Develoment Of Therapeutic Approcahes For COPD- New Targets And Therapies

Question 1

What nicotine FREE replacement therapies are there?

Answer 1

*champix (Pfizer)- varenicline tartrate
-selective nicotine receptor partial agonist
-reduced cravings
*Zyban (GSK)- bupropion
-extended release antidepressant alleviating nicotine withdrawals

Question 2

What inflammation targets can be used in COPD therapy?

Answer 2

*prevent neutrophil infiltration
Target NSP’s - neutrophil serine proteases - role in chronic inflammation and lung tissue destruction- blocking reduces disease progression

Question 3

What two approaches are there for NSP inhibition?

Answer 3

*use of NATURAL recombinant protein inhibitors - alpha1 antitrypsin- AAT deficiency leads to lung tissue destruction ie emphysema- lead to early onset COPD
*use of SYNTHETIC small molecule inhibitors

Question 4

What does alpha1 antitrypsin inhibit?

Answer 4

Neutrophil elastase- used in inflammation. Block means reduces inflammation

Question 5

What is there an imbalance of in COPD?

Answer 5

Proteases and antiproteases

Question 6

What is alpha 1 anti trypsin?

Answer 6

Serase protein inhibitor- anti protease- inhibits neutrophil elastase
Deficiency causes lung degradation

Question 7

What is the impact of smoking on AAT?

Answer 7

Smoking oxidises the Met358 residue of the region which docks into neutrophil elastase- AAT can’t bind effectively.

Question 8

What is the downside of plasma derived AAT?

Answer 8

High production costs
Alternative
rAAT- lower production costs and higher availability

Question 9

What is are examples of synthetic anti-protease inhibitors?

Answer 9

*Sivelestat
-Competitive inhibitor of neutrophil elastase
-Approved in Japan- poor pharmacokinetics, organ toxicity risk

*Alvelestat
-selective inhibitor for neutrophil elastase (600 fold more selective for NE than other NP)

*POL6014 (Polyphor)
-highly selective reversible inhibitor of NE

Question 10

What are three major challenges in development of suitable elastase inhibitors?

Answer 10

1) sufficient potency
2)securing selectivity
3)achieving metabolic stability under pathophysiological conditions

Question 11

What are other targets for COPD intervention, other than Neutrophil elastase inhibition?

Answer 11

*non-selective phoshodiesterase inhibitor- Theophylline - severe COPD- suppress cytokine release- reverse corticosteroid resistance ie low dose theophyline combined with corticosteroids
*PDE4 inhibition- roflumilast- reduces no. of inflammatory cells eg neutrophils
*inflammatory mediator antagonists- TNFa inhibitors, downregulation of NF-KB, chemokine inhibitors, antioxidants