Biomedical Engineering Reference
In-Depth Information
have been problems in clinical development of drugs in this class because of
side effects. A recent pilot study in COPD patients with a 5
0
-lipoxygenase
inhibitor BAYxl005 showed only a modest reduction in sputumLTB
4
concen-
trations but no effect on neutrophil activation markers (39).
Cysteinyl-LTs are important bronchoconstrictors in patients with
asthma and are largely derived form mast cells, whereas in COPD
cys-LTs do not appear to be increased (34,40). There is, therefore, no
rationale for the use of cys-LT receptor antagonists in COPD.
B. Antioxidants
As discussed in Chapter 12, oxidative stress is increased in patients with
COPD (41,42), particularly during exacerbations, and reactive oxygen spe-
cies contribute to its pathophysiology (43). Furthermore, as discussed in
Chapter 15, oxidative stress may also lead to steroid resistance through an
inhibitory effect on HDAC2 activity. This suggests that antioxidants may
be of use in the therapy of COPD. N-Acetyl cysteine (NAC) provides
cysteine for enhanced production of the antioxidant glutathione (GSH)
and has antioxidant effects in vitro and in vivo. A systematic review of stu-
dies with oral NAC in COPD suggested a small reduction in exacerbations
(44). More effective antioxidants, including stable glutathione compounds,
analogs of superoxide dismutase, and selenium-based drugs, are now in
development for clinical use (45,46).
C. Nitric Oxide Synthase Inhibitors
Oxidative stress and increased nitric oxide release from activity of iNOS
may result in the formation of peroxynitrite; this is a potent radical that
nitrates tyrosine residues on proteins and may alter their function. 3-
Nitrotyrosine may indicate peroxynitrite formation and is markedly
increased in sputum macrophages of patients with COPD (47). Selective
inhibitors of iNOS are now in development and one of these, a prodrug
of l-N
6
-(1-imminoethyl)lysine (L-NIL) gives a profound and long-lasting
reduction in the concentrations of nitric oxide in exhaled breath (48). Other
drugs, such as ebselen, may act as peroxynitrite scavengers (49).
D. Chemokine Inhibitors
As discussed in Chapter 11, several chemokines are involved in neutrophil
chemotaxis, these being mainly chemokines of the CXC family, and
chemokine antagonists are of potential therapeutic benefit in COPD (50).
Interleukin-8 levels are markedly elevated in the sputum of patients with
COPD and are correlated with disease severity (51). Blocking antibodies
to IL-8 reduce the chemotactic response of neutrophils to sputum from
COPD patients (33,38). A human monoclonal antibody to IL-8 is now in
