Serum interferon

Calf kidneys, dog kidneys and rhesus monkey kidneys were treated with trypsin to give suspensions of cells. The suspensions were centrifuged and the packed cells diluted with 400 volumes (calf cells) or 200 volumes (dog cells and rhesus monkey cells) of a growth medium consisting of 5% horse serum and 0.5% lactalbumen hydrolysate in Earle s saline, with 100 units/ml each of penicillin and streptomycin. These media were used separately to produce Semliki Forest/calf interferon, Semliki Forest/dog interferon and Semliki Forest/rhesus monkey interferon. The cell-containing growth medium was dispensed into 500 ml medical flat bottles (70 ml in each). The cultures were incubated at 36°C. Confluent sheets of cells (monolayers) were formed in 5 to 6 days. The growth medium was then removed and the monolayers were washed with isotonic phosphate-buffered saline, pH 7.5. 

Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases associated with hepatitis B and hepatitis C vims infections with high incidences. Here, an acyclic retinoid has been shown to suppress the posttherapeutic recurrence after interferon-y or glycerrhicin treatment in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induced the disappearance of serum lectin-reactive a-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of... 

Lampertico P, Del Ninno E, Manzin A, Donato MF, Rumi MG, Lunghi G, Morabito A, Clementi M, Colombo M (1997) A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 26 1621-1625... 

Osborn BL, Olsen HS, NardeUi B, Murray JH, Zhou JX, Garcia A, Moody G, Zaritskaya LS, Sung C (2002) Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 303 540-548 Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-Conl with natural recombinant interferons-alpha antiviral, antiproliferative, and natural kiUer-inducing activities. J Interferon Res 12 55-59... 

Pastore G, Santantonio T, Milella M, Monno L, Mariano N, Moschetta R, PolUce L (1992) Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon. J Hepatol 14 221-225 Pawlotsky JM (2006) Therapy of hepatitis C from empiricism to eradication. Hepatology 43 S207-S220... 

Parissis JT, Adamopoulos S, Venetsanou KF, Mentzikof DG, Karas SM, Kremastinos DT. Serum profiles of C-C chemokines in acute myocardial infarction possible implication in postinfarction left ventricular remodeling. J Interferon Cytokine Res 2002 22(2) 223-229. 

The bDNA assay was used to study the clinical impact of coinfection and the effects of interferon-a and ribavirin therapy of HGV/GBV-C RNA levels in patients chronically infected with both HGV/GBV-C and HCV (Lau et al, 1997 Martinot et al., 1997 McHutchinson et al., 1997). There were no differences in the clinical, biochemical, or histological features of the coinfected patients compared with those infected with HCV alone. Interferon-a treatment caused a marked but usually transient reduction in serum levels of HGV/GBV-C RNA, and ribavirin caused a modest reduction of viral load of 0.5 to 1 log10. 

Kobayashi, Y., et al. (1993). Quantitation and typing of serum hepatitis C vims RNA in patients with chronic hepatitis C treated with interferon-(3. Hepatology 18, 1319-1325. 

McHutchinson, J. G., etal. (1997). Hepatitis C and G co-infection Response to interferon therapy and quantitative changes in serum HGV-RNA. Hepatology 26, 1322-1327. 

Braun and Alsenz6 used an ELISA to detect aggregates in interferon-alpha (IFN-a) formulations. They analyzed IFN-a formulations for possible aggregate formation because all marketed interferons are reported to induce antibodies to some extent. Because of its stabilizing effects, human serum albumin (HSA) is used in the formulation of marketed IFN-a at a great excess over IFN-a itself. HSA can also interact with other proteins. Braun and Alsenz developed an ELISA for the detection of both IFN-a-IFN-a and HSA-IFN-a aggregates. A MAb was used for the capture and detection of the IFN-a and a polyclonal for the detection of HSA. The assay is shown schematically in Figure 11.4. 

The synthetic polymeric components as well as their combinations with proteins such as human serum albumin (HSA), bovine serum albumin (BSA), human serum albumin/a-interferon mixtures (HSA-IFNa) and myoglobin (MYO) did not give any negative response to in vitro and in vivo biocompatibility tests, such as platelet aggregation, complement activation, acute toxicity, and acute thromboembolic potential. 

High temperatures can break native S-S bonds and form new S-S bonds which can lock the protein into a denatured eonfiguration [89]. Low pH, sodium dodecyl sulfate. Tween 80, chaotropie salts, and exogenous proteins have been used to protect proteins from thermal inaetivation [90]. Ethylene glycol at 30-50% was used to protect the antiviral activity of P-interferon preparations [91]. Human serum albumin was used in recombinant human interferon-Psei-n which resulted in increased thermal stability [62]. Water-soluble polysaeeharides sueh as dextrans and amylose [92], as well as point-specific (site-directed) mutagenesis [93] have also been used to increase thermal stability of therapeutie proteins and peptides. 

The presence of a certain number of amino acids is significant for the restitution of the immune system s cells, interferon synthesis process and other factors realization of the immune defense system. The decrease of full-form protein consumption is one of the causes of secondary immune-deficiency states. The significance of ascorbic acid presence for the immune system is supported by the fact that its concentration in the neutrophil granulocytes is 150 times higher than in the blood serum. The significance of retinol s and carotenoids role is supported in the cases of cell differentiation, where DNA synthesis increase, and proliferation decrease thus stabilizing the organism when under infection. 

Immunogenicity Nine percent of patients treated with peginterferon alfa-2a with or without ribavirin tablets developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. 

Interferon beta-1 b- Peak serum concentrations occurred between 1 and 8 hours. Bioavailability, based on a total dose of 0.5 mg given as 2 subcutaneous injections at different sites, was approximately 50%. 

Mean serum clearance values ranged from 9.4 to 28.9 mL/min/kg and were independent of dose. Mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 to 2.88 L/kg. IV dosing 3 times/week for 2 weeks resulted in no accumulation of interferon beta-la or beta-lb in the serum of patients. 

Hepatic injury Hepatic injury, including elevated serum hepatic enzyme levels and hepatitis, some of which have been severe, has been reported postmarketing. Monitor patients for signs of hepatic injury and exercise caution when interferons are used concomitantly with other drugs associated with hepatic injury. 

Elevated concentrations of TNF have been found in the joints of RA patients and the stools of Crohn disease patients and correlate with elevated disease activity. In Crohn disease, infliximab reduces infiltration of inflammatory cells and TNF production in inflamed areas of the intestine and reduces the proportion of mononuclear cells from the lamina propria able to express TNF and interferon. In RA, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion and vascular cell adhesion molecule-1, chemoattraction, and tissue degradation. After treatment with infliximab, patients with Crohn disease or RA have decreased levels of serum IL-6 and C-reactive protein compared with baseline. 

Interferon alfa-2b (Intron A) is a recombinant DNA product derived from the interferon alfa-2b gene of human white blood cells. Its mechanism of antitumor action involves binding to a plasma membrane receptor but is otherwise poorly understood. Its serum half-life is 2 to 3 hours after parenteral administration. 

Pharmacokinetics Interferon beta-la-. After IM administration, peak serum levels attained in 3-15 hr. Biologic markers increase within 12 hr and remain elevated for 4 days. Half-life 10 hr (IM). Interferon beta-lb Half-life 8 min-4.3 hr. 

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