Virus maturation inhibition

inhibits glycosyltransferase, thereby reducing glycoprotein maturation causes membrane changes —> blocks budding

FIGURE 49-3 Interferon-mediated antiviral activity occurs via multiple mechanisms. The binding of IFN to specific cell surface receptor molecules signals the cell to produce a series of antiviral proteins. The stages of viral replication that are inhibited by various IFN-induced antiviral proteins are shown. Most of these act to inhibit the translation of viral proteins (mechanism 2), but other steps in viral replication also are affected (mechanisms 1, 3, and 4). The roles of these mechanisms in the other actions of IFNs are under study. Key: IFN = interferon; mRNA = messenger RNA; Mx = specific cellular protein; tRNA = transfer RNA; RNase L = latent cellular endoribonuclease; 2'5'A = 2'-5'-oligoadeny-lates; eIF-2a = protein synthesis initiation factor.

Conversely, IFNs may mediate some of the systemic symptoms associated with viral infections and contribute to immunologically mediated tissue damage.

ABSORPTION, DISTRIBUTION, AND ELIMINATION

After intramuscular or subcutaneous injection of IFN-a, absorption is >80%. Plasma levels are dose-related, peaking at 4-8 hours and returning to baseline by 18-36 hours. Levels of 2-5(A) synthetase in peripheral blood mononuclear cells show increases beginning at 6 hours and lasting through 4 days after a single injection. An antiviral state in peripheral blood mononuclear cells peaks at 24 hours and returns to baseline by 6 days after injection. Intramuscular or subcutaneous injections of IFN-fi result in negligible plasma levels, although increases in 2-5(A) synthetase levels may occur. After systemic administration, low levels of IFN are detected in respiratory secretions, CSF, eye, and brain.

Because IFNs induce long-lasting cellular effects, their activities are poorly predicted from usual pharmacokinetic measures. After intravenous dosing, clearance of IFN from plasma occurs in a complex manner. With subcutaneous or intramuscular dosing, the plasma elimination t122 of IFN-a ranges from 3 to 8 hours, largely due to distribution to the tissues, cellular uptake, and catabolism in the kidney and liver. Negligible amounts are excreted in the urine. Clearance of IFN-a2 is reduced by ~70% in dialysis patients.

Attachment of IFN proteins to large, inert polyethylene glycol (PEG) molecules (pegylation) slows absorption, decreases clearance, and provides higher and more prolonged serum concentrations that enable once-weekly dosing. Two pegylated IFNs are available: peginterferon alfa-2a and peginterferon alfa-2b. PegIFN alfa-2b has a 12,000-Da PEG that increases the plasma t122 from 2 to 3 hours to 30-54 hours. PegIFN alfa-2a contains a branched-chain 40,000-Da PEG bonded to IFN-a2a and has a plasma t122 of ~80-90 hours. For pegIFN alfa-2a, peak serum concentrations occur up to 120 hours after dosing and remain detectable throughout the weekly dosing interval; steady-state levels occur 5-8 weeks after initiation of weekly dosing. For pegIFN alfa-2a, dose-related maximum plasma concentrations occur at 15-44 hours after dosing and decline by 96-168 hours. These differences in pharmacokinetics may be associated with differences in antiviral effects. Increasing PEG size is associated with longer t122 and less renal clearance. About 30% of pegIFN alfa-2b is cleared renally; pegIFN alfa-2a is cleared primarily by the liver. Dose reductions in both pegylated IFNs are indicated in end-stage renal disease.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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