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How Does Interferon Work in Your Body
  Overview of Pharmacodynamic Properties
Excerpted from full report from Adis Intl., written by Caroline Perry and Blair Javis; www.adis.com; report supported by grant from Roche, manufacturer of Pegasys
The interferons are a family of naturally occur-ring proteins with nonspecific regulatory activity. These cytokines are secreted by many mammalian cells and influence cell growth and differentiation, modulate the immune response and inhibit the replication of a number of viruses including hepatitis B and C. Although the antiviral, immunomodulatory and anti-inflammatory properties of interferon-a are thought to contribute towards its beneficial effects in patients with chronic hepatitis C, the exact mechanism of action of this cytokine in hepatitis C has yet to be established. [20] The mechanisms of action of interferon-a have been reviewed in detail elsewhere; [21-23] this section therefore provides a brief overview of its putative antiviral activity in patients with chronic hepatitis C. Unlike many anti-HIV drugs, which target the functions of HIV proteins, the antiviral activity of interferon-a is achieved by its ability to alter interactions between the host and virus in a complex man-ner.
[22] After administration, interferon-a binds to high-affinity receptors on the target cell surface which activates a cascade of reactions in the cell and triggers the activation of many genes. The numerous cellular activities of interferon-a are mediated by the products of these interferon-o -inducible genes. [21,22] The antiviral activity of interferon-a is achieved via two different but complementary mechanisms. Firstly, interferon-a induces a nonspecific antiviral state in the virus-infected cell [e.g. by stimulating the 2,5-oligoadenylate synthetase (OAS) system and Mx proteins] which leads to the inhibition of HCV replication. Secondly, the drug induces immunomodulatory effects that intensify specific host immune responses against the virus. [22] The immunomodulatory effects of interferon-a are triggered by its binding to the surface receptors of immune cells. Activation of macrophages, natural killer cells and cytotoxic T lymphocytes, and stimulation of the production of type 1 T-helper cells are among the many imunomodulatory effects produced by the drug. Interferon-a also has anti-inflammatory properties, which are achieved via inhibition of the production of tumour necrosis factor-a , interleukin (IL)-1 and IL-8 and stimulation of the production of IL-10, a cytokine that produces a down-regulation of the pro-inflammatory response and modulation of hepatic fibrogenesis. [22]
Data on the pharmacodynamic properties of peginterferon-a -2a (40kD) (Pegasys) in humans are limited at present. However, preliminary results of one in-vestigation showed that the pharmacological activity of interferon-a -2a is augmented by pegylation. [24] The activity of OAS, a key effector protein synthesised in response to interferon-a stimulation and involved in interferon-mediated inhibition of viral function, [21,22] increased with dose in volunteers (number not reported) after single 45, 135 or 270ug subcutaneous doses of peginterferon-a -2a (40kD), or single 3 or 18MU subcutaneous doses of interferon-a -2a. [24] Notably, maximum serum OAS activity occurred approximately 48 hours after administration of the dose and remained at about this level for up to 168 hours (1 week) before declining in the peginterferon-a -2a (40kD) [135ug] treatment groups, [24] reaching baseline after the second week following administration. Interferon-a -2a 3MU produced less OAS activity than the 18MU dose and, as with the higher dose, OAS activity declined 24 hours after administration. [24]
Editorial note: in the end the performance of Pegasys in humans is what counts. In other words its ability to reduce viral load to undetectable levels and sustain this is what counts. Pegasys is in the FDA review process for approval. It is not yet available in the pharmacy, only in studies. FDA approval and commercial availability is expected in Summer 2002.
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