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

IL-4, IL-13
FcεRI
Mast cell
FcεRII/CD23
Histamine
Cys-LTs
PGD 2
1055
CHAPTER 36
B lymphocyte
IgE
Anti-IgE
omalizumab
Macrophage
T lymphocyte
Chronic
inflammation
Eosinophil
Figure 36–12. Immunoglobulin (Ig)E plays a central role in allergic diseases. Blocking IgE using an antibody, such as omalizumab,
is a rational therapeutic approach. IgE may activate high-affinity receptors (FcεRI) on mast cells as well as low-affinity receptors
(FcεRII, CD23) on other inflammatory cells. Omalizumab prevents these interactions and the resulting inflammation. cys-LT, cysteinylleukotriene;
IL, interleukin; PG, prostaglandin.
PULMONARY PHARMACOLOGY
New Drugs in Development for Asthma and
Chronic Obstructive Pulmonary Disease
Novel Mediator Antagonists. Blocking the receptors or synthesis of
inflammatory mediators is a logical approach to the development of new
treatments for asthma and COPD. However, in both diseases many different
mediators are involved, and therefore blocking a single mediator
is unlikely to be very effective, unless it plays a unique and key role in
the disease process (Barnes, 2004; Barnes et al., 1998a). Several specific
mediator antagonists have been found to be ineffective in asthma, including
antagonists/inhibitors of thromboxane, platelet-activating factor,
bradykinin, and tachykinins. However, these blockers have often not
been tested in COPD, in which different mediators are involved. A number
of other approaches are under study, as noted next.
CRTh2 Antagonists. Chemotactic factor for T H
2 cells has been identified
as prostaglandin D 2
, which acts on a DP 2
receptor (Chapter 33). Several
CRTh2 antagonists are now in development for asthma with promising
initial results (Pettipher et al., 2007).
Endothelin Antagonists. Endothelin has been implicated in some of
the structural changes that occur in asthma and COPD. Endothelin
antagonists are approved for the treatment of pulmonary hypertension
and might be useful in treating the structural changes that occur
in asthma and COPD, but so far they have not been tested.
Antioxidants. Oxidative stress is important in severe asthma and
COPD and may contribute to corticosteroid resistance. Existing
antioxidants include vitamins C and E and N-acetyl-cysteine. These
drugs have weak effects, but more potent antioxidants are in development
(Kirkham and Rahman, 2006).
Inducible Nitric Oxide Synthase Inhibitors. NO production is
increased in asthma and COPD as a result of increased inducible NO
synthase (iNOS) expression in the airways (Chapter 3). NO and
oxidative stress generate peroxynitrite anion (O=N-O-O − ), which
may nitrate proteins, leading to altered cell function. Several selective
iNOS inhibitors are now in development (Hobbs et al., 1999),
and one of these, L-N 6 -(1-imminoethyl)lysine (L-NIL), gives a profound
and long-lasting reduction in the concentrations of NO in
exhaled breath (Hansel et al., 2003). An iNOS inhibitor was found
to be ineffective in asthma, however (Singh et al., 2007).
Cytokine Modifiers. Cytokines play a critical role in perpetuating
and amplifying the inflammation in asthma and COPD, suggesting
that anti-cytokines may be beneficial as therapies (Barnes, 2008a).
Although most attention has focused on inhibition of cytokines,
some cytokines are anti-inflammatory and may have therapeutic
potential.
IL-5 plays a pivotal role in eosinophilic inflammation and is
also involved in eosinophil survival and priming. It is an attractive
target in asthma because it is essential for eosinophilic inflammation,
there do not appear to be any other cytokines with a similar
role, and lack of IL-5 in gene knockout mice does not have any deleterious
effect. Anti-IL-5 antibodies inhibit eosinophilic inflammation
and airway hyperresponsiveness in animal models of asthma,
and they markedly reduce circulating and airway eosinophils in
asthma patients but have no effect on airway hyperresponsiveness
or clinical features of asthma (Flood-Page et al., 2007; Leckie et al.,
2000). In carefully selected patients with severe asthma and persistent
eosinophilia despite high doses of corticosteroids, there is a significant
reduction in exacerbations (Haldar et al., 2009). Blocking