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PubMed1995

[Development of interferon antibodies during the treatment of skin diseases with low-dose recombinant interferon alpha-2a].

In this study, we determined the frequency of interferon antibodies in patients with skin diseases treated with low doses of recombinant interferon alpha 2a (1.5 - 18 x 10(6) IU). We assayed serum specimens from 181 patients with malignant melanoma or cutaneous T cell lymphomas (78 patients treated with recombinant interferon alpha 2a and 103 patients in control group) for interferon antibodies before treatment and every 6 months for at least 18 months. Neutralizing interferon alpha 2a antibodies were detected in 27 of 77 treated patients (35%), but none in control group (p < 10(-6)): 38.2% in melanoma and 12.5% in T cell lymphomas. However antibody formation was not correlated with nonresponse or with frequency of interferon antibodies in patients receiving the combined therapy: interleukin-2 and interferon alpha 2a.

Adult↗
PubMed1995

Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors.

Interferon consensus sequence binding protein (ICSBP) is a member of the interferon regulatory factor (IRF) family of proteins that include IRF-1, IRF-2, and ISGF3gamma which share sequence similarity at the putative DNA binding domain (DBD). ICSBP is expressed exclusively in cells of the immune system and acts as a repressor of interferon consensus sequence (ICS) containing promoters that can be alleviated by interferons. In this communication, we have searched for functional domains of ICSBP by dissecting the DBD from the repression activity. The putative DBD of ICSBP (amino acids 1-121) when fused in frame to the transcriptional activation domain of the herpes simplex VP16 (ICSBP-VP16) is a very strong activator of ICS-containing promoters. In addition, ICSBP-VP16 fusion construct transfected into adenovirus (Ad) 12 transformed cells enabled cell surface expression of major histocompatibility complex class I antigens as did treatment with interferon. On the other hand, the DBD of the yeast transcriptional activator GAL4 was fused in frame to a truncated ICSBP in which the DBD was impaired resulting in a chimeric construct GAL4-ICSBP. This construct is capable of repressing promoters containing GAL4 binding sites. Thus, ICSBP contains at least two independent domains: a DBD and a transcriptional repressor domain. Furthermore, we have tested possible interactions between ICSBP and IRFs. The chimeric construct GAL4-ICSBP inhibited the stimulated effect of IRF-1 on a reporter gene, implying for a possible interaction between IRF-1 and ICSBP. Electromobility shift assays, demonstrated that ICSBP can associate with IRF-2 or IRF-1 in vitro as well as in vivo. Thus, ICSBP contains a third functional domain that enables the association with IRFs. These associations are probably important for the fine balance between positive and negative regulators involved in the interferon-mediated signal transduction pathways in cells of the immune system.

Base Sequence↗
PubMed1995

Combined treatment with interferon alpha-2b and ribavirin for chronic hepatitis C in patients with a previous non-response or non-sustained response to interferon alone.

Ten patients with chronic hepatitis C, six of whom had not responded and four of whom had responded in a non-sustained fashion to interferon-alpha treatment alone, were given interferon alpha-2b and ribavirin in combination during 24 weeks. Interferon alpha-2b was given subcutaneously, at a dose of 3 MU thrice weekly, together with ribavirin orally, at a dose of 1,000-1,200 mg/day. All four patients with a prior non-sustained response to interferon alone had normal alanine aminotransferase (ALT) levels at the end of treatment as well as during follow-up (> or = 24 weeks post treatment). Furthermore, all four lost serum HCV-RNA at the end of treatment and three continued to be negative during follow-up. Among patients with a prior non-response to interferon alone three of six had normal ALT levels at the end of treatment and one at follow-up. Two of six became HCV-RNA negative at cessation of treatment, one of whom was negative also at follow-up. All former non-sustained responders and one of six non-responder patients thus showed a sustained biochemical response with eradication of HCV-RNA from serum in all cases but one. It is concluded that combination therapy with interferon alpha-2b and ribavirin offers a chance of sustained biochemical response with eradication of the viremia in patients who have not shown a persistent response to interferon-alpha alone.

Adult↗
PubMed1993

Lymphoblastoid interferon in chronic hepatitis C patients who were "non responders" to recombinant interferon alpha (rIFN alpha).

The aim of this study was to investigate whether there is a variable responsiveness of the hepatitis C virus and/or of the affected host to different types of interferon. We treated 21 patients affected by chronic hepatitis C who failed to respond to recombinant alpha interferon, after a four-month interval, with lymphoblastoid interferon. Alanine transaminase (ALT) serum level was normal in 9 patients (43%) at the end of treatment. At the end of a 12 months treatment-free follow-up serum ALT remained normal in 3 patients, 4 patients relapsed and 2 dropped-out. As yet there are no reports of differences in the therapeutic efficacy of the two types of interferon used in our study. The good response to the lymphoblastoid interferon in our non responders to recombinant alpha interferon may be due to the immune modulation induced by the four-month wash-out interval between the two therapies or to a different virus sensitivity to this interferon.

Adult↗
PubMed1988

Interferon-alpha and interferon-gamma reduce excessive collagen synthesis and procollagen mRNA levels of scleroderma fibroblasts in culture.

The effects of interferon-alpha and interferon-gamma on collagen synthesis and mRNA levels of type I and type III procollagens were studied in skin fibroblasts cultured from affected and unaffected skin sites of two patients with localized scleroderma (morphea). Both scleroderma cell lines exhibited elevated type I and type III procollagen mRNA levels to account for the increased procollagen synthesis, when compared to the unaffected controls. Interferon-gamma treatment resulted in a dose-dependent reduction in collagen synthesis and procollagen mRNA levels in scleroderma fibroblasts. A 72-h exposure to interferon-gamma reduced procollagen mRNA levels in the scleroderma fibroblast lines to the levels exhibited by the unaffected control fibroblasts. The suppressive effect of interferon-alpha on procollagen mRNA levels was somewhat weaker than that of interferon-gamma. The results suggest potential use of interferon-gamma in treatment and prevention of human fibrotic conditions.

Cells, Cultured↗
PubMed1996

Effect of interferon on the health-related quality of life of multiple myeloma patients: results of a Nordic randomized trial comparing melphalan-prednisone to melphalan-prednisone + alpha-interferon. The Nordic Myeloma Study Group.

In a Nordic multi-centre trial, 583 previously untreated multiple myeloma patients were randomized to receive melphalan-prednisone or melphalan-prednisone+ interferon alpha-2b at a dose of 5 million units subcutaneously, 3 d/week. A quality-of-life study was integrated into the trial, using the EORTC QLQ C-30 questionnaire supplemented with 11 questions concerning interferon toxicity. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 90% of the patients participated in the quality-of-life study, and 83% completed all questionnaires submitted to them. During the first year of treatment the patients on interferon reported significantly more fever, chills, dry skin, fatigue, pain, nausea/vomiting and appetite loss than the control patients. There was a moderate reduction of the global quality-of-life score and slight, non-significant, reductions of physical, emotional, cognitive, social and role functioning scores. After the first year there were no statistically significant differences in any toxicity, symptom or quality-of-life score, except for an increased frequency of dizziness in the interferon group. As only 60% of the patients remained on interferon after 24 months, our data probably underestimate the potential toxicity of the drug. Although there was no significant survival benefit for the interferon patients, a 5-6 months prolongation of the response and plateau phase duration was observed. However, by intention-to-treat analysis, there was no late quality-of-life benefit for the interferon patients to compensate for the early impairment. Thus, the clinical significance of the plateau-phase prolongation is uncertain.

Activities of Daily Living↗
PubMed1998

Consensus interferon: a novel interferon for the treatment of hepatitis C.

Although alpha interferons are currently the only therapies approved for treatment of HCV infection approximately half of the treated patients do not respond to the standard regimen of IFN-alpha-2b 3 MU administered 3 times per week (tiw) for 6 to 12 months. Of those who do demonstrate a response, 50-80% will relapse within 6 months after treatment cessation. Thus, the overall response to treatment is low. This paper focuses on studies that have been conducted with a newly developed interferon, Consensus Interferon (CIFN), in the treatment of chronic Hepatitis C. This type-1 interferon links the most common occurring amino acid sequences at each position of available natural alpha interferons into one 'consensus' protein. The thus synthesized molecule shows a 10-fold higher in vitro biological activity as compared to single recombinant IFN-alpha-2b or IFN-alpha-2a, possibly due to its greater binding affinity to interferon receptors. In patients with chronic hepatitis C, CIFN 9 micrograms, three times weekly for 24 weeks, proved to be equally efficacious and as safe as IFN-alpha-2b, but compared to 3 MU IFN-alpha-2b, CIFN 9 micrograms demonstrated improved responses in patients with high baseline viral titres. Retreatment of subjects who had responded but relapsed following standard dose IFN therapy for 6 months, with 15 micrograms CIFN three times weekly for 48 weeks, resulted in a sustained virological response rate of 58%. When previous non-responders to standard IFN therapy were retreated a 13% sustained response to the higher dose of CIFN for 48 weeks was observed. The higher dose of CIFN was well-tolerated and not associated with an increase in the incidence of side-effects. CIFN proved to be an effective and safe therapy in the treatment of patients with chronic hepatitis C and the retreatment of patients who either failed previous interferon treatment or had relapsed after its cessation.

Adult↗
PubMed1986

The use of interferon functional assays in the laboratory monitoring of patients with hepatocellular carcinoma receiving interferon.

Patients with hepatocellular carcinoma receiving recombinant leukocyte alpha interferon therapy were monitored using a series of assays to evaluate various components of the interferon system. Pretherapy serum interferon concentrations were not elevated significantly in these patients, although elevated levels were recorded after initiation of therapy. Both before and after interferon treatment, the peripheral blood leukocytes of the patients were shown to be capable of producing both gamma and alpha interferon when appropriately stimulated in vitro. The patients' peripheral blood leukocytes also responded to interferon therapy, with 85% resisting viral replication after treatment was initiated. However, interferon did not appear to be of therapeutic value in these patients.

Adult↗
PubMed1985

Decreased production of interferon alpha and interferon gamma in leucocyte cultures of schizophrenic patients.

In a first approach to measure the activity of the interferon system in schizophrenic patients, leucocyte cultures of schizophrenic patients and normal control individuals were set up using a whole blood assay. In this system both lymphoproliferation and the induction of interferon was tested. The lymphoproliferation (LP) test was performed with one bacterial recall antigen (PPD) and four different mitogens (phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and a novel mitogen derived from mycoplasma arthritidis - MAS). For induction of interferon two inducers of interferon alpha (Corynebacterium parvum and Newcastle disease virus (NDV] and two inducers of interferon gamma (PHA and Con A) were tested. Leucocytes of the patients responded to C. parvum, NDV and Con A with significantly lower titers of interferon, whereas the responses to PHA were lower than those of normals, but this difference was not significant. Regarding the LP test, significantly lower responses of the patients were obtained with PHA and Con A, whereas there were no significant differences when the responses to MAS, PWM or PPD were compared. Although our data cannot rule out a role of the medications in the defects observed, they may be indicative of a defect in the interferon system of schizophrenic patients.

Adult↗
PubMed1992

Anti-proliferative effect on human pancreatic cancer cells of natural human tumour necrosis factor-beta combined with natural human interferon-alpha or interferon-gamma.

The anti-proliferative effects of natural cytokines, human tumour necrosis factor-beta, natural human interferon-alpha and natural human interferon-gamma, on three human pancreatic cancer cell lines (PANC-1, MIA PaCa-2 and BxPC-3) were investigated in vitro. The anti-proliferative effect was determined using the dye uptake method and analysed for synergism by the median effect principle. Tumour necrosis factor-beta, as a single agent, had little anti-proliferative effect on any of the three cell lines, whereas interferon-alpha and interferon-gamma exhibited a strong anti-proliferative effect against two cell lines (MIA PaCa-2 and BxPC-3) and one cell line (BxPC-3), respectively. When tumour necrosis factor-beta and interferon-alpha were administered together (ratio 1:1), a synergistic effect was observed against PANC-1 cells. The combination of tumour necrosis factor-beta and interferon-gamma (ratio 10:1) was synergistic against both PANC-1 and MIA PaCa-2 cells. A synergistic anti-proliferative effect of tumour necrosis factor-beta and interferons was, therefore, observed even for cell lines that showed little biological response to each cytokine alone. The data suggest that some future improvement in the treatment of pancreatic cancer may be obtained by using combination cytokine therapy.

Cell Division↗
PubMed1987

The potency of interferon-alpha 2 and interferon-gamma in a combination therapy of dendritic keratitis. A controlled clinical study.

Forty-five patients with virologically confirmed dendritic keratitis were treated in a randomized, double-blind controlled study with a basic therapy of trifluorothymidine (TFT) eye drops. In addition they received different human recombinant interferon (rHu IFN) eye drops. The following results were obtained for average healing times: TFT plus one drop daily of rHu IFN-alpha 2 arg (30 million iu/ml): 3.3 days, TFT plus rHu IFN-gamma (30 million iu/ml): 3.9 days, TFT plus a mixture of alpha plus gamma (0.3 million iu/ml each): 6.1 days, TFT plus a mixture of alpha plus gamma (1.5 million iu/ml each): 3.3 days. High-titer gamma interferon did not significantly differ from high-titer alpha interferon in the combination therapy of dendritic keratitis. A mixture of alpha plus gamma at a moderate titer (1.5 million iu/ml each) was as effective as a high-titer mono-preparation. Adding a low-titer interferon mixture gave no better therapeutic results than antiviral monotherapy. Thus it seems possible to save about 90% of interferon commonly used in the combination therapy of dendritic keratitis by applying a mixture of different suitable interferons instead of interferon monospecies.

Clinical Trials as Topic↗
PubMed2005

Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C.

AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon. METHODS: Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. Patients were treated with conventional interferon alfa-2b (48/98 patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 mug peginterferon alfa-2b) in combination with weight-adapted ribavirin (800-1 200 mg/d). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R). RESULTS: Therapy with pegylated interferon alfa-2b produces comparable scores for depression (ANOVA: P = 0.875) as compared to conventional interferon. Maximums of depression scores were even higher and cases of clinically relevant depression were frequent during therapy with peginterferon. Scores for anger/hostility were comparable for both therapy subgroups. CONCLUSION: Our findings suggest that the extent and frequency of depressive symptoms in total are not reduced by peginterferon. Monitoring and management of neuropsychiatric toxicity especially depression have to be considered as much as in antiviral therapy with unmodified interferon.

Adolescent↗
PubMed1991

[Relation between interferon-inducing activity of natural interferon inducers and their chemical structure].

The interferon-inducing activity of new derivatives of gossypol, a low molecular weight natural polyphenol, and its model compounds was studied in regard to their chemical structure. The active groups required for development of optimal interferon inductors on the basis of the natural polyphenols were defined. As a result of the studies the new interferon inductor AC-1 which is a condensation product of gossypol, a natural polyphenol, and a cellulose derivative was isolated. The interferon-inducing activity of AC-1 was investigated with respect to its dose and the administration route. High interferon-inducing activity of the interferon inductor after its administration by any route in doses of 10 to 100 mg/kg was demonstrated. The serum interferon titers reached 2560 units/ml.

Administration, Oral↗
PubMed1980

Potentiation of antitumor effect of virus-induced interferon by mouse immune interferon preparations.

In inbred DBA/2 mice, the antitumor activities of separate and combined preparations of mouse immune interferon and mouse virus-induced interferon on the development of P388 tumors were studied. Immune interferon alone (25 U/day) did not affect tumor development. Virus-induced interferon alone (25,000 U/day) delayed tumor development and increased survival time. The mouse immune interferon preparations significantly enhanced or potentiated the antitumor effects of mouse virus-induced interferon when the interferons were used in combined therapy.

Animals↗
PubMedDate not supplied

[Combined action of a specific vaccine, exogenous interferon and an interferon inducer on the development of acute experimental encephalomyelitis].

Comparative studies of the effectiveness of specific vaccine, exogenous interferon, and interferon inducer poly I:C in mice experimentally infected with human acute encephalomyelitis (HAE) virus showed the interferon inducer poly(I) X poly(C) to exert the highest protective activity (up to 72.5% protection). Irrespective of the inoculation route (intraperitoneal, intramuscular, intravenous), the vaccine in combination with interferon or interferon inducer poly(I) X poly(C) produced a considerably higher level of protection of mice (78.5%) against fatal infection with HAE virus than each of the preparations used alone. Studies of the humoral and cellular immunity reactions showed that increased protection levels after the combined use of interferon inducer and vaccine were due to interferon production and activation of the mechanisms of cellular antiviral immunity.

Acute Disease↗
PubMedDate not supplied

[Interferon status and the activity of dsRNA-dependent enzymes in volunteers and influenza patients receiving human recombinant alpha 2-interferon (reaferon)].

The national recombinant preparation of alpha 2-interferon (reaferon) after intramuscular inoculation in a daily dose of 3 X 10(6) units/ml to human volunteers was found in the blood serum within 1-2 hours. In 85% of the subjects given the preparation, a 2-8-fold rise in interferon titers in the blood serum and in 64% an increase in interferon leukocyte reaction (ILR) by the 5th day after the beginning of the treatment were observed. In the examined influenza patients given the preparation, interferon circulation in the blood serum, increased ILR and 2-5A synthetase enzyme levels were demonstrated. Tests for interferon of the blood sera of patients given reaferon by inhalation revealed no significant rise in its level, in contrast to cases with reaferon intramuscular injections. It is assumed that the immunomodulating effect of the preparation given by inhalation is mediated through the hypothalamus. Thus, parameters of the interferon system may be corrected by administration of reaferon.

2',5'-Oligoadenylate Synthetase↗
PubMed2005

Ribavirin plus interferon versus interferon for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades and most patients are diagnosed based on the presence of hepatitis C virus ribonucleic acid and elevated transaminases. OBJECTIVES: To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials and pharmaceutical companies, until May 2004. SELECTION CRITERIA: We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon alone for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the sustained loss of hepatitis C virus and liver-related morbidity plus all-cause mortality. We separately analysed patients who were naive, relapsers, or non-responders to previous antiviral treatment. Random-effects and fixed-effect model meta-analyses were performed for all outcomes. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). MAIN RESULTS: We included 72 randomised trials with 9991 patients. Most trials had low methodological quality but we did not find any significant influence of quality on our results. Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.73, 95% CI 0.71 to 0.75) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.76), relapsers (RR 0.63, 95% CI 0.54 to 0.73), and non-responders (RR 0.89, 95% CI 0.84 to 0.94) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.46, 95% CI 0.22 to 0.96), but not in naive, relapsers, or non-responders individually. Combination therapy also had a significant beneficial effect on the histological response. Combination therapy significantly increased the risk of anaemia (RR 10.48, 95% CI 5.34 to 20.55), which occurred in 22% of patients on combination therapy. Combination therapy also significantly increased the risk of dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnea, fatigue) adverse events. Accordingly, combination therapy significantly increased the risk of treatment discontinuation (RR 1.19, 95% CI 1.01 to 1.39). AUTHORS' CONCLUSIONS: Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus and improving liver histology. This may lead to reduced morbidity and mortality. However, combination therapy significantly increased the risk of several adverse events.

Antiviral Agents↗
PubMed1997

Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection.

Hepatitis C virus (HCV) genotype 1b and high pretreatment virus load are predictive factors of poor response to interferon therapy in patients with chronic hepatitis C. To further examine the factors predicting the response to interferon in patients with genotype 1b infection, we analyzed 110 consecutive patients with HCV who were treated with a total of 624 million units of lymphoblastoid interferon alfa. Thirty-six patients (33%) were responders, while the remaining 74 patients (67%) were nonresponders. Multivariate analysis showed that a high virus titer (assessed by serum core protein level, P = .0021) and the presence of more than two amino acid substitutions in the interferon sensitivity-determining region (ISDR) (P = .0036) correlated significantly with the response to interferon therapy. Because mutations analyzed by direct sequencing of polymerase chain reaction (PCR) products may reflect artifacts of direct sequencing, we further analyzed quasispecies of HCV in this region by cloning and sequencing. Although PCR-based analysis of responders with multiple amino acid substitutions in the ISDR showed the presence of a small amount of wild-type strain in their serum, the results obtained by direct sequencing and cloning were essentially the same. A longitudinal study of quasispecies in 2 patients who showed a dramatic change in the virus titer showed no conversion from wild type to mutant or vice versa. Our results indicate that amino acid substitutions and virus load are independent predictors of the response to interferon therapy. The ability of some patients with no mutation in the ISDR or high virus load to eliminate the virus suggests the presence of other unidentified factors, host or viral, that influence the response to interferon therapy.

Adult↗