Lecture 12 - Current and Future CF Therapies Flashcards
What is a CF centre of excellence?
A centre with over 50 CF patients
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
Two uses for antimicrobials in CF
Prophylactic, for exacerbations
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’
Advantage of nebulised antimicrobials
Can be targeted directly to LRT
Lower dose can be used –> Reduced side effects
Ways to susceptibility test patient microbes
Sputum test
How can resistance be avoided in CF patients?
Always give at least 2 different antibiotics
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
Bacteria which can be spread between CF patients
1)
2)
3)
1) Pseudomonas
2) Burkholderia cepacia
3) MRSA
Way to reduce disease spread in hospitalised CF patients
Patient segregation - Don’t allow 2 CF patients to interact
Mucolytics
1)
2)
3)
1) Recombinant human deoxyribonuclease-1 (pulmozyme)
2) Hypertonic saline
3) Mannitol
Effect of mannitol
Osmotic agent
Draws water into airway surface liqud
Anti-inflammatory agents for CF
1)
2)
3)
1) Azithromycin
2) Glucocorticosteroids
3) NSAID - Ibuprofen
Issues with glucocorticosteroids and NSAID therapies
Many side-effects
EG: NSAIDs are nephrotoxic for long-term use
Energy requirements of CF patients
120-150% of normal
Proportion of CF diet that is fat
35-40%
Pancreatic enzyme tablet
Creon
When is creon taken?
With all foods containing fat, protein or complex carbohydrates
Creon dose
500-2000 units of lipase/kg body weight/meal
What is most CF antibiotic research focussed on?
Novel delivery systems
Can direct delivery of antibiotics can reduce side effects, increase microbicidal activity
Sildenafil
Viagra
Potential uses for sildenafil
Antiinflammation, treat chronic hypertension
Novel antibiotic delivery mechanisms
1)
2)
1) Dry powder inhaler
2) Nebulised
Future anti-inflammatory therapies for CF 1) 2) 3) 4)
1) Glutathione
2) Sildenafil
3) KB001A
4) Alpha-1 antitrypsin
Glutathione therapy
Replaces glutathione, an important antioxidant
What is sildenafil?
Phosphodiesterase inhibitor
What is KB001?
A humanised monoclonal Fab fragment
Targets Pseudomonas virulence factor, reduces local inflammation
What is alpha-1 antitrypsin?
An antiprotease
Can help resist overwhelming of antiproteases by neutrophil response
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
Non-viral gene therapy vectors
Cationic liposomes complexed with plasmid DNA expressing CFTR
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
Problems with possible stem-cell therapy
1)
2)
1) Under 1% frequency of engraftment in lungs
2) Almost always causes severe lung damage
Example of a successful protein rescue therapy
Ivacaftor
Ivacaftor
Potentiator protein
Keeps defective class III mutation CFTR channel open
Corrects G551D mutation
Positive aspects of Ivacaftor
1)
2)
3)
1) Significant improvement in lung function
2) Significant weight increase
3) Significant decrease in symptoms
Proof that ivacaftor corrects underlying defect of type III CF
Chloride sweat values are normal
Ivacaftor dosage
150mg tablet, twice daily
Drawbacks of ivacaftor
1)
2)
1) $294,000 per patient per year
2) G551D affects 4% of patients worldwide
What is lumacaftor?
A corrector, which is used to treat type II mutations
Increases F508del CFTR trafficked to cell surface
Reason for combining lumacaftor and ivacaftor
Once type II proteins trafficked to surface, don’t function properly
Efficacy of lumacaftor
CFTR transport 15% of wild type
Efficacy of lumacaftor combined with ivacaftor
CFTR transport 30% of wild type
Ataluren
A small molecule compound, promotes read-through of premature stop codons (type I mutation)
