 months in the 22 microg and 44 microg groups respectively, and the proportion of relapse-free patients was significantly increased (p<0.05). Interferon beta-1a delayed progression in disability, and decreased accumulated disability during the study. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group. INTERPRETATION: Subcutaneous interferon beta-1a is an effective treatment for relapsing/remitting MS in terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated. Longer-term benefits may become clearer with further follow-up and investigation.

Adult↗

PubMedDate not supplied

Interferon receptors during treatment of chronic hepatitis B with interferon.

The in vitro binding of 125I-labelled human alpha-interferon to peripheral blood mononuclear cells from 13 patients with chronic hepatitis B during interferon therapy was assayed in order to identify changes in the number of interferon receptors during treatment. Nine patients were treated with human alpha-interferon (Hu alpha-IFN) or human beta-interferon (Hu beta-IFN) daily for 4 weeks. During therapy, receptor sites per cell decreased by 40%. Two weeks after therapy ceased, this number had returned to the pretreatment level. The other four patients were given Hu alpha-IFN daily for 2 weeks, no injections for 2 weeks, and daily injections for 2 weeks. During both periods of therapy, receptor sites decreased by 40%. The number increased to 94% of the pretreatment level 1 week after the first period and to 101% 2 weeks later. It was 80% 1 week after the second period of injections and 108% 2 weeks later.

Adult↗

PubMed2006

Inhibition of interferon signaling by the Kaposi's sarcoma-associated herpesvirus full-length viral interferon regulatory factor 2 protein.

Interferon (IFN) signal transduction involves interferon regulatory factors (IRF). Kaposi's sarcoma-associated herpesvirus (KSHV) encodes four IRF homologues: viral IRF 1 (vIRF-1) to vIRF-4. Previous functional studies revealed that the first exon of vIRF-2 inhibited alpha/beta interferon (IFN-alpha/beta) signaling. We now show that full-length vIRF-2 protein, translated from two spliced exons, inhibited both IFN-alpha- and IFN-lambda-driven transactivation of a reporter promoter containing the interferon stimulated response element (ISRE). Transactivation of the ISRE promoter by IRF-1 was negatively regulated by vIRF-2 protein as well. Transactivation of a full-length IFN-beta reporter promoter by either IRF-3 or IRF-1, but not IRF-7, was also inhibited by vIRF-2 protein. Thus, vIRF-2 protein is an interferon induction antagonist that acts pleiotropically, presumably facilitating KSHV infection and dissemination in vivo.

Cell Line↗

PubMed1988

Effects of interferons, interferon inducers and growth factors on phagocytosis measured by quantitative determination of synthetic compound ingested by mouse bone marrow-derived macrophages.

Sodium salt of 9-oxo-10-acridineacetohydroxamic acid (HCA), a new synthetic compound, forms small crystals in aqueous solution. These crystals were easily phagocytized by the mouse bone marrow-derived macrophages. The ingested HCA crystals were visible under light microscope as dark granules. The degree of phagocytosis was estimated by the spectroscopic measurements of absorption of ingested HCA. About 10 day-old cultures of mouse bone marrow-derived macrophages were found to be suitable for a study on the effect of murine or human interferons. It was observed that murine interferons alpha, beta and gamma at low concentrations (10-200 U/ml) stimulated and higher concentrations (400-1000 U/ml) had no effect on the phagocytosis. Previous treatment of interferons with anti-IFN sera abolished the effect of the interferons. CMA-induced interferon and growth factors were found to modify the phagocytic activity of macrophage cultures.

Acridines↗

PubMed1999

Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group.

The likelihood of a sustained response to a course of interferon in patients with chronic hepatitis C correlates with several clinical and viral factors, including age, viral genotype and initial levels of hepatitis C virus (HCV) RNA in serum. The role of race and ethnicity has not been assessed. We evaluated the association of race with response to interferon in a large randomized, controlled trial using either consensus interferon (9 microg) or interferon alfa-2b (3 million units) given three times weekly for 24 weeks. African-American patients participating in the study were similar to white patients in mean age (43 vs. 42 years) and baseline levels of HCV RNA (3.6 vs. 3.0 million copies/mL) but had lower rates of cirrhosis (5% vs. 12%) and more frequently had viral genotype 1 (88% vs. 66%: P =.004). Most strikingly, the rates of end-of-treatment and sustained virological responses were lower among the 40 African-American patients (5% and 2%) than among the 380 white patients (33% and 12%) (P =.04 and.07). Rates of response among Hispanic and Asian-American patients were not statistically different than non-Hispanic white patients. Median viral levels decreased by week 24 of therapy by 2.5 logs in white patients (from 3.0 to 0.012 million copies/mL) but by only 0.5 logs among African- American patients (from 3.6 to 1.8 million copies/mL). Thus, there are marked racial differences in virological responses to interferon in hepatitis C that must be considered in assessing trials of interferon therapy and in counseling patients regarding treatment. The differences in response rates are as yet unexplained.

Adolescent↗

PubMed1989

A gamma-interferon-induced factor that binds the interferon response sequence of the MHC class I gene, H-2Kb.

Transcription of class I genes of the major histocompatibility complex (MHC) can be induced by interferons. Treatment of HeLa cells with interferon-gamma induces a DNA-binding factor, IBP-1, specific for a site within the interferon response sequence (IRS) of the H-2Kb promoter. The mol. wt of IBP-1, as estimated by photoactivated protein-DNA crosslinking analysis, is approximately 59 kd. Point-mutation of this binding site abolishes IBP-1 interaction and the ability of the MHC promoter to respond to interferon. Induction of this binding activity is rapid and closely parallels the previously reported time course of transcriptional activation of endogenous MHC class I genes. Treatment of cells with cycloheximide, a protein synthesis inhibitor, blocked the induction of the DNA-binding activity. An oligonucleotide derived from the virus- and double-stranded RNA-inducible promoter of the interferon-beta 1 gene is able to bind IBP-1. Sequences similar to the IBP-1 binding site are found upstream of many interferon-responsive genes.

Animals↗

PubMed1978

Quantitative determination of human leukocyte interferon by microfluorometric immunoassay with FITC-labeled anti-interferon immunoglobulin.

The possibility of quantitative determination of human leukocyte interferon using FITC-labeled anti-interferon antibody was studied. Anti-interferon immunoglobulin of high specific activity was obtained as a result of long-term immunization of a donkey with human leukocyte interferon preparation and subsequent fractionation and immunoadsorption steps. This immunoglobulin was labeled with FITC and then used for titration of human leukocyte interferon by the fluorescence inhibition immunoassay. The titres of different preparations of human leukocyte interferon in the immunoassay were comparable with the titres of the same preparations detected by the inhibition of a cytopathic effect of VSV.

Animals↗

PubMed1978

Murine interferon system regulation: isolation and characterization of a mutant 3T6 cell engaged in the semiconstitutive synthesis of interferon.

We describe the isolation and characterization of a virus-resistant mutant of murine 3T6 cells. The mutant, designated 3T6-VrB2, displays a high degree of resistance to infection by members of the toga-, rhabdo- and picornavirus classes. The level of this resistance to infection is similar to the parent 3T6 pretreated with approximately 100 lU/ml of interferon. Upon co-cultivation of 3T6-VrB2 cells with interferon-sensitive mouse cells, an antiviral state is induced in the latter cells as measured by a reduction of virus yield following infection. The nature of the induction is defined by a series of experiments using anti-mouse interferon antiserum. In the presence of this antiserum, the ability of the mutant to induce an antiviral state in interferon-sensitive mouse cells upon co-cultivation is eliminated. Additionally, growth of the mutant cells in the presence of this antiserum causes a reversal of the virus-resistant phenotype. Our results indicate that 3T6-VrB2 contains a mutation affecting the regulation of the murine interferon system such that the cell is engaged in the semiconstitutive synthesis of interferon.

Cell Line↗