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Pharmacology of Interferon. Interferon. Natural Interferons. Man Made Interferons (Recombinant). Interferon Basics. Interferons play an important role in the first line of defense against viral infections Interferons are part of the non-specific immune system
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PharmacologyofInterferon Downloaded from www.pharmacy123.blogfa.com
Interferon Natural Interferons Man Made Interferons (Recombinant) Downloaded from www.pharmacy123.blogfa.com
Interferon Basics • Interferons play an important role in the first line of defense against viral infections • Interferons are part of the non-specific immune system • Interferons are made by cells in response to an appropriate stimulus Downloaded from www.pharmacy123.blogfa.com
Types on Interferon • alpha (leukocyte interferon) • produced by virus infected leukocytes • beta (fibroblast interferon) • produced by virus infected fibroblasts or epithelial cells • gamma (immune interferon) • produced by certain activated T cells & NK cells Downloaded from www.pharmacy123.blogfa.com
How Does It Prevent Viral Replication? virus cells (Other stimuli: exogenous ds RNA, LPS, bacterial components) Downloaded from www.pharmacy123.blogfa.com
How Does It Prevent Viral Replication? virus interferon Downloaded from www.pharmacy123.blogfa.com
How Does it Prevent Viral Replication? No replication virus Inhibitory proteins Downloaded from www.pharmacy123.blogfa.com
Interferon Response to Acute Viral Infection Downloaded from www.pharmacy123.blogfa.com
Effects of Interferon Treatment Downloaded from www.pharmacy123.blogfa.com
Mechanisms of Action • IFN alpha and beta • induction of inhibitory protein synthesis • IFN gamma • inc class II MHC molecules of APC • Inc ability of macrophages to resist viral infx and kill other cells if infected • All IFN • inc class I MHC molecules • inc activity of NK cells Downloaded from www.pharmacy123.blogfa.com
Viral Defense Against Interferon • block interferon binding to cells • inhibit action of interferon-induced protein kinase • inhibit NK function • interfere with cell surface expression MHC • block complement activation • prevent apoptosis in host cell Downloaded from www.pharmacy123.blogfa.com
Indications for Interferon • alpha • Hepatitis B & C, Hairy cell leukemia, Chronic myeloid leukemia, multiple myeloma, low grade lymphomas, Kaposi’s Sarcoma, Melanoma • beta • Multiple Sclerosis, (Ulcerative colitis) Downloaded from www.pharmacy123.blogfa.com
Indications for Interferon • gamma • Chronic granulomatous disease, Chronic Myeloid Leukemia, Renal cell Carcinoma Downloaded from www.pharmacy123.blogfa.com
Incomplete List of Interferons • Actimmune • Alferon • Avonex • Betaserone • Infergen • Intron • Wellferon, etc Downloaded from www.pharmacy123.blogfa.com
HCV Epidemiology • HCV is leading cause of liver disease • 4 million Americans have been exposed • approx 3 million are infected • HCV infection leads to decompensated cirrhosis and hepatocellular carcinoma • HCV-related cirrhosis is the most common reason for OLT in the US NIH Consensus Development Conference Statement 2002 Downloaded from www.pharmacy123.blogfa.com
Distribution of HCV Downloaded from www.pharmacy123.blogfa.com
Management of Hepatitis C • Consensus Statement in 2002 • treatment eligible patients • IVD users, consume alcohol, comorbidities (depression, HIV coinfections) • pegylated interferon with ribiviran better than peginterferon monotherapy or standard interferon-ribivarin Downloaded from www.pharmacy123.blogfa.com
HCV Infection Downloaded from www.pharmacy123.blogfa.com
Interferon in Hepatitis C • Monotherapy • standard interferon 3 Million units inj tiw (Low Sustained virologic response) • Combination therapy • standard interferon with ribivarin • pegylated interferon with ribivarin Downloaded from www.pharmacy123.blogfa.com
Interferon in HCV • Limitations • monotherapy not very effective • cumbersome dosing (TIW) • multiple side effects Downloaded from www.pharmacy123.blogfa.com
Interferon Side Effects (Hepatitis C Data) • Flu-like symptoms • Headache • Nausea, vomiting, diarrhea • Depression, irritability, anxiety • Injection site reactions, partial alopecia • Hematologic abnormalities • Autoimmune disorders Downloaded from www.pharmacy123.blogfa.com
Management of Side Effects • Depression (77% Manns et al, Lancet 2001) • NIH consensus - “monitor patients for depression and prescribe antidepressants when necessary” • Hematologic abnormalities • neutropenia and thrombocytopenia • treatment options include decreasing dose or giving hematopoietic growth factors Downloaded from www.pharmacy123.blogfa.com
Pegylated Interferon • HCV is an ideal setting for peginterferon • polyethylene glycol (PEG):interferon • Pegylation was developed to overcome disadvantages of standard interferon • shields IFN from enzymatic degradation thus lowers systemic clearance • allows less frequent dosing • achieve higher/sustained serum [interferon] Downloaded from www.pharmacy123.blogfa.com
Fried et al: Peginterferon Alfa-2a Plus Ribavirin 56% 44% 29% P=<0.001 Downloaded from www.pharmacy123.blogfa.com
Differences in PEG • peginterferon alfa-2b • linear molecule • weight 12 kDa • peginterferon alfa-2a • larger, branched molecule • weight 40 kDa Downloaded from www.pharmacy123.blogfa.com
Peginterferon Downloaded from www.pharmacy123.blogfa.com
Pharmacologic Parameters of Peginterferons Downloaded from www.pharmacy123.blogfa.com
Weight-Based Dosing and Peginterferon Therapy • Once weekly dosing • alfa 2b • weight based dosing (1-1.5 mcg/kg/week) • high volume of distribution • kidney, heart, liver and throughout the bloodstream • alfa 2a • fixed dose at 180 mcg/week • low volume of distribution Downloaded from www.pharmacy123.blogfa.com
Conclusions • Interferons are important in the nonspecific immune response • Interferons are effective in the treatment of patients with chronic hepatitis • Pegylated interferons are superior therapies for patients with HCV • Side effects should be monitored closely Downloaded from www.pharmacy123.blogfa.com