New Pharmacotherapy for Asthma Flashcards
Name some reasons for the need of new asthma treatments
- Compliance
- Oral meds - easier development and better compliance
- Severe asthma not responsive to treatment
- Steroid resistance
- Specific therpaies for phenotyped asthma
- Disease modifying drugs (no cure)
Name some advantages and disadvantages of oral therapies
Advantages
- Better adherence
- Easier to develop
- May treat concomitant allergic disease
Disadvantages:
- Side Effects
What is the rescue therapy for asthma?
Salbutamol/Terbutaline (SABA)
Interpret the data from SYGMA 1; O’Byrne et al NEJM 2018
There is a significant decrease of 64% in severe exacerbations per year in patients recieiving Symbicort prn compared to terbutaline prn.
Potential change in rescue therapy
Interpret these results from SYMGA 1: O’Bryne NEJM 2018
What does this imply
Using symbicort leads to a much smaller daily dose of ICS compared to Bud
Prostaglandin D2 is produced mainly by what cells? What are its two effects and which cells and receptors does PGD2 work on?
Produced by mast cells
Inflammation
- DP1
- Bronchial Vessel
- Dendritic Cell
- DP2
- Th2 cells
- ILC2 cells
- Eosinophils
Bronchoconstriction
- TP
- Ariway smooth muscle cells
Interpret the data on PGD2 antagonists
Graph 1
- Significant decrease in sputum eosinophils after treatment
- Decrease is sustained during treatment
- Washout at 12 weeks caused an increase of sputum eosinophils - no sig difference between placebo
Graph 2
- No sig difference in asthma control copmared to placebo
Outline the mechanism of allergy icluding cytokines
What are the two type of asthma (include sub-groups)
T2 immunity
-
Eosinophilic
- Corticosteroid sensitive
Non-T2 immunity (30-50% severe asthma)
-
Neutrophilic
- Steroid insensitive
-
Paucigranulocytic
- Bad asthma, but no inflammation
- Steroid insensitive
Non-T2 immunity thought to be T1 and T3 but no further knowledge known
Which cells produce IL-5 (4)
Th2 cells
Mast Cells
ILC2 cells
(Epithelial Cells)
What are the effects of IL-5 and what receptor do they act on?
IL-5Rα
- Priming/activation
- Differentiation in bone marrow
- Survival in tissue
Outline the mechanism of eosinophilic inflammation from allergen or virus
What IL-5 therapy do we hav for asthma?
- Anti-IL-5 antibody
- Mepolizumab (sc)
- Reslizumab (iv)
- Anti-IL5Rα
- Benralizumab (sc)
What are the effects of IL-13
- Class switch B cells to make IgE
- Sensitises Mast Cells
- Activates M2 macrophage
- TGF-β
- IL-10
- Fibrosis
- Mucus Hypersecretion
- Stimulate eotxain release from epithelial cells
- CCL 11 -> eosinophil recruitment
- Steriod Resistance
What current IL-13 therapies do we have?
- Anti-IL-13 antibody
- Lebrikizumab
- Tralokinumab
- Anti-IL4Rα antibody
- Dupilumab
Anti-IL-4Rα is a shared common receptor for IL-13 and IL-4
What is a biomarker used for IL-13
IL-13 is difficult to measure directly, so a surrogate is needed
- Periostin
- IL-13 stimulates its release from epithelial cells
- FeNO
- Giving IL-13 increases FeNO and giving anti-IL13 decreases FeNO
Studies for lebrikizumab showed no significant differences in FEV1 (0-24wks), exacerbations, symptoms or ACQs. Phase 3 studies have negative results and development has stopped. Dupilumab is an alternative. Interpret the data below
- ↑FEV1
- ↓Exacerbations
Had little effect on blood eosinophils
Describe the effects of TSLP in asthma
Describe the mechanism of neutrophilic inflammation in asthma
What is the mechanism of action of cromoglycate
Acts on GPR 35 coupled to TRPA1 receptor
TRPA1 is Ca channel signalling for cough, AHR and mast cell activation
What is the limitation of cromoglycates
Only last 1-2 hours
Need to develop longer lasting effetcs
What is the ideal drug for asthma
- Oral, once daily
- Compliance
- No side effects
- Specific for asthma
- Individualised therapy
- Pharmacogenomics
- Cure?
