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Phase II trials of interferons-alpha and -beta in advanced sarcomas.

Interferons (IFNs)-alpha and -beta were administered to patients with metastatic sarcomas in two different Eastern Cooperative Oncology Group studies. In one study, patients received IFN-alpha 2b, 20 million units/m2 i.v. 5 days/week x 4, then 10 million units s.c.t.i.w. In the second study, patients received IFN-beta ser 180 million units t.i.w. Of 87 patients evaluable for response, there were three responses in 64 patients (5%) treated with IFN-alpha-2b and no responses in 23 patients treated with IFN-beta ser. Severe or life-threatening fatigue with decline in performance status complicated treatment of 37% of patients receiving IFN-alpha 2b and 17% of patients receiving IFN-beta ser. Further investigation of IFNs in sarcomas should depend on evidence from preclinical studies demonstrating synergistic effects of IFNs combined with a cytoreductive modality which has proven activity in these malignancies.

Adult

Herpes simplex virus type 2 and pseudorabies virus associated growth factors and their role in the latency in vitro.

A putative herpes simplex virus type 2 (HSV-2) growth factor (HSGF-2) was detected in a crude extract from virus infected mouse embryo cells. This factor, similar to previously described pseudorabies virus (PRV) associated growth factor (PRGF) was shown to have ability to morphologically transform non-transformed cells and to repress the transformed phenotype of transformed cells. Both activities could be neutralized with two, out of seven monoclonal antibodies directed against glycoprotein B of HSV-2. Both PRGF and HSGF-2 were detected in human embryo lung cells latently infected with PRV or HSV-2 either at 41 degrees C, or in the presence of phosphonoacetic acid. Human alpha-2 interferon, when present in medium of latently infected cells enhanced the production of both HSGF and PRGF. On the contrary, when latently infected cells were treated with 5-azacytidine the synthesis of both PRGF and HSGF-2 was completely blocked and the virus reactivated from latency replicated to higher titers than in non-treated cells. The role of PRGF and HSGF-2 in the establishment, maintenance and reactivation of latency, as well as in cellular transformation is discussed.

Animals

Serum hepatitis C virus (HCV)-RNA and response to alpha-interferon in anti-HCV positive chronic hepatitis.

Hepatitis C virus (HCV) replication was assessed before and during alpha-interferon (IFN) treatment in 22 anti-HCV positive patients with posttransfusion or sporadic chronic hepatitis (CH). Eleven patients were "responders" and 11 patients "non-responders" to IFN. Thirteen anti-HCV negative healthy subjects and five anti-HCV negative patients with autoimmune CH served as controls. Serum HCV-RNA was detected by the polymerase chain reaction (PCR) in all untreated anti-HCV positive patients but in none of the anti-HCV negative subjects. PCR primers from the 5'-noncoding (NC) region were more sensitive than primers from a non-structural (NS5) region in detecting HCV-RNA (21/22, 95% vs. 7/22, 32%, respectively). Positive strand HCV-RNA titre and positivity rate for the negative strand were similar in responders and non-responders before IFN treatment, as well as anti-c100-3 titre by enzyme-linked immunosorbent assay (ELISA), and anti-5-1-1, anti-c33c, anti-c22 positivity rate by immunoblot assay (RIBA). HCV-RNA positivity by both NC and NS primers was more frequent before IFN among responders. During IFN treatment, serum HCV-RNA was detectable, mostly at low titres, in 1 (NC positive) of the 11 responders and in 9 (4 NS positive and 5 NC positive) of the 11 non-responders. Among the four non-responders who were NS positive during IFN, three were NC positive before IFN. Serum HCV-RNA was always found in our post-transfusion or sporadic anti-HCV positive patients with CH. Viraemia generally decreased during IFN treatment, but no available HCV markers clearly distinguished responders from non-responders before IFN treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

The ultrastructure of the noninvolved urothelium of tumor-bearing patients before and after interferon treatment.

The ultrastructural morphology of the noninvolved urothelium of tumor-bearing patients before and after interferon-alpha 2b (IFN-alpha 2b) treatment was investigated. The ultrastructure of the normal bladder urothelium has been reported. The noninvolved urothelium of our patients already showed deviation from the normal. At the end of therapy, we noted a partial restoration of the urothelium to its normal morphology with the reestablishment of some of its normal features, i.e., a well-developed Golgi apparatus, the existence of parts of the asymmetric unit membrane, and the appearance of nuclear bodies. Prevention of tumor recurrence by restoring the ultrastructural morphology of the noninvolved urothelium with IFN-alpha 2b is a subject worthy of further investigation.

Aged

Treatment of basal cell carcinoma with intralesional interferon alpha: a case report and literature review.

We report the case of a 76 year old man with three ulcerated basal cell carcinomas on his lower limbs. He was considered unsuitable for surgical therapy and was treated by intralesional interferon alpha-2b (Intron A) injections. Twenty months post therapy two of the three treatment sites remain clinically cured. Recurrence occurred at the site which received the smallest total dose of interferon. A review of the therapeutic trials of interferon alpha for basal cell carcinoma is presented. We conclude that interferon alpha-2b is a useful agent for treatment of basal cell carcinoma in selected patients.

Aged

Treatment of subfoveal choroidal neovascular membranes with systemic interferon-alpha 2a.

Systemic interferon-alpha has recently been reported to be useful in the treatment of choroidal neovascular membranes (CNVM) in age-related macular degeneration. To further investigate its effect we treated eight patients with subfoveal choroidal neovascular membranes of various aetiologies including idiopathic, age-related macular degeneration and myopic chorioretinal degeneration. Only one of the eight patients responded with an angiographically demonstrated decrease in the size of the CNVM; this was in a patient from the idiopathic group. Considerable side-effects were reported with marked lethargy and malaise limiting compliance with some patients. Although this is an initial report with limited patient numbers and follow-up, it does suggest a role for interferon-alpha in patients with idiopathic neovascular membranes where the retina is otherwise normal, but raises some doubt as to its efficacy in the treatment of age-related macular degeneration.

Adult

Effect of interferon (IFN) on refractory idiopathic thrombocytopenic purpura: administration of 6 million units of recombinant IFN alpha-2b.

Five patients (six courses) with refractory idiopathic thrombocytopenic purpura (ITP) were given 6 million units of recombinant interferon (IFN) alpha-2b in 12 doses to achieve an improved response rate compared to previous studies using 3 million units. From the initial IFN administration, the platelet count increased from a pre-treatment level of 20.7 +/- 17.7 x 10(3)/microliters (mean +/- SD) and reached its first peak in weeks 2 or 3 of therapy (p < 0.05). In week 5, the platelet count made its second and maximum peak (66.5 +/- 57.9 x 10(3)/microliters; p < 0.05). A relatively good response of the platelet count (an increase to > 50 x 10(3)/microliters) was observed in three patients (four courses) out of five. These responses were not much faster or more improved than in previous reports, and a dose of 6 million units may be too large to treat some ITP patients. The platelet-associated IgG level showed a tendency to be reduced with IFN therapy. The mechanism for the increase of the platelet count may be the modification of platelet autoantibody production.

Adult

[The clinico-laboratory dynamics in the reaferon treatment of glomerulonephritis patients with the nephrotic syndrome].

Overall 40 chronic glomerulonephritis patients with nephrotic syndrome were treated by reaferon. All the patients underwent clinical and laboratory examinations and nephric biopsy. As a result of the treatment, all the patients demonstrated an increase of the level of glomerular filtration, stabilization of protein and lipid metabolism along with the lowering of diurnal proteinuria. Reaferon exerted a beneficial effect on cellular factors of immunity. In some cases, the use of reaferon can be a definite alternative of the conventional treatment methods.

Adolescent

[The use of interferon in the combined therapy of juvenile rheumatoid arthritis].

The efficacy of recombinant gene engineering alpha 2-interferon (reaferon) was studied and compared in 60 patients suffering from verified juvenile rheumatoid arthritis (JRA). Reaferon was shown to possess good tolerance and to produce an adequate therapeutic effect. The combined use of reaferon and methotrexate permits potentiating the therapeutic effect of interferon and avoiding side effects seen with methotrexate used alone. Besides, it makes it possible to reduce the incidence of respiratory infections which are often associated with exacerbation of the underlying disease when treated by conventional methods.

Administration, Rectal

alpha-Interferon treatment of chronic hepatitis C in young patients with homozygous beta-thalassemia.

BACKGROUND: Chronic infection with the hepatitis C virus (HCV) and iron overload are the main causes of chronic liver disease in subjects with homozygous beta-thalassemia (HBT). Iron overload can be counteracted by intensive chelation. alpha-interferon reduces viremia and necroinflammation in patients with chronic HCV hepatitis. METHODS: To assess the effectiveness and safety of alpha 2b-Interferon (IFN), we enrolled in an open pilot trial of treatment 12 patients with HBT and biopsy-proven anti-HCV positive chronic hepatitis. IFN was given at a dose of 5 MU/m2 thrice weekly for 8 weeks, then 3 MU/m2 thrice weekly for 18 weeks. Patients were followed up to 24 months after stopping treatment when a second liver biopsy was performed in subjects with sustained response (normal ALT during follow-up). RESULTS: Two patients discontinued IFN at 7 weeks because of haemolytic anemia and one after 8 weeks due to persistent fever. Among 9 subjects completing the protocol, 5 normalized ALT while on treatment and a further 2 within two months after stopping IFN. A sustained response was obtained altogether in 5 patients, since ALT relapsed in 2 responders. None of the 3 subjects who discontinued IFN and of the 2 patients who did not respond to treatment normalized ALT over a 24 months follow-up. Post-treatment liver histology in long-term responders showed a reduction of portal, periportal and lobular necroinflammation, while siderosis was essentially unchanged. CONCLUSIONS: Although the pattern of response to IFN in HCV-infected subjects with HBT might differ from that of non-thalassemics, due to peculiar side effects and delayed response, the drug appears to be effective and deserves further investigation.

Adolescent

[Treatment with interferon alfa-2a in the chronic phase of Philadelphia-positive chronic myeloid leukemia].

PURPOSE: To evaluate the cytologic and cytogenetic response attained with interferon alpha-2a (IFN, Roferon*A) in patients with Ph '-positive chronic myelogenous leukaemia (CML) in the chronic phase. MATERIAL AND METHODS: A prospective study was carried out on 22 CML patients diagnosed in the Haematology Service at the Princesa Hospital in Madrid. The therapeutic regime consisted of two phases: A) Hydroxyurea was given until the white-cell count was reduced to 15-20 x 10(9)/L. B) Roferon*A was then given subcutaneously at a doses of 5 MU/m2 per day. The follow-up was performed weekly, and monthly once the leucocyte count had stabilized. The cytologic and cytogenetic response was assessed by bone marrow aspiration performed after 6, 9, 12 and 18 months. The toxicity was evaluated in accordance with the WHO recommendations. RESULTS: The median follow-up is 263 days (21-930). Thirteen patients (65%) had initial complete haematological response and 3 (15%) had partial response. The mean time to achieve response was 42 days (0-321). In the last evaluation, 69% of the patients were in sustained haematological remission (53% complete and 16% partial) with median follow-up of 232 days (21-930). The cytogenetic response was evaluable in 13 patients (follow up > or = 6 months): three attained complete response (23%) and three others partial response (23%). The commonest untoward effects were hypertriglyceridaemia (100%) and myelosuppression (86%). Grade-III thrombocytopenia was seen in 19% of the patients and grade-III anaemia or leucopenia in 5%. No infectious or haemorrhagic complications have appeared. Therapy was discontinued in 3 patients (14%), two due to severe flu-like syndrome and one for parkinsonism after 809 days of treatment. At the moment of evaluation two patients had died, one in lymphoid blastic crisis on day 217 and the other in the immediate post-BMT period. CONCLUSION: Treatment with interferon-alpha 2A is useful in the chronic phase of CML. An important number of responses can be attained, even in patients in the late chronic phase, and the toxicity seems acceptable.

Adolescent

Highly active effect of alpha interferon in blocking the cutaneous delayed hypersensitivity.

A group of 13 patients with contact dermatitis to various chemical compounds such as potassium dichromate, nickel sulphate, formaldehyde and balsam of Peru, was investigated by patch test and by the agreement between the history of disease and the patch test, the specific allergen involved in each special case could be demonstrated. Two-three days after the first patch test three normal skin areas were chosen. The first area was intradermally infiltrated with alpha-2a Interferon (IFN) (100,000 I.U. in 1 ml), the second area was infiltrated with saline and the third area, considered as control, did not receive any treatment. Once more the corresponding allergen was applied into the skin in a second patch-test. After 48 hours in the IFN infiltrated area, only the delayed contact hypersensitivity become negative thus proving that alpha-2a IFN behaves as an efficient inhibitor of these immune effector reactions. Since the lymphocytes involved in the delayed type hypersensitivity reactions (in our case contact dermatitis) belong to the T helper line, i.e., are CD-4 positive cells we conclude that alpha-2a IFN in vivo is an efficient inhibitor of the activation of these cells. This effect achieved by any CD-4(+) DTH clones does not depend on their antigenic specificity. Some clinical trials are now in progress in our laboratory to turn to account this important biological effect in the clinical practice as an efficient inhibitor in skin contact dermatitis.

Adolescent