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

1054 were not on concomitant corticosteroid therapy, suggesting there is
a causal link (Nathani et al., 2008).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Future Developments. One of the major advantages of antileukotrienes
is their effectiveness in tablet form. This may increase
compliance with chronic therapy and makes treatment of children
easier. Montelukast is effective as a once-daily preparation (10 mg
in adults, 5 mg in children). In addition, oral administration may
treat concomitant allergic rhinitis. However, the currently available
clinical studies indicate a relatively modest effect on lung function
and symptom control, which is less for every clinical parameter
measured than with ICS. This is not surprising: There are many
mediators besides cys-LTs involved in the pathophysiology of
asthma, and it is unlikely that antagonism of a single mediator would
be as effective as steroids, which inhibit multiple aspects of the
inflammatory process in asthma. Similarly, if anti-leukotrienes are
functioning in asthma as bronchodilators and anti-constrictors, it is
unlikely that they will be as effective as a 2
agonist, which will
counteract bronchoconstriction regardless of the spasmogen. It is
likely that anti-leukotrienes will be used less in the future because
combination inhalers are the mainstay of asthma therapy.
An interesting feature of the clinical studies is that some
patients appear to show better responses than others, suggesting that
leukotrienes may play a more important role in some patients. The
variability in response to anti-leukotrienes may reflect differences
in production of or responses to leukotrienes in different patients,
and this in turn may be related to polymorphisms of 5-LO, LTC 4
synthase, or cys-LT 1
receptors that are involved in the synthesis of
leukotrienes (Tantisira and Drazen, 2009).
It is unlikely that further advances can be made in cys-LT 1
-
receptor antagonists if montelukast, a once-daily drug, is giving
maximal receptor blockade. Cys-LT 2
receptors may be important in
vascular and airway smooth muscle proliferative effects of cys-LT
and are not inhibited by current cys-LT 1
-receptor antagonists (Back,
2002). The role of the cys-LT 2
receptor in asthma is unknown, as is
the value of its blockade. 5-LO inhibitors have some potential in
COPD, cystic fibrosis, and possible severe asthma as LTB 4
may contribute
to neutrophil chemoattraction in the lungs of these conditions.
IMMUNOMODULATORY THERAPIES
Immunosuppressive Therapy
Immunosuppressive therapy (e.g., methotrexate,
cyclosporine A, gold, intravenous immunoglobulin) has
been considered in asthma when other treatments have
been unsuccessful or to reduce the dose of oral steroids
required. However, immunosuppressive treatments are
less effective and have a greater propensity to side
effects than oral corticosteroids and therefore cannot be
routinely recommended. The role of immunosuppressive
therapy in COPD and cystic fibrosis has not been
evaluated.
Anti-IgE Receptor Therapy
Increased specific IgE is a fundamental feature of allergic
asthma. Omalizumab is a humanized monoclonal
antibody that blocks the binding of IgE to high-affinity
IgE receptors (FcεR1) on mast cells and thus prevents
their activation by allergens (Figure 36–12) (Avila,
2007). It also blocks binding on IgE to low-affinity IgE
receptors (FcεRII, CD23) on other inflammatory cells,
including T and B lymphocytes, macrophages, and
possibly eosinophils, to inhibit chronic inflammation.
Omalizumab also reduces levels of circulating IgE.
Clinical Use. Omalizumab is used for the treatment of patients with
severe asthma. The antibody is administered by subcutaneous
injection every 2-4 weeks, and the dose is determined by the titer
of circulating IgE. Omalizumab reduces the requirement for oral
and inhaled corticosteroids and markedly reduces asthma exacerbations.
It is also beneficial in treating allergic rhinitis. Because of
its very high cost, this treatment is generally used only in patients
with very severe asthma who are poorly controlled even on oral
corticosteroids and in patients with very severe concomitant allergic
rhinitis (Walker et al., 2006). It may not be useful in concomitant
atopic dermatitis due to the high levels of circulating IgE that
cannot be neutralized. It may also be of value in protecting against
anaphylaxis during specific immunotherapy. The major side effect
of omalizumab is an anaphylactic response, which is uncommon
(<0.1%) (Cox et al., 2007).
Specific Immunotherapy
Theoretically, specific immunotherapy with common
allergens should be effective in preventing asthma.
Although this treatment is effective in allergic rhinitis
due to single allergens, there is little evidence that
desensitizing injections to common allergens are effective
in controlling chronic asthma (Rolland et al., 2009).
Overall, the benefits of specific immunotherapy in
asthma are small, and there are no well-designed studies
comparing this treatment with effective treatments
such as ICS. Sublingual immunotherapy is safer, but its
role in asthma therapy has not yet been defined.
Because there is a risk of anaphylactic and local reactions,
and because the course of treatment is time consuming,
this form of therapy cannot be routinely
recommended for asthma.
The cellular mechanisms of specific immunotherapy are
of interest. Specific immunotherapy induces the secretion of
the anti-inflammatory cytokine IL-10 from regulatory helper T-
lymphocytes (T reg
) and this blocks co-stimulatory signal transduction
in T cells (via CD28) so that they are unable to react to
allergens presented by antigen-presenting cells (Larche et al.,
2006). Applying an understanding of the cellular processes
involved might lead to safer and more effective approaches in the
future. More specific immunotherapies may be developed with
cloned allergen epitopes, T-cell peptide fragments of allergens,
CpG oligonucleotides, and vaccines of conjugates of allergen and
toll-like receptor (TLR)-9 to stimulate T H
1 immunity and suppress
T H
2 immunity (Broide, 2009).