DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1610 without known airway disease, and acute deteriorations in lung function,
including fatal outcomes, have occurred in those with underlying
asthma or chronic obstructive airway disease. Tolerability in more serious
bronchopulmonary disorders or in intubated patients is uncertain.
Zanamivir is not generally recommended for treatment of patients with
underlying airway disease (e.g., asthma or chronic obstructive pulmonary
disease) because of the risk of serious adverse events.
Preclinical studies of zanamivir revealed no evidence of mutagenic,
teratogenic, or oncogenic effects (pregnancy Category C). No
clinically significant drug interactions have been recognized to date.
Zanamivir does not diminish the immune response to injected
influenza vaccine.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Therapeutic Uses. Inhaled zanamivir is effective for the prevention
and treatment of influenza A and B virus infections.
Early zanamivir treatment (10 mg [two inhalations] twice
daily for 5 days) of febrile influenza in ambulatory adults and children
≥5 years of age shortens the time to illness resolution by 1-3 days
(Eiland and Eiland, 2007) and in adults reduces by 40% the risk of
lower respiratory tract complications leading to antibiotic use (Kaiser
et al., 2000). Once-daily inhaled, but not intranasal, zanamivir is
highly protective against community-acquired influenza illness, and
when given for 10 days, it protects against household transmission
(Eiland and Eiland, 2007). Intravenous zanamivir is protective against
experimental human influenza and is being evaluated for the 2009
nH1N1 EUA.
ANTI-HEPATITIS VIRUS AGENTS
A number of agents are available for treatment of hepatitis
B virus (HBV) and hepatitis C virus (HCV) infections.
Several agents (e.g., interferons, ribavirin, and the
nucleoside/nucleotide analogs lamivudine, telbivudine,
and tenofovir) have other uses as well (Chapters 59 and
65). Therapeutic strategies for these two chronic viral
infections, hepatitis B and C, are very different and are
described separately.
Drugs Used Mainly for Hepatitis
C Virus Infection
Hepatitis C is one of the most common chronic virus
infections in the developed world and is associated with
significant morbidity and mortality. Untreated, this
virus can cause progressive hepatocellular injury with
fibrosis and eventual cirrhosis. Chronic HCV is also a
major risk factor for hepatocellular carcinoma.
Although the virus is quite prolific, producing several
billion new particles every few days in an infected
individual, this RNA virus does not integrate into chromosomal
DNA, and it does not establish latency per se.
Therefore the infection is, in theory, curable in all
affected individuals. The current standard of care for
treatment is a combination of peginterferon alfa and ribavirin,
which produces a high cure rate in selected virus
genotypes only (McHutchison et al., 2009). Recent
advent of highly effective oral agents that are pharmacologically
selective for this pathogen, including HCV
protease inhibitors and polymerase inhibitors, bring
hope for curative combinations of oral agents. It is likely
that treatment recommendations for this infection will
change radically in the coming decade.
Interferons
Classification and Antiviral Activity. Interferons (IFNs)
are potent cytokines that possess antiviral,
immunomodulatory, and antiproliferative activities
(Biron, 2001; Samuel, 2001) (Chapter 35). These proteins
are synthesized by host cells in response to various
inducers and, in turn, cause biochemical changes
leading to an antiviral state in cells. Three major classes
of human interferons with significant antiviral activity
currently are recognized: α (>18 individual species), β,
and γ. Clinically used recombinant α-IFNs (Table
58–2) are non-glycosylated proteins of ~19,500 Da, the
pegylated forms predominating in the U.S. market.
IFN-α and IFN-β may be produced by nearly all
cells in response to viral infection and a variety of other
stimuli, including double-stranded RNA and certain
cytokines (e.g., interleukin 1, interleukin 2, and tumor
necrosis factor). IFN-γ production is restricted to T-
lymphocytes and natural killer cells responding to antigenic
stimuli, mitogens, and specific cytokines. IFN-α
and IFN-β exhibit antiviral and antiproliferative actions;
stimulate the cytotoxic activity of lymphocytes, natural
killer cells, and macrophages; and upregulate class
I major histocompatibility (MHC) antigens and other
surface markers. IFN-γ has less antiviral activity but
more potent immunoregulatory effects, particularly
macrophage activation, expression of class II MHC
antigens, and mediation of local inflammatory
responses. In addition, interferons downregulate production
of a number of cellular proteins, which may be
an equally important mediator of the pharmacological
benefit of these agents.
Most animal viruses are inhibited by IFNs,
although many DNA viruses are relatively insensitive.
Considerable differences in sensitivity to the effects of
IFNs exist among different viruses and assay systems.
The biological activity of IFN usually is measured in
terms of antiviral effects in cell culture and generally is
expressed as international units (IU) relative to reference
standards.
Mechanisms of Action. Following binding to specific
cellular receptors, IFNs activate the JAK-STAT signaltransduction
pathway and lead to the nuclear translocation
of a cellular protein complex that binds to genes