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

1056 IL-4 and IL-13, which determine IgE synthesis (Figure 36–12), has
so far proved to be ineffective in clinical studies.
TNF- may play a key role in amplifying airway inflammation,
through the activation of NF-B, AP-1, and other transcription
factors. TNF- production is increased in asthma and COPD, and it
may be associated with the cachexia and weight loss that occur in
some patients with severe COPD. In COPD patients and in patients
with severe asthma, anti-TNF- blocking antibodies have been ineffective,
at the expense of increasing infections and malignancies
(Rennard et al., 2007; Wenzel et al., 2009).
Chemokine Receptor Antagonists. Many chemokines are involved in
asthma and COPD and play a key role in recruitment of inflammatory
cells, such as eosinophils, neutrophils, macrophages, and lymphocytes
into the lungs. Chemokine receptors are attractive targets
because they are hepta-spanning membrane proteins; small molecule
inhibitors are now in development (Donnelly and Barnes, 2006;
Viola and Luster, 2008). In asthma, CCR3 antagonists, which should
block eosinophil recruitment into the airways, are the most favored
target, but several small molecule CCR3 antagonists have failed in
development because of toxicity. In COPD, CXCR2 antagonists,
which prevent neutrophil and monocyte chemotaxis due to CXC
chemokines such as CXCL1 and CXCL8, have been effective in animal
models of COPD and in neutrophilic inflammation in normal
subjects, and are now in clinical trials in COPD patients.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Protease Inhibitors
Several proteolytic enzymes are involved in the chronic inflammation
of airway diseases. Mast cell tryptase has several effects on airways,
including increasing responsiveness of airway smooth muscle
to constrictors, increasing plasma exudation, potentiating eosinophil
recruitment, and stimulating fibroblast proliferation. Some of these
effects are mediated by activation of the proteinase-activated receptor
PAR2. Tryptase inhibitors have so far proved to be disappointing
in clinical studies.
Proteases are involved in the degradation of connective tissue in
COPD, particularly enzymes that break down elastin fibers, such as
neutrophil elastase and matrix metalloproteinases (MMP), which are
involved in emphysema. Neutrophil elastase inhibitors have been difficult
to develop, and there are no positive clinical studies in COPD
patients. MMP9 appears to be the predominant elastolytic enzyme in
emphysema, and several selective inhibitors are now in development.
New Anti-Inflammatory Drugs
Phosphodiesterase Inhibitors. The preservation and elevation of cellular
cyclic AMP in inflammatory cells often reduces cell activation
and release of inflammatory mediators. PDE4 is the predominant
PDE isoform in inflammatory cells, including mast cells, eosinophils,
neutrophils, T lymphocytes, macrophages, and structural cells such as
sensory nerves and epithelial cells (Houslay et al., 2005), suggesting
that PDE4 inhibitors could be useful as an anti-inflammatory treatment
in both asthma and COPD. In animal models of asthma, PDE4
inhibitors reduce eosinophil infiltration and responses to allergen,
whereas in COPD they are effective against smoke-induced inflammation
and emphysema. Several PDE4 inhibitors have been tested
clinically, but with disappointing results; their usefulness has been
limited by side effects, particularly nausea, vomiting, headaches, and
diarrhea. In COPD, an oral PDE4 inhibitor, roflumilast, has some
effect in reducing exacerbations and improving lung function, but
side effects also limit its efficacy (Fabbri et al., 2009). Of the four
subfamilies of PDE4, PDE4D is the major form whose inhibition is
associated vomiting; inhibition of PDE4B is important for antiinflammatory
effects. Thus, selective PDE4B inhibitors may have a
greater therapeutic index. Inhaled PDE4 inhibitors to reduce systemic
absorption and adverse responses have proved to be ineffective. PDE5
inhibitors are vasodilators that are used in the treatment of pulmonary
hypertension.
NF-B Inhibitors. NF-B plays an important role in the orchestration
of chronic inflammation (Figure 36–9); many of the inflammatory
genes that are expressed in asthma and COPD are regulated by
this transcription factor (Barnes and Karin, 1997). This has prompted
a search for specific blockers of these transcription factors. NF-B
is naturally inhibited by the inhibitory protein IB, which is
degraded after activation by specific kinases. Small molecule
inhibitors of the IB kinase IKK2 (or IKK) are in clinical development
(Karin et al., 2004; Kishore et al., 2003). These drugs may be
of particular value in COPD, where corticosteroids are largely ineffective.
However, there are concerns that inhibition of NF-B may
cause side effects such as increased susceptibility to infections,
which has been observed in gene disruption studies when components
of NF-B are inhibited.
Mitogen-Activated Protein Kinase Inhibitors. There are three major
MAP kinase pathways, and there is increasing recognition that these
pathways are involved in chronic inflammation (Delhase et al.,
2000). There has been particular interest in the p38 MAP kinase
pathway that is blocked by a novel class of drugs, such as SB203580
and RWJ67657. These drugs inhibit the synthesis of many inflammatory
cytokines, chemokines, and inflammatory enzymes (Cuenda
and Rousseau, 2007). The p38 MAPK inhibitors are in development
for the treatment of asthma (they inhibit T H
2 cytokine synthesis) and
for COPD (they inhibit neutrophilic inflammation and signaling of
inflammatory cytokines and chemokines). However, clinical studies
have revealed marked adverse effects and toxicities; inhaled delivery
is being explored.
Mucoregulators
Many pharmacological agents may influence the secretion of mucus
in the airways, but there are few drugs that have demonstrably useful
clinical effects on mucus hypersecretion (Rogers and Barnes, 2006).
Mucus hypersecretion occurs in chronic bronchitis, COPD, cystic
fibrosis, and asthma. In chronic bronchitis, mucus hypersecretion is
related to chronic irritation by cigarette smoke and may involve neural
mechanisms and the activation of neutrophils to release enzymes
such as neutrophil elastase and proteinase-3 that have powerful stimulatory
effects on mucus secretion. Mast cell–derived chymase is also
a potent mucus secretagogue. This suggests that several classes of
drugs may be developed to control mucus hypersecretion.
A major problem in assessing the effects of drugs on mucus
hypersecretion is the difficulty in accurately quantifying airway
mucus production, quality, and clearance. Several current drugs for
airway disease might affect mucus production. Systemic anticholinergic
drugs appear to reduce mucociliary clearance, but this
is not observed with either ipratropium bromide or tiotropium bromide,
presumably reflecting their poor absorption from the respiratory
tract. 2
Agonists increase mucus production and
mucociliary clearance and have been shown to increase ciliary beat