Lecture 12 - Current and Future CF Therapies Flashcards Preview

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Flashcards in Lecture 12 - Current and Future CF Therapies Deck (43):
1

What is a CF centre of excellence?

A centre with over 50 CF patients

2

Physiotherapy techniques for CF
1)
2)
3)
4)
5)

1) Gravity assisted drainage
2) Active cycle of breathing techniques
3) Autogenic drainage
4) Positive expiratory pressure
5) Activity, exercise

3

Two uses for antimicrobials in CF

Prophylactic, for exacerbations

4

What is the procedure for treating a severe infection in CF?

Take patient to hospital, put them on IV antibiotics for a few weeks

'Tune up'

5

Advantage of nebulised antimicrobials

Can be targeted directly to LRT
Lower dose can be used --> Reduced side effects

6

Ways to susceptibility test patient microbes

Sputum test

7

How can resistance be avoided in CF patients?

Always give at least 2 different antibiotics

8

Difficulties in treating CF patients with antibiotics
1)
2)
3)

1) Side effects, especially from long-term use
2) Antibiotic resistance in bacteria
3) CF patients have different pharmacokinetics. Often need much higher doses, EG: aminoglycosides

9

Bacteria which can be spread between CF patients
1)
2)
3)

1) Pseudomonas
2) Burkholderia cepacia
3) MRSA

10

Way to reduce disease spread in hospitalised CF patients

Patient segregation - Don't allow 2 CF patients to interact

11

Mucolytics
1)
2)
3)

1) Recombinant human deoxyribonuclease-1 (pulmozyme)
2) Hypertonic saline
3) Mannitol

12

Effect of mannitol

Osmotic agent
Draws water into airway surface liqud

13

Anti-inflammatory agents for CF
1)
2)
3)

1) Azithromycin
2) Glucocorticosteroids
3) NSAID - Ibuprofen

14

Issues with glucocorticosteroids and NSAID therapies

Many side-effects
EG: NSAIDs are nephrotoxic for long-term use

15

Energy requirements of CF patients

120-150% of normal

16

Proportion of CF diet that is fat

35-40%

17

Pancreatic enzyme tablet

Creon

18

When is creon taken?

With all foods containing fat, protein or complex carbohydrates

19

Creon dose

500-2000 units of lipase/kg body weight/meal

20

What is most CF antibiotic research focussed on?

Novel delivery systems

Can direct delivery of antibiotics can reduce side effects, increase microbicidal activity

21

Sildenafil

Viagra

22

Potential uses for sildenafil

Antiinflammation, treat chronic hypertension

23

Novel antibiotic delivery mechanisms
1)
2)

1) Dry powder inhaler
2) Nebulised

24

Future anti-inflammatory therapies for CF
1)
2)
3)
4)

1) Glutathione
2) Sildenafil
3) KB001A
4) Alpha-1 antitrypsin

25

Glutathione therapy

Replaces glutathione, an important antioxidant

26

What is sildenafil?

Phosphodiesterase inhibitor

27

What is KB001?

A humanised monoclonal Fab fragment
Targets Pseudomonas virulence factor, reduces local inflammation

28

What is alpha-1 antitrypsin?

An antiprotease
Can help resist overwhelming of antiproteases by neutrophil response

29

Problems with gene therapy
1)
2)
3)

1) Lungs are still an effective barrier to foreign bodies
2) Viral vectors have caused deaths of some testing volunteers
3) Unmethylated CpG DNA on plasmid, which can cause mild flu-like symptoms

30

Non-viral gene therapy vectors

Cationic liposomes complexed with plasmid DNA expressing CFTR

31

Outcome of gene therapy trials
1)
2)
3)

1) Proof of concenpt
2) Most only stage I and II trials
3) Over 30 trials to date

32

Problems with possible stem-cell therapy
1)
2)

1) Under 1% frequency of engraftment in lungs
2) Almost always causes severe lung damage

33

Example of a successful protein rescue therapy

Ivacaftor

34

Ivacaftor

Potentiator protein
Keeps defective class III mutation CFTR channel open
Corrects G551D mutation

35

Positive aspects of Ivacaftor
1)
2)
3)

1) Significant improvement in lung function
2) Significant weight increase
3) Significant decrease in symptoms

36

Proof that ivacaftor corrects underlying defect of type III CF

Chloride sweat values are normal

37

Ivacaftor dosage

150mg tablet, twice daily

38

Drawbacks of ivacaftor
1)
2)

1) $294,000 per patient per year
2) G551D affects 4% of patients worldwide

39

What is lumacaftor?

A corrector, which is used to treat type II mutations
Increases F508del CFTR trafficked to cell surface

40

Reason for combining lumacaftor and ivacaftor

Once type II proteins trafficked to surface, don't function properly

41

Efficacy of lumacaftor

CFTR transport 15% of wild type

42

Efficacy of lumacaftor combined with ivacaftor

CFTR transport 30% of wild type

43

Ataluren

A small molecule compound, promotes read-through of premature stop codons (type I mutation)