Table 3– Drugs that may have indirect anti-inflammatory actions

Drug	Pros	Cons	Drugs under development
Agents that reverse glucocorticoid resistance	Several agents reverse glucocorticoid resistance by blocking the underlying mechanisms	Clinical studies are required	Activation of HDAC2 Theophylline Curcumin Resveratrol Inhibitors of P-glycoprotein Inhibitors of MIF
Bronchodilators	Bronchodilators have the potential to reduce inflammation by decreasing dynamic hyperinflation and influencing resistive breathing Low-dose theophylline has anti-inflammatory effects	Studies on the effect of β₂-agonists on contractility of the diaphragm are controversial Tiotropium reduces lung hyperinflation but has not convincingly demonstrated an anti-inflammatory effect There is no documentation that anti-inflammatory effects of theophylline are due to a decrease in loaded breathing	β₂-agonists Long-acting antimuscarinic agents Methylxanthines
Antioxidant strategies Protease inhibitors	Thiol compounds Potent mucolytic Mild effects on exacerbation rates Nrf2 activators Protection seen in animal models Induce a variety of phase II genes/enzymes SOD mimetics Protection seen in animal models Inhibit extracellular matrix remodelling Lipid peroxidation and protein carbonylation inhibitors/blockers Inhibit lipid peroxidation chain reactions Most MMP inhibitors prevented emphysema and small airways thickening in preclinical models of COPD	Thiol compounds Lack of bioavailability Cause bronchoconstriction Nrf2 activators Dramatically degraded in severe COPD GOLD stages Carbonylation/oxidation of Nrf2/Keap1 Prophylactic-potent inducer is needed Clinical studies are required SOD mimetics May impair phagocytosis Alter endogenous redox homeostasis Clinical studies are required Lipid peroxidation and protein carbonylation inhibitors/blockers Poor bioavailability Low presence at the site of microenvironment Clinical studies are required Clinical development has been stopped for many MMP and NE inhibitors for various reasons	Thiol compounds N-acetyl-L-cysteine (NAC) N-acystelyn (NAL) N-isobutyrylcysteine (NIC) Glutathione esters S-carboxymethylcysteine (carbocysteine) Erdosteine Fudosteine Thioredoxin Procysteine Ergothioneine Inducers of glutathione biosynthesis (Nrf2 activators) Antioxidant vitamins (vitamin A, E, C) β-carotene CoQ₁₀ Polyphenols Curcumin Resveratrol Quercetin Green tea catechins Nitrone spin traps NXY-059 STANZ Porphyrins SOD and glutathione peroxidase mimetics M40419, M 40403, M40419 Ebselen Lipid peroxidation and protein carbonylation inhibitors/blockers Edaravone Lazaroids MMP inhibitors Tissue inhibitors of metalloproteases Antibiotics
Protease inhibitors (cont.)	NE inhibitors may not only protect the lungs from NE-mediated tissue damage but also control over exuberant inflammatory responses	Reversible NE inhibitors can release NE Major side-effects (relevant toxicity)	Small molecule inhibitors Ilomastat (GM-6001) CP-471,474 Marimastat RS-113,456 NE inhibitors Endogenous inhibitors Epi-NE-4 Synthetic small molecule NE inhibitors Reversible inhibitors Sivelestat (ONO-5046) Midesteine (MR-889) ONO-6818 ICI 200,880 AZD-9668 Irreversible inhibitors Peptide boronic acids Peptide aldehydes Substituted tripeptide ketones β-lactams

SOD: superoxide dismutase; MMP: matrix metalloproteinase; COPD: chronic obstructive pulmonary disease; NE: neutrophil elastase; GOLD: Global Initiative for Chronic Obstructive Lung Disease; MIF: migration inhibitory factor.