RespoLecoDecko 1 Flashcards
(538 cards)
1
Q
Describe asthma histopathology
A
Mucus Plugs in Lumen Epithelial fragility Smooth muscle hypertrophy BM thickening Vasodilation + Angiogenesis Increased SubMucosal gland size Cellular (eosinophilic infiltration) Bronchoconstriction
2
Q
Describe COPD histopathology
A
Mucus hypersecretion + plugs
Emphysema
Small airways disease - reduced alveolar attachments + fibrosis - stenosis
Neutrophilic/macrophage infiltration
3
Q
Asthma + COPD contrasts
A
No parenchymal destruction in Asthma Not as much bronchoconstriction/reactivity in COPD BM thickening increased in Asthma SM increased more in asthma More fibrosis in COPD
4
Q
Presentation + clinical differences. Asthma
A
Variable, Wheeze, usually child onset, Good steroid and bronchodilator response
5
Q
Presentation + clinical differences. COPD
A
Persistent + worsening symptoms
SOB exertion
>45yo, usually elderly.
POOR steroid and B/D responses
6
Q
What happens to LF in asthma?
A
Controlled asthma = Normal (peaks and troughs)
Severe = declines - no response to Rx and inc irreversible remodelling
7
Q
Asthma BD response in percentage
A
73%
8
Q
COPD BD response in percentage
A
5.5%
9
Q
Non susceptible COPD smoker percentage
A
80-85% non-susceptible
Fletcher C Brit Med J 1977
10
Q
Predominant inflammatory cells + cytokines in asthma
A
Mast cells
Eosinophils
TH2 cells
CYst LTs + NO + IL 4/5 + histamine
11
Q
Predominant inflammatory cells in COPD
A
Macrophages
Neutrophils
TC1
TNF-a, IL-8, LTB4, proteases, ROS
12
Q
What cytokine do alveolar macrophages produce to recruit more macrophages in COPD (overloaded)
A
MCP-1
Macrophage chemoattractant protein 1
13
Q
What cytokines do activated macrophages produce to attract neutophils in COPD?
A
IL-8
LT-B4
14
Q
What two classes of secretions do neutrohils secrete that are damaging in the pathology of COPD
A
ROS + Proteases
15
Q
What molecule increases goblet cell numbers leading to mucus hypersecretions?
A
EGF
16
Q
What molecule is produced by epithelial cells and stimulates fibroblasts?
A
TGF-B1
17
Q
How do elastase levels differ in asthma/smoking/COPD
A
asthma
18
Q
List the 6 main effects of oxidants
A
Decrease antiprotease activity (increases proteolysis) Increase mucus secretions Deplete antioxidants Activate NFkB Plasma leakage by damage Isoprostane production
19
Q
What does NFkB activation cause?
A
IL8 and TNFa secretion -> neutrophil chemoattractant
20
Q
Effects of GC on inflammatory cells in asthma
A
Studies depict large reductions in mast cells, eosinophils and T lymphocytes
(80/94/87% at high dose 8 weeks)
Booth et al, Faurschou et al
21
Q
Effects of GC on inflammatory cells in COPD
A
No differences in macrophages or neutrophils in comparison to baseline or placebo
Keatings V et al
22
Q
Effects of GC on IL8 and TNFa in COPD
A
No significant decreases
Keatings V et al
23
Q
Anticholinergics in COPD, why do they work?
A
Increased cholinergic drive in COPD, nicotine/smoking??
24
Q
What mediators cause bronchoconstriction in asthma?
A
Histamine, leukotreine c4/d4
25
COPD where does airway narrowing occur?
Can involve large airways but often begins in small airways
26
COPD, what does reduced MEF25 / FEF 75 mean?
Small airways
27
MEF75 / FEF 25?
Large airways
28
When does airway closure occur in COPD pts
Dynamic compression. Occurs at larger volumes than in normal people due to increased RV and reduced airway calibre. (reduced traction from parenchyma)
29
RV/TLC ratio in COPD
Increased
30
CO Helium and air
TLCO+KCO
Helium only changes concentration by dilution
CO moves in, can work out residual amount
TLCO = transfer across lung CO
KCO = diffusion per litre of lung
31
GOLD 1
Mild
FEV1/FVC < 70%
FEV1> 80%
32
GOLD 2
Mod
FEV1/FVC < 70%
FEV1 50-80%
33
GOLD 3
SEVERE
FEV1/FVC < 70%
FEV1 30-50%
34
GOLD 4
Very severe
FEV1/FVC < 70%
FEV1 <30% (OR <50% with resp failure)
35
What change indicates reversibility with BDs
200mls or 12% change
36
RV, TLC, RV/TLC changes in asthma exacerbation?
All increased
37
FEV1, FVC and FEV/FVC in asthma exacerbation
Reduced
38
Compliance in Asthma
No change
39
Challenge test asthma result?
Dose that reduces FEV1 by 20%
40
Ex induced asthma result?
Fall of FEV1 >10% at exercise
41
TLCO/KCO in asthma
N or Increased
42
Hyperventilation of cold air causes
Bronchoconstriction
43
Why does hyperventilation of cold air cause bronchoconstriction?
Thought to be due to rise in osmolarity of the epithelial lining. Dries out
44
More winter deaths males or females?
Women
45
Why do more women die of respiratory disease in winter?
Elderly female worse at temperature sensation.
| Old people do not shiver
46
Why more CV deaths in winter?
Peripheral Vasoconstriction causes increased BP
| Disease CVD most correlated with termperature
47
What is the trend of COPD deaths in Winter?
Increasing deaths from 15deg to -10deg.
Increasing deaths from 15 deg to 25 deg (not as peaked as winter). What will occur with global warming?
With ageing risk increases
48
Cross correlation shows MI deaths peak how many days later?
3
49
Cross correlation shows respiratory deaths peak how many days post extreme temperatures?
12 days later
| Probably due to ventilation/abx
50
What occurs with respiratory symptoms with temperature?
Same with mortality
51
Symptoms worse with older people and women when?
Winter months
52
Why does depression / anxiety increase in winter?
Less likely to leave house
53
Health related quality of life in winter?
Reduced HRQOL
54
List main causes of seasonality (inc resp symptoms)
Temperature, humidity, UV, atmospheric pollution, virus survival, cross infection (indoors), immunity
55
Which respiratory viruses increase in winter?
Influenza A (just post christmas), Influenza B (after christmas march), resp synctial, M pneumonia
56
Which respiratory viruses increase in summer?
Parainfluenza + corona (and rhinovirus/chlamidya al yr)
57
When does rhinovirus dip?
August
58
What is the most common cause of resp admissions to hospitals in young children?
RSV, does cause bronchiolitis in kids
59
How far can a sneeze carry a virus?
5m
60
What conditions do lipid enveloped respiratory viruses survive in best?
Cool temperatures around 8 deg ie flu, corona, RSV
| UV light may kill
61
What conditions do non-lipid enveloped respiratory viruses survive in best?
Warm eg rhino + adeno
62
Which person in the family transmits disease?
Children, very little immunity and poor hygeine in comparison to elderly people.
Study showed that infected children infected all brothers and sisters and half of parents
Pertola et al 2008 Joural of infectious disease
63
What does crowding in winter result in
Inc infections -> even though indoors and warmer inc people on tubes etc.
64
In trenches 4x as many in the trenches got colds in comparison to those at barracks. Why is this?
Inhalation of cool air dries airway epithelium which inhibits airway defence - cilia + phagocytic activity of leukocytes.
65
What did the eurostudy show?
Surveyed 8 countries.
Increase in deaths in 1 deg fall of temp is greater in warmer countries. Due to the fact that in colder countries ie Finland each individual wears more clothes and have warmer indoor temperatures than warmer countries. More protection.
66
What are the trends of seasonal deaths in russia?
No real increase in winter - adequate protection.
67
What is a benefit of cold air?
Reduced breathlessness
| stimulates cold receptors in face
68
Mortality increases in hot weather are worst in what countries?
Those with cooler temperatures -> more insulation on home
69
IHD, CVD, resp diseases + all cause increase on the same days as heat waves. What is the study that depicts this?
WR Keatings Environmental Research 2006
70
What are the RFs for heat related deaths?
```
>80yo
Dependency (bed ridden)
Drugs - antidepressants, alcohol, diuretcs
CVD disease
Neurological disease
Endocrine - DM, hyperthyroid
Any skin disorder that impairs sweating
Resp GI infections or septicaemia
```
71
What is the carrier rate (rough) for CF UK?
1/25
72
What is the incidence of CF in UK
1 in 2500
73
How many CF patients are there in the UK?
7000
74
CF inheritance
autosomal recessive
75
How many mutations are there in CF?
Over 2000
76
Function of CF gene
cAMP regulated Cl- and HCO3- channel on apical membrane
77
What is the low volume hypothesis in CF?
Cl- does not move out of defective channel.
Na+ therefore moves in.
Abnormal movement of water and depletion of water content in mucus. Thick hard mucus etc etc....
78
Name other manifestations of CF
Sinus infections
Infertility in men
Intestinal blockages
High salt content in sweat
Failure to thrive/gain weight
Focal billiary cirrhosis (duct obstruction)
Exocrine pancreas insufficiency (faltering growth)
79
Describe class 1 CF mutations
No synthesis
12%
Normally stop codon
80
Describe class 2 CF mutations
Block in processing
Delta F508
87%
81
Describe class 3 CF mutations
Block in gating ie opening/closing
5%
g551d
82
Describe class 4 CF mutations
Altered conductance - no problem in opening and closing but problem in ions getting through abnormal channel
D1152H
5%
83
Describe class V CF mutations
Reduced synthesis / survival
3849
5%
84
What percentage of pancreatic enzyme activity results in pancreatic exocrine sufficiency?
30%
| Accurso et al JCF 2014
85
How much CFTR function does severe disease usually have?
<1%
86
How do potentiators work in CF?
Increases flow of ions through CFTR - opens more freq
87
How do correctors work?
Increase cell processing and delivery of CFTR to membrane
88
What is ivacaftor?
Potentiator
89
When is it best to start potentiators?
From birth/young as possible
90
When did newborn CF screening start?
2007
91
How are newborns screened for CF?
IRT (immunoreactive trypsinogen), genotype, sweat test
92
Advantages of early screening in CF?
Better nutrition
| Prevention of infections and damage (ie resulting bronchiectasis), earlier physio, genetic counselling
93
Disadvantages of screening in CF
Missed cases - rare genotypes
False positives
Loss of awareness of clinical presentation?
94
Sweat test. How does it work?
Sweat from two samples from different limbs are analysed using macroduct system
NR <30mmol/L
Borderline 30-60mmol/L
Confirmed >60mmol/L
95
List Ix for CF
CF sweat test
CFTR genotyping
Stol elastase (if panc insuff)
Nasal potential differences testing
96
Spirometry in CF
N early then Ob
97
What is multi-breath washout?
A more sensitive technique than spirometry, where time taken for a tracer gas to be fully absorbed is measured.
98
Flucloxacillin is used prophylactically in CF from diagnosis, why?
Staph A is prevalent from a young age in CF
99
Why does some evidence suggest that flucloxacillin should not be used from birth in CF?
A study has depicted that children on Fluc acquire Pseudomonas A sooner. Currently this is being tested in another study RCT
100
P Aeruginosa is difficult to clear in CF, why?
This G-ve opportunistic bacteria can exist in planktonic or biofilm state. Biofilm hard to clear in thickened CF mucus. Also has abx resistance
101
Resp Rxs for CF
```
Clearance = physio, mucolytics - DNAse / saline
Abx
Anti-inflammatories?
Anti-fungals
Transplant
```
102
What is a bacteriophage?
Virus that kills bacteria
- Self amplifying and self limiting
- No reported side effects
- Highly specific
103
Bacteriophage MoA
- Phage attaches to bacteria
- Inserts DNA into bacteria
- bacteria genome replicates
- Reverse transcription and production of bacteriophage components
- assembles
- enzymes break down peptidoglycan walls -> leaves bacteria
IN MICE study depicted that bacterial cell counts and inflammatory cell counts were both reduced as depicted by BAL with Pa01 Bacteriophage admission.
104
Discuss nutritional aims / diets for CF
Improve fat absorption -> lifelong PERT and antacids
Increase intake -> high fat/calorie
Supplement diet -> fat soluble vitamins, extra feeds / gastrostomy
105
FVC ranges N-Severe
Normal - 80-120%pred
Mild - 70-80%
moderate - 50-70%
Severe - <50%
106
What is PD20 in provocation testing?
Dose required to see 20% red in FEV1
107
What is the PD20 of methacholine?
1.5mg/ml
108
Typical cough hypersensitivity patient characteristics
PM women, multiple drug Hx, multiple GP appointments, cough to aerosols/talking, always carry lozengers etc
109
List 3 most common causes (11 total) & associations of chronic cough. 8 weeks plus
GORD, rhinosinusitis, Asthma >- ALL 90%
| Infection, Ace inhibitors, COPD, CF, neoplasm, ILD, Foreign Body Inhalation, smoking
110
How does oesophageal impedence work?
Pairs of currents. Interrupted by acid presence. When impedence stops at a level, reflux does not occur there
111
What did a cochrane analysis show with regards to PPI usage in chronic cough?
Esomeprazole did not reduce cough severity / cough scores but trial of PPI still recommended.
Lack of large multi-centre trials
112
Surgery for GORD
Nissens fundoplication. Lack of long term followups and trials. Severe dysphagia, flatulence and bowel symptoms possible
113
3 potential Mechanisms of cough in Asthma?
Airways inflammation -> peripheral nerve sensitisation
Constrictor stimuli - bronchoconstrictor induced
Coexistent triggers -> Nasal disease, refulx, bronchiectasis
114
61% of asthmatics still have cough post Rx (mod-sev). What paper?
Teeter Chest 1998
115
List 3 uncommon causes of chronic cough
OSA, large tonsils, Ear, fungal associated, hypothyroid, ear (arnolds reflex)
116
44% of cough patients have _______ + STUDY
OSA Sundar Cough 2010
117
CPAP significantly reduces cough STUDY
Birring Cough 2007
118
What is tracheobronchopathia osteochondroplastica?
Formation of benign submucosal nodules growing from submucosal layer of the airways, protruding into bronchial lumen
119
What is arnolds nerve?
Auricular branch of vagus nerve
120
What is the Arnold-ear cough reflex?
Whereby 5% of pts have cough reflex from stimulation in ear ie even a cotton bud
121
What is holmes-adie syndrome?
Anisocoria + ankle tendon areflexia + hyperhydrosis and syncope. Associated with chronic cough.
122
What is the proposed mechanism of chronic cough in holmes-adie?
Thought to be due to a loss in thinly myelinated afferents in the lung, trachea and larynx. This loss may lead to denerveation hypersensitivity of the secondary neurons in the nucleus solitarius
123
What proportion of pts have unexplained cough?
40%
124
Idiopathic Cough Pathology
- Enhanced sensitivity (inc density of nerves + capsaicin sensitivity)
- Increased TRPV1 expression
- Inc mediators and inflammatory cells described in some studies. Relationship unknown.
- Goblet cell hyperplasia - cause or consequence?
125
How does theobromine prevent cough?
| Theobromine = caffeine + theophylline
Direct dose dependent inhibition of sensory nerve depolarisation in guinea pigs. Interestingly more efficacious than codeine as an antitussive.
126
Idiopathic cough Rxs
Cloves, hot ginger infusions, steam inhalation with vick vaporub - MAURICE THORAX 1994,
antihistamines, ICS, gabapentin, neb bupivicaine (anaesthetic), LAMA, Low dose opiate
Physio/Speech if fails
127
List 3 CV causes of Cough syncope
Carotid artery stenosis
Constrictive pericarditis
Sinus arrest
128
List 3 neuro causes of cough syncope
Arnold chiari
Posterior cranial fossa meningioma
Autonomic dysfunction
129
List 2 resp causes of cough syncope
Smoking
| OSA
130
Disadvantages bronchial biopsy and lavage
Invasive
Not repetitive
Contraindications of severe patients
Cannot be used in children
131
List common gases and molecules analysed in exhaled breath tests?
```
NO
CO
Ethane
Pentane
Ammonia
```
132
What can be measured in breath condensate?
oxidants, mediators and metals
133
How is eNO measured?
Chemiluminescence analyser adds NO to O3 -> NO2* and O2.
| Nitrite with radical then splits into nitrite and light. Able to measure light produced.
134
Advantages of eNO
NI, direct readings, reproducible
135
Limitations of eNO
High cost?
Compliance
Originally not transportable
136
What is the normal NO measurement with inhalation?
<5PPB
137
Explain the marked flow dependency of NO in eNO + STUDY
Low flow rates produce higher NO, opposite for higher.
50mls per second flow rate required
Silkoff PE et al AJRCCM 1997
138
What could an eNO of <5 indicate?
PCD, CF, bronchopulmonary dysplasia
139
What could an eNO of 20-35 (adults), 15-25 (kids) indicate?
Eosinophillic inflammation may be present
- Could also be cold/flu
- Could be normal if atopic
140
What could an eNO of >35 (adults) and >25 (Kids) indicate?
Eosinophillic inflammation = highly likely
- Likely to respond to an antiinflammatory
Could indicate:
- Poor ICS compliance
- ICS unresponsive
- ICS dose inadequate
141
Why do asthmatics have raised eNO?
Inflammation upregulates nitric oxide synthase
142
What trend of NO did Kharitonov SA et al discover? AJRCCM 1995
NO only rises in inflammatory late response in asthma
143
What correlation was seen with NO and methacholine/eosinophils? Jatakanon et al thorax 1998
Increased bronchoconstriction + eosin = increased NO
144
What correlation was seen with ICS and NO?
| Kharitonov Thorax 2002
Dose dependent decrease in NO with inc ICS. Stopping ICS increased NO
145
Flow independent eNO measures...
Inflammation at periphery
146
Flow dependent eNO measures
Inflammation in airways
147
Explain process of inducing sputum
Aerosol of hypertonic saline 5%. 4x5 mins
Pt must blow nose and wash mouth before
Tiny risk of bronchoconstriction
148
What differences were seen by Green RH et al Lancer 2002 when managing pts with sputum eosinophils rather than BTS guideines?
Considerably less exacerbations in sputum eosino management
149
Limitations of induced sputum
```
Safety concerns?
Must leave intervals
Reproducibility issues
Time consuming
Training required
```
150
Main problem with exhaled breath condensate EBC?
Poor validation. Ie isoprostanse Montuschi p et al AJRCCM 2000
pH is reproducible.
151
List factors which may influence EBC biomarkers
```
Ambient air
Duration and temperature of condensation
Breathing pattern
Age and Gender
Food
Circadian changes
Tobacco smoking
Medications
```
152
Discuss safety of EBC
No lung function changes
Mo changes in composition of airway lining fluid
No airway inflammation
No real risk of cross infection
153
Discuss reproducibility of EBC?
Sample volume reporducible
Effect of different breathing patterns unknown
Reproducibility of biomarkers is variable
154
Limitations of EBC
```
Origin of mediators unknown
Flow-dependency
Nasal/oral contamination
Lack of reference values
Dilution factors
Large scale multi-centre comparative studies required
```
155
Advantages of EBC
NI, simple
Safe (even safer than LF)
Can be performed in a variety of settings and on severe pts
No intervals between repeating
156
Single breath measurement of bronchial blood flow. How does this work?
Inhale mixture of inert and highly soluble (egC2H3) and inert and highly insoluble (SF6). By comparing the ratios of the two per unit time bronchial blood flow can be measured.
157
Blood flow increased in asthma
Normal in COPD
STUDY NAME
```
Paredi et al resp research 2005
Chest 2007 (copd)
```
158
What is SAM?
Synthetic absorptive matrix - absorbs neat epithlial fluid. Elute in known volume buffer -> analysis
159
Nasal ELF and bronchial ELF correlate STUDY
Batista et al ERS 2016
160
Hurdles for CF gene therapy
Innate epithelial defense cannot differentiate between Rx and pathogens -> clears all
How to get gene into DNA - cell membrane / across cytoplasm full of enzymes / into nuclear memrbane (DNA too large)?
Persuade nucleus to read exogenous rather than endogenous DNA
161
Problems of using a virus as vessel for gene in CF therapy?
Viral clearance 2-3 weeks
| Immunity develops
162
What method of instillation is used in clinical trials for CF?
Liposome - fuses with cell membrane
163
25% improvement in early CF studies. Why does this not correspond to clinical benefit?
May not improve pt symptomatically
One dose = lasts a few weeks = not a life time
Multidose trial extremely expensive
164
CMV promotor used to drive CF gene initially, why did this not work?
Expression reduced greatly by two weeks
165
hCEF1 - human elongation factor 1a promoter was used instead of CMV promoter. Why was this better?
Had initially slower onset
| Gene was transcribed even 28 days later -> fewer visits as a pt if potential Rx
166
Yet, even post hCEF1a use as a promoter the plasmid DNA was destroyed. Which sequence seen in bacteria caused this?
CpG
167
List 5 caveats of an optimal liposome?
```
Pass epithelium
Can be given repeatedly
Stable in a nebuliser
Manufactured to GMP standards
Non-toxic
```
168
Why can't in vitro studies be relied on for liposome selection?
Completely different results seen in vivo and vitro
169
What is the wave 1 CF gene therapy product called?
pGM169
170
What is a possible conundrum with pt selection for Gene therapy with regards to age?
Young may see more benefit and easier to deliver
| Older have more parameters to measure to track effects of gene, but harder to deliver
171
How does lung clearance index work?
Measure how long it takes to clear inhaled inert gas.
| Takes longer with increased obstruction
172
pGM169 was tried nebulised. What problems were encountered?
Patients got chest infections + flu like symptoms with wet secretions. Volume and duration of nebuliser too high
173
What was the result of the multidose gene therapy trial with regards to FEV1 (pGM169)?
FEV1 prevented 3.7% decrease in lung function p<0.05
| remained same
174
When patients were split by lung function and analysed (pGM169) what was seen?
FEV1 70-90% had no improvement. Treatment effect 0.2%
| FEV 50-70% had Rx effect of 6.4%
175
What was the hypothesis for the differing responses seen in 50/70 and 70/90 FEV1 groups (pGM169)?
More mucus obstruction in smaller airways when severe
Therefore more deposited in larger airways.
Large airways influence FEV1 more
Therefore LARGER dose for 70-90% group
176
Why is sendai virus a positive choice of vessel for pGM169?
F and HN surface proteins allow epithelial aggregation
177
Why is lentivirus a positive vessel choice for pGM169?
Able to incorporate DNA into genome. Combine FHN with lentivirus
178
What vessel was used in wave 2?
F/HN pseudotyped lentivirus
179
How successful was Lentivirus vs liposome?
500x more effective
180
How long does lentivirus last?
Forever. Can be repeatedly administered (unknown)
181
What effect was seen on inflammation with lentivirus?
Reduced in comparison to liposome
| No clinical evidence of neoplasm caused by lentivirus
182
What dictates REM sleep?
Circadian Rhythm
183
List factors that influence sleep
```
Age
Circadian Rhythm
Deprivation
Substances
Disorders
```
184
What change to sleep cycle occurs with age?
Reduced REM and stage 4
185
Where does volitional breathing control occur?
Cortex - primary motor and sensory
| Activity also detected in medulla
186
What tract, volitional breathing?
Corticospinal
| Laghi AJRCCM 2003
187
What tract, automatic breathing?
Bulbospinal
| Laghi AJRCCM 2003
188
What cells control reflex breathing in brain?
Prebotzinger
| Smith et al 1991
189
How do Prebotzinger cells work?
complex of cells that cross inhibit and activate one another generating potentials.
190
What is desirable about prebotzinger location?
Close to medulla - responds to changes in CSF ie pH
191
What did McKay et al discover in 2005 Nat NeuroSci?
Knockout of botzinger caused apnoea in REM initially, then in Non-REM sleep.
192
How does minute ventilation alter in sleep?
10% reduction -> increases to 13 in REM
193
How does alveolar ventilation alter in sleep?
Reduced by 15% (by 20% in rem)
194
How does TV alter in sleep?
Reduced 11-13%
195
How does RR alter in sleep?
No sig changes
196
Why does CO2 rise in sleep?
May be due to removal of voluntary breathing
May be due to relaxation of muscles - larynx etc
Or both?
Study MORRELL et al JAP 1996 on laryngotomy patients showed that CO2 still rose in sleep, suggesting the former has more of a role
MOST LIKELY OVERALL DUE TO REDUCED CO2 SENSITIVITY
197
How does reduced CO2 sensitivity occur?
CO2 sensed by neurones in the retro-trapegoid nucleus.
Dendrites projected into medulla and prebotzinger.
Less active during sleep.
In REM prebotzinger = disordered -> disordered breathing
198
What did Thomson et al JAP 2005 discover?
Ventilated a patient. When asleep they manipulated C02 levels to below threshold. Pt stopped breathing + woke up -> volitional breathing
199
What is the apnoeic threshold? Skatrud + dempsey 1983
40. 9 = Pt stops breathing
| 42. 0 = Pt starts breathing
200
What happens to PCO2 when waking up?
Decreases - increased MV results in more blowoff
201
Discuss pathoP of CSA
- reduced respiratory drive to resp pump muscles
- If pt wakes up CO2 is blown off briefly
- If pt drifts back off to sleep then CO2 is too low to stimulate breathing
- Apnoeic event occurs
- Apnoeic event is delayed as blood must flow round body
- Forms continous apnoeic cycle. Breathing as CO2 rises, increased breathing blows off CO2 -> apnoea
Cheynes stokes breathing pattern
No attempt at breathing in central
202
Discuss pathoP of OSA
Airway muscles relax -> apnoea -> arousal -> patent airway and CO2 blowoff
Pt then falls asleep
Low CO2 causes apnoea again
PT will try to breath in initial apnoeic event
203
Why do HF patients get CSA?
Delay in circulation.
204
What are the other (minor and postulated) mechanisms behind OSA?
36% have poor resp muscle responsiveness
36% have poor resp control ie over breath in response to high CO2 -> increased blow off
37% have low arousal threshold ie deep deep sleepers
205
Why are old people susceptible to OSA?
- Increased sagging of neck
| - Wake up more in general therefore the increased V seen when waking has a greater effect
206
By how much does CO2 rise in sleep?
3-8mmhg
207
Cough is repressed by...
Sleep and anaesthetics
208
Afferent cough nerves
Vagus and superior laryngeal
209
Where is the cough centre?
Medulla
210
List the two implicated receptors in the lungs and airways in chronic cough
Rapidly adapting stretch receptors
| C-fibre nociceptors
211
What are rapid adapting stretch receptors?
Small myelinated A-delta nerve fibres
212
What are C fibre nociceptors?
Free nerve endings, unmeylinated
213
What ganglions do cough nerves pass through?
Nodose
| Jugular
214
What activates neurones in Jugular ganglion?
Acid, mechanical, capsaicin, bradykinin
215
What activates neurones in the nodose ganglion?
Acid, mechanical
216
What is proof that higher centres can be involved in chronic cough?
Voluntary suppression
Dec freq in sleep
Significant placebo effect in studies
Voluntary cough can be reduced independently of reflex ie stroke/MND
Activation of supramedullary pathways during urge to cough
Activation of mid-brain pathways in chronic cough
217
What are the Secondary outflows of cough?
Mechanisms enhancing defensive function of cough
- Bronchoconstriction
- Mucus secretion
Mechanisms opposing mechanical stresses of cough
- Perineal muscles
- Lower oesophageal sphincter
- Respiratory muscle activation
Changes in breathing pattern
Cardiovascular changes
- Changes in cardiac output and blood pressure
- Changes in heart rate
218
What is CCHS chron cough HS?
A clinical syndrome characterised by troublesome coughing often triggered by low levels of thermal, mechanical, or chemical exposure
Repeat irritations in the throat or chest that result in cough paroxysms that are difficult to control
219
What is the concept of CHHS?
Cough-response to stimuli curve shifted so pt responds to innocuous stimuli.
Echoed with capsaicin studies
Chung Lancet Resp Med 2013
220
When is a capsaicin enhanced cough response seen?
```
Post-viral infections
Eosinophilic-associated cough (asthma,CVA, eos bronchitis)
COPD
Cough associated with rhinitis
Cough associated with gastrooesophageal reflux
Bronchiectasis
Pulmonary fibrosis
‘Idiopathic’ cough
```
221
What receptors are increased in chronic cough?
TRPV1
222
What patho may be occuring that cause chronic cough?
Increased excitability of afferent nerves increased by chemical mediators eg bradykinin, PGE2
Increase in receptor numbers eg TRPV-1 (capsaicin receptor), voltage-gated channels
Neurotransmitter increase eg neurokinins in brain stem
Changes in nerve densities
Cortical plasticity?
223
An increase in what cell type is often seen in chronic cough?
Mast cells
224
List centrally acting anti-tussives?
Codeine, dihydrocodeine, morphine etc..
| Gabapentin/amitryptaline
225
List peripherally acting anti-tussives?
Moguistine
| Levodopropizine
226
Were TRPV1 antagonists effective?
No.
227
Abdulqawi et al Lancet 2015 discovered what drug was effective in chronic cough?
P2X3 (AF-219)
228
What is tested initially in in vitro models and rodents?
Pharmacodynamics
Pharmacokinetics
Toxicology NOEL/NOAEL
Mutagenicity
Interaction potential
Carcinogenesis - long term toxicity studies
Reproductive + fertility testing -> one non rodent and TWO species
229
How is mutagenicity tested?
Ames test, mouse lymphoma, micronucleus test
230
What is tested to determine interaction potentials?
PPB
CYTP450
Effects on transporters
231
What are the pre-requisites for studying drugs in man?
```
Adequate pre-clinical package
- ie safety studies to cover duration of study
Appropriate drug formulation
Clinical Rationale + Study protocol
Rish:benefit analysis - investigators brochure
CTA - clinical trials application UK
Ethics committee permission
Clinical trials registry number
```
232
What occurs in phase 1
Healthy volunteer studies (not in Ca) to establish safety/tolerance, PK (including food), ?pharmacodynamics/PoM
STARTING DOSE 10% of proposed
233
What occurs in phase 2a?
Small studies in patients to establish tolerance, PK differences, efficacy
POP
234
What occurs in phase 2b?
Dose ranging study (establishing optimal dose). 3 doses vs placebo + active comparator
POC
235
What occurs in phase 3?
Larger efficacy studies and comparator
Risk:benefit
Close monitoring of side effects.
Long term tolerance must be established in at least 100 patients for 1 year
Usually submit for licence to market drug with the registration authority
236
What occurs in phase 4?
Post marketing studies
| Safety, economic ben, new indications
237
What study proved that high dose ICS + LABA is statistically significant in reducing exacerbations in asthma? What were the problems
FACET study 1997
BUT only a decrease from 0.9 per yr to 0.5
- significant due to sample size
- is it really that desirable? 1 er yr vs 0.5...
238
What additional studies are required for INHALED products?
Device - humidity effects, particle distribution, safety features, effect of spacer
Phase 1 - in vivo deposition studies
2 - bronchospasm study + optimum flow-rate
4 - PMS = 3-6 months
239
Why inhaled therapy in resp diseases? + studies
Smaller dose - BENET et al 1990
Faster onset - SELF et al 1992
Incidence of side effects is less - Newman et al 1983
240
When was modern inhaler (MDI) invented?
1956
241
Advantages MDI
```
Compact Portable
Quick Rx time
Multidose
inexpensive
Drug in sealed cannister
```
242
Disadvantages of MDI
Difficult coordination
CFC-free only after HFA
High oral depositon
DIFFICULT to assess emptiness
243
What are spacers for?
Removes coordination aspect of MDIs
Reduces oropharyngeal impact
Smaller particles and greater lung deposition as allows time for propellant evaporation
pMDIs with spacer are as effective as nebs in patients with acute asthma - Morgan et al 1982
244
DPI advantages
Compact Portable
Quick Rx time
Breath activated -> less coordination
No propellants
245
Disadvantages DPI
```
reliant on sufficient inspiratory flow
High oral dep
Older devices no multidose
Contain additives
Humidity leads to drug degradation
```
246
Nebs advantages
```
Relaxed tidal breathing
Large doses can be given
Aerosol many drug solution
No propellants
Suitable for old and acutely ill
```
247
Dis Nebs
```
Bulky
Long Rx time
Expensive
Wasted drug in nebuliser
Need power source
Variation in aerosol output between models
```
248
Adv Soft mist inhalers (SMIs)
Compact
Multidose
slow mist
small droplets
249
Disad SMIs
Only one device available currently
Some coordination necessary
Contain some additives
250
Hanani chest 1994 found
Most health workers UNCERTAIN about correct use inhalers
| Resp PTs>Nurses>doctors
251
What did Plaza et al 2012 JAMPDD find?
Doctors knowledge (N>1500) of inhaler techniques remain poor ~14.5%
252
How much standard dose is wasted in older inhalers?
80% wasted
Biddiscombe thorax 1993
Most impacts oropharynx
253
List aerosol factors that influence lung depostion?
Particle size, density and charge
Lipophilic
Hygroscopicity
Plume speed and duration
254
How does particle size influence deposition
If too large then affected by inertial compaction -> cannot follow changes inairstream direction
255
How does particle charge influence deposition
More attraction to epithlium
256
List patient factors influencing lung deposition?
| Labiris BRJ Clin Pharm 2003
Inspiratory flow and volume
Airway disease + severity
Device acceptance
Compliance
257
What particle size deposits in oropharynx? Chrystyn Allergy 1999
>6 microns
258
What particle size impacts larger airways? Chrystyn Allergy 1999
2-6microns
259
What particle size impacts alveoli? Chrystyn Allergy 1999
<2microns
260
Which study used gamma camera images of tc99 labelled salbutamol to demonstrate effects of particle size on deposition (NB lecturer)
Biddiscombe AJRCCM 2005
| Oral deposition increases with particle size
261
What is the relationship between particle size and flow?
| Biddiscombe AJRCCM 2005
```
Small particles less effected by flow (deposition actually increases)
Large particles (3microns
```
262
Name one other benefit of HFAs vs CFC use as propellant (besides enviro)
HFAs are propelled at a slower rate
| Also warmer
263
Solution vs Suspension
Solution -> no need to shake
264
What is a smart nebulisers?
Only delivers drugs on inhalation
Digital logging systems
Aid adherence
265
List roles of mitochondria
```
Stress response
inflammation
Apoptosis cytC pathway
energy production
Biosynthesis
Redox homeostasis
Calcium homeostasis
Iron homeostasis
```
266
What stimulates mitochondrial biogenesis?
Energy depletion
Activators of cell division
Thyroid hormones
267
What occurs in the nucleus with regards to mitochondrial biogenesis?
PGC-1a TF results in transcription of mitochondrial proteins AND Tfam
268
What happens to Tfam in the mitochondria?
Triggers mitochondrial DNA, transcription and replication. Results in mitochondrial fission
269
In what configurations can mitochondria exist in and what are the implications?
Fusion = Fused together
Fission = separate
Fusion = more efficient energy production
Normally an equilibrium
270
When do mitochondria fuse?
METABOLICALLY ACTIVE
Exchange of mitochondrial contents/metabolites/nutrients
More energy
271
When do mitochondria separate?
WHEN AT REST
| Required for removal of damaged mitochondria
272
In what ways can mitochondrial Morphology be assessed?
Morphology
- electron microscopy
- Fluorescence microscopy
273
In what ways can mitochondrial respiration be assessed?
Oxygen electrodes
| Fluorescence probes - oxygen quenches fluorescence resulting i signal proportional to O2
274
In what ways can mitochondrial ATP production be assessed?
Bio-luminescence detection of luciferase activity is proportional to conc ATP in sample
275
In what ways can mitochondrial membrane potential be assessed?
Fluorescence dye - amount that enters is proportional to potential
276
In what ways can mitochondrial ROS be assessed?
Fluorescence dye - oxidised by ROS -> produces signal
277
How does oxygen stress cause mito dysfunction and eventual cell death?
ROS leads to MitoDNA damage - affects biogenesis
Electron trans. chain breaks down - EVEN more leakage of ROS
When E trans. chain breaks down the membrane potential is lost
This then results in energy loss and increased permeability of membrane
278
How do mitochondria respond to acute low level oxidative stress?
Increase ROS results in "danger signal"
Causes increased transcription of PGC-1a.
This increases Mito Biogenesis. Increases healthy mito numbers - increases ATP and decreases ROS
279
How do mitochondria respond to acute low level oxidative stress, OTHER than increasing biogenesis?
Via mitochondrial fusion
- Express mitofusins 1+2 (MFN) on outer membrane
- Express optic atrophy 1 (OPA1) on the inner membrane
MFNs fuse + provide energy for GTP hydrolysis (for fusion of inner membranes OPA1 and outer MFN1/2)
Share MtDNA, nutrients and metabolites etc
280
How do mitochondria respond to prolonged oxidative stress?
Fission - splitting
Prolonged oxidative stress damages mito in the fusion linkage system.
Increased ROS results in translocation of dynamin related protein 1 (DRP1) form the cytosol to the outer membrane.
DRP1 binds to FIS1 (receptor mitochondrial fission 1)
DRP1 assembles to multimeric rings which promote GTP hydrolysis mediated constriction and separation of the mito.
Damaged Mito = targeted for mitophagy
281
Discuss Mitophagy
Mito labelled for destruction via PINK1 translocation from inner to outer membrane.
PINK1 recruits Parkin which ubiquitinates proteins and recruits adaptor protein p62 and light-chain 3 (LC3).
LC3 becomes lipidated and forms an autophagosome around mito.
Eventual fusion of autophagosome and lysosomes
282
What happens if oxidative stress mechanisms fail in mitochondria?
Accumulation of defective mitochondria -> cell dysfunction.
If mitochondria under stress then Cyt C leaks out ensuing apoptosis
If mitochondria lyses then necrosis ensues -> mito DNA, ATP, formyl peptides and fragments recognised by TLRs + formyl peptide receptor 1 -> inflammation
283
How can mito from COPD patients be sampled?
Bronchoscopy with brushing or biopsy
284
Describe COPD mitos
Swollen, hyperfused, with cristae depletion
285
Describe mito membrane potential differences in COPD
Significantly reduced
| Weigman and Michaeloudes J allergy 2015 (also echoed in mouse studies)
286
Describe mito respiration differences in COPD N and Smoking?
Max resp = N>smokers>emphysema
| Weigman and Michaeloudes J allergy 2015 (also echoed in mouse studies)
287
Describe mito ATP production differences in COPD N and Smoking?
Normal ~= smokers > COPD
| Weigman and Michaeloudes J allergy 2015 (also echoed in mouse studies)
288
What was seen in emphysema induced mice with addition of Co-enzyme q10? (mito targeted antioxidant)?
Sig red in inflammatory cell presence
289
What did Michaeloudes et al discover in 2017 with regards to MSC and mito?
Mitochondria are donated from IPSc->airway smooth muscle cells
290
How many adults are breathless?
10% adults
30% 70+
25% A+E
291
What percentage of chronic dyspnoea is respiratory?
53%
292
What proportion of diagnoses were correct post H+E in "an algorithmic approach to chronic dyspnoea"? What did this rise to post PFT?
55%
72%
293
Why is it difficult to assess people via FEV1 and EF, when both correlate with VO2 max?
Outliers who may have low FEV1 but very good VO2 max etc
| Massive inter-individual variation
294
In tier one for unexplained dyspnoea in "an algorithmic approach to dyspnoea" how many received accurate diagnosis?
Tier 1: H+P, Labs, PFTs, CXR
36%
295
In tier two for unexplained dyspnoea in "an algorithmic approach to dyspnoea" how many received accurate diagnosis?
Tier 2 - CPET cardiopulmonary exercise testing
70%
296
Why is CPET a good investigation?
```
Able to work out breakdown in system:
Ventilation
Gas exchange
CO
Circulation
O2 extraction
```
297
What does ventilation vs Waste gas clearance show?
Degree of deadspace - Must ventilate more to rid of waste // waste build up with dead space
298
Why is it good to witness the CPET?
Discomfort/perception/constriction vs values
299
Why are GPs poor with dyspnoea?
Prevalence of asthma.
Leading questions ie "is it worse when cold"//"Have you heard wheeze?" Which will often ensure positive answers
EG
70% IPF trialled on blue inhaler?
Not all wheeze is asthma: time for patients to exercise their rights - J hull Thorax 2015
300
In tier three for unexplained dyspnoea in "an algorithmic approach to dyspnoea" how many received accurate diagnosis?
Tier 3 -
CT, VQ, Bronchos, thoracentesis
Cardio - stress echo, nuclear stress test, cardiac catheterisation
UGI endo + Sinus CT
99%
301
What are ILDs?
Any disease involving the alveolar interstitium - between endothelium and epithelium
302
Key Ix for ILDs
```
HRCT = optimum
LFT
CXR
Bloods
Echo - PHTN
Gallium
Bronchoscopy
Biopsy
Often need multiple tests
```
303
List 3 diag criteria for IPF
1) exclusion of other ILDs
2) presence of UIP (usual interstitial pneumonia) on CT in pts who have not had biopsy
3) Specific combinations of CT and lung biopsy pattern in pts subject to biopsy
304
List radiological features of IPF?
Subpleural basal prdominance
Reticular patterns
Honeycombing
Absence of features that are INCONSISTENT with UIP
305
Why is IPF important?
Incidence has doubled to nearly 3000 in 15 yrs
1/100 deaths in UK
People are unaware of it?
Poor prognosis, 11th in relation to cancers.
5yr survival = 20% -> more deaths than ovarian, myelomas, leukaemias
306
What happens in normal lung in injury to epithelium?
Plts adhere to exposed collagen. Activation clotting factors.
Cytokine release stimulates fibrocytes to expand and produce collagen
Epithelial debridement (apoptosis)
Replacement with stem cells
Apoptosis of fibroblasts
307
Discuss genetic involvement in IPF
50% of susceptibility = genetic
1/20 IPF have rellative with gene.
Muc5B, intergins, cell ageing
308
Discuss environmental involvement in IPF
Dusty working conditions
EBV
Chronic GORD
Cig smoking
309
What did Molyneaux et al AJRCCM 2014 discover with regards to IPF?
Increased bacterial load in IPF compared to COPD + Control
310
What is seen with regards to alveolar epithelium in IPF?
T2 epithelial cells prematurely apoptose/do so in higher numbers
311
What is seen with regards to stem cells in IPF?
Ageing results in a reduction in the amount of times a stem cell can divide - less able to repair
312
What is seen with regards to coagulation in IPF?
Increased coagulation - local activation of clotting factors
313
What is seen with profibrotic inflammatory cells in IPF?
Increased numbers. Gibbons et al AJRCCM 2011 showed that removing macrophages in IPF mouse resulted in reduced fibrosis
314
What is seen with regards to GFs in IPF?
Upregulation of pro-fibrotic growth factors
| Downregulation of GFs associated with wound healing resolution
315
What is seen with regards to fibroblasts in IPF?
Large increase
| ALSO increase in GF receptors = increase matrix formation
316
What is the relationship between stiffness and matrix composition
As compliance is reduced conversely matrix composition increases
317
What imbalance of mediators (and specifcs) is seen in IPF
Profibrotic
CTGF, TGFb, PDGF, FXa, VEGF
Antifibrotic red
PGE2, IFN-y, HGF
318
Av IPF Pt
male 50+, former smoker, work in a dusty environment
319
What is seen in an IPF exacerbation?
ALI occurs
Results in increased damage to alveoli
INCREASED fibrotic response
50% die within 4 weeks
320
List challenges in IPF trials
Differing end points
Late vs early
Lack of events in trial patients (exacerb)
321
What is the most responsive measurement in IPF?
FVC
Rate of decline = good prognostically
DLco is also reduced (BUT OPEN TO variation within different machines)
6 minute walk can be used -> but hard when very severe
322
Prednisolone, azathioprine and N acetyl cysteine were previously given in IPF. Why are they no longer?
Small trial involving 27 patients showed improvement.
| Larger RCT showed that this treatment actually killed IPF sufferers soon.
323
Rxs for IPF
Lung transplant
Perfenidone (small molecule) not sure full mechanism.
Halved decline in FVC
(SE = rash + GI)
Nintedanib = TK inhibitor - anti GF - originally for SCLC
Roughly 50% red (DIARRHOEA)
324
What was seen in a study involving cotrimoxazole in IPF?
only 2/3rds reached end of trial
Not tolerated by others.
Did reduce exacerbation and hospitalisations
325
What was seen in a study involving thalidomide in IPF?
Does aid cough in IPF
326
What was seen in a retrospecive study involving PPIs in IPF?
Some evidence to suggest PPIs beneficial
| - slower rate of progression
327
What was seen in a study involving sildenafil in IPF?
Aided PHTN
328
Complications IPF
RF, PHTN, LC, infections, exacerbations
329
Other aspects of IPF Rxs
O2
Pulmonary rehab
Infection prevention and flu vaccines
330
ICS use in asthma. What is seen with 2 weeks Rx?
Improvement of FEV1. PEF, symptomatic scoring, dose-dependent effect on inflammatory cells.
BOOTH ET AL 1996
331
What percentage decreases are seen with 250ug inhaled and 100ug inhaled after two weeks therapy with ICS? (FP)
250
Mast 30% dec
Eosin + T cells 50%
1000ug
All roughy 85%
Booth et al
332
Reported ICS S/E in children
BM loss, growth velocity (terry harper)
| Cataracts / glaucoma
333
What are the "soft steroids" butixicort and tipredane? Did they work?
Steroids that are activated by esterases in the lungs. Did not work - abandoned
334
What is Ciclesonide (ICS)?
An ICS prodrug. Becomes an activated CS
335
What did Taylor DA et al discover with regards to the efficacy of ciclesonide in asthma?
Significantly reduced pc20 at 50, 200 and 800ug levels
Significantly reduced sputum eosinophils
Took too long to develop though
336
Discuss the structure of the GC receptor?
NT(AF1)-DBD-LBD(AF2)
NT = activation domain - recruits cofactors
DBD = DNA binding domain
LBD = ligand binding domain
337
Where is most of the GR?
Cytosol
| Associated with mitochondria at rest
338
What two p domains is NFkB formed of?
p65 and p50
339
List stimulators of NFkB
```
IL1
TNFa
LPS
OXidative stress
UV
TLR
Cigarettes
Haematopoietic Cytokines
```
340
What does NFkB activate?
Cytokines IL6/8
ICAM adhesion molecules
iNOS and COX2 inflammatory enzymes
Various Receptors
341
What is the relationship of NFkB and asthma?
Inc NFkB activation asthma
Increased
Huge upregulation in patients who dies in asthma
Graham Heart
342
Transrepression depends on a physical interaction between what molecules?
GR and NFkB
| Similar mechanisms for AP1 (another inflammatory TF)
343
Two mechanisms of action of GCs?
GR dimer - DNA binding = transactivation
- Inc anti-inflammatory proteins
- Does increase S/Es
GR monomer - Transrepression - inhibution of TFs - NFkB, NF-AT, AP1
- Decreases inflammatory cytokines, proteins, adhesion molecules etc
344
What is the aim for GC drug development (with regards to MoA)
To concentrate on Transrepression
| transact produces S/Es
345
Compound A was produced by Gsk. What benefit did it have have over typical ICS?
Sig reduction in Calcium loss in bones (osteoporosis) compared to dex and pred in rat models (assessed skull caps)
346
What is the effect of p38 MAPK inhibitors on GR function?
Augments response to ICS.
| Thought to phosphorylate GR and alter co-factor associations
347
What did Kent et al 2009 discover with regards to p38 MAPK inhibitors in COPD?
Restores steroid sensitivity in macrophages
348
How does oxidative stress influence macrophages? What was measured in the studies by Marwick and Hakim?
Induces steroid insensitivity. h2O2 used
| Measured TNF-a and CXCL8 respectively
349
What did chalmers et al Thorax et al 2002 discover with regards to asthma and smoking?
Change in PEF with fluticasone 1mg in asthma smokers is -5%, non smokers = improvement of 26%
Eosinophilia change -1.8% in non smokers
In asthma there was NO CHANGE in eosinophilia
350
GR translocation is reduced in what diseases?
Severe asthma - shown in ASM cells
| COPD - shown in macrophages
351
What effect does oxidative stress have on GR receptor translocation? Why is this?
Hakim 2012
Reduces GR nuclear translocation. Modulated by H2O2. Defective importin 7 / Ran GTP system which translocates GR across nuclear membrane.
Hakim 2012
352
What was knocked out to prove oxidative stress reduces GR import and function?
Importin 7 knocked out in mice.
| Suggested restoring nuclear import improves GR function.
353
HDAc2 is reduced in what diseases?
Asthma and COPD
354
What does HDAC2 over expression in COPD macrophages result in? Ito et al 2006 JEM
Restores sensitivity to Dex
| Ito et al 2006 JEM
355
What drug targets HDAC2?
Theophylline.
| Improved neutrophilia in COPD FORD ET AL 2010
356
Absence of which PI3K restores steroid sensitivity? (reduced BAL neutrophils in COPD)
John Marwick
Delta
| NOT GAMMA
357
Steroid receptor expression is reduced in what diseases?
NO CHANGE IN SEVERE ASTHMA
| 50% dec in COPD
358
What effects do beta agonists have on ICS Rx?
| FACET study 1997, Greening et al 1994
Appears to augment ICS response. Greater improvents in PEF/exacerbations
Raman analysis mass spec shows the drugs impact onto lung surface together
359
What is the pharmacology behind B agonist augmentation of ICS Rx?
GCs able to reverse B2 adrenoceptor desensitisation/ Adcock M 2016
OR
GCs increase B adrenoceptor expression
OR
B agonists increase GR nuclear translocation
360
What did Fulfil GSK study show?
Triple therapy better than laba/lama
361
What happens to SaO2 in sleep?
Decreases Awake-Slow wave-REM
| Stradling et al 1985
362
When does increased nocturnal paCO2 turn into chronic high CO2?
If the patient is not treated
363
What does nasal inhalation measure?
Resp Musc Strength
364
Why does biPAP work in hypoventilation?
Augments ventilation which is REDUCED in sleep and REM
365
What happens to TV in sleep
Reduced
366
Contrast CPAP and NIV/BIPAP?
PEEP vs greater insp pressure
Continuous vs intermittent
Pt still breaths vs doesnt breath
Increases lung volume + FRC vs rests resp muscles
367
Why assisted ventilatopn for COPD?
PEEP keeps airway closure
FRC improve
Makes breathing easier
Reduces hyperinflation . Helps clear CO2
368
NMD, OBS, COPD. Long term ventilation?
Nickol et al 2005 showed dose response with day 5 and 3 months of ventilation. Improvements in symptoms, bicarb, paco2 and paO2
369
Asthma mABs
| LIABLE TO BE ASKED ABOUT IN EXAM
Asthma mABs
| EXAM
370
Asthma mABs
| 2 ICS/LABA combinations?
Symbicort - Turbuhaler
| Seretide - GSK
371
Asthma mABs
| Rough cost of drug development?
$2bn per drug
372
Asthma mABs
| What is Proof of Concept?
Usually 1st testing in man (stage 1 healthy)
| Assessment of pharmacokinetics, safety, pharmacodynamics, clinical efficacy
373
Asthma mABs
| What is the vienna chamber? Fritz HORAK
Chamber containing 14 seated subjects that can expose individuals to antigens
Pollen disperser + trap
Environmental exposure chambers can seat up to 100
374
Asthma mABs
| How do inhaled allergen tests work?
Inhaled allergen at ohrs
0-2 hrs see early AHR and dec in FEV1 - MAST CELL MEDIATED (20%) fall
3-10 hrs - late "eosinophil reaction" - slightly lower FEV1 dec usually
375
Asthma mABs
| How do skin prick tests work? WHAT ARE THEY FOR?
```
To determine which mild asthmatics require inhaled allergen testing + which allergen to test
Common allergens tested for
- Cat/Dog dander
- Grass pollen
- House dust mites
```
NO SMOKING ICS LABAS LAMAS SMOKING SABAS
Compare after 6 weeks therapy
376
Asthma mABs
| What were the effects of corticosteroid on the asthma inhaled allergen testing?
BLOCKS THE LATE ASTHMATIC REACTION
377
Asthma mABs
| Dramatically effective drug for RhA
Anti-TNFa
378
Asthma mABs
| What happened in the Northwick park TGN disaster?
Tested mAB anti-CD-28
Caused all 6 volunteers to have cytokine storms
- Did introduce safeguards
- Worked out function of CD28 quickly
379
Asthma mABs
| What cytokines to TH2/ILC2 cells produce in asthma?
IL4,5,9,13
380
Asthma mABs
| What are mast cells known to release in acute inflammation of asthma?
Histamine
| Heparin
381
Asthma mABs
| What are Eosinophils known to release in chronic inflammation?
MBP - major basic protein
ECP - Eo cationic protein
EPO - Eo peroxidase
CLC - Charcoat Leyden Crystals
382
Asthma mABs
| What pathway do MoABs target in asthma?
Type 2 mediated pathway of inflammation
| WTF..??
383
Asthma mABs
| What do DCs release which may be targets?
OX40L
384
Asthma mABs
| What does resp epithelium release which could be targeted in asthma?
TSLP
IL-25
IL-33
385
Asthma mABs
| What receptors do ILC/TH2s have which may be targeted in the Rx of asthma??
```
CD4
CD25
TNFR
GM-CSF
IL17R
```
386
Asthma mABs
| What cytokines do THD/ILCs release which could be targeted in asthma?
IL4 (+R)
IL5 (+R)
IL9
IL13
387
Asthma mABs
| What receptor do mast cells have which could be targeted in asthma?
IgE Fc Receptor + M1 epitope
388
Asthma mABs
| What happened with mAB Anti-IgE [Omalizumab] to SOLUBLE IgE Fc? Chang Tse 2006
No initial effect on FEV1
- LONG TERM studies + cochrane review showed
- dec exacerbations
- halves emergency visits
- able to step ICS dose down
389
Asthma mABs
| What were the problems with omalizumab antiIgE?
<100k severe asthmatics in UK
| 20k per yr per pt
390
Asthma mABs
| Describe the early studies in antiIgE
```
2 inhaled allergen studies
- ineffective inhaled
- IV effective in stopping late response
Tried in mod-severe 317 pts
- little effect on symptoms/LF
- was steroid sparing
Novartis then made the courageous decision to go into phase 3
- use did sig dec exacerbation
```
391
Asthma mABs
| What was seen when trialling M1 prime epitope? (Stops B cells producing IgE)
Able to inhibit (early slightly) early and late reactions
Dec serum IgE
Dec eosinophil numbers
392
Asthma mABs
| What happened with anti IL-5 (eosinophilic factor - production/release of eosinophils)?
Worked brilliantly in animal models
Inhaled allergen challenge showed NO effect on late asthma reaction
NO EFFECT ON LAR
DID have a pronounced effects on blood eosinophils and halved mucosal eosinophils.
1 injection reduced eosinophils even over 4 months PETER BARNES
BUT BUT BUT only halved airway mucosal eosinophils
393
Asthma mABs
| What does anti IL5 work on? [mepolizumab GSK]
Hypereosinophilic syndrome
Eosinophilic oesophagitis
Nasal Polyps
AND SEVERE EOS Asthma
394
Asthma mABs
What did the DREAM study
SIRIUS and MENSA show? Ian Pavord [mepolizumab GSK]
Anti-il-5 did work if selecting by eosinophils. (originally sputum -> blood) >300/uL
HALVED AER
RED ICS BY 50%
DEC symptoms
BUT blood eosinophils are very very very variable - double with mod exercise
395
Asthma mABs
| How did Reslizumab, Teva's anti-IL-5 do in trial?
Given IV
Halves exacerbatiosn
Licenced in 2015 (also eosino)
396
Asthma mABs
| What is Benralizumab?
mAB against IL-5R
| Seemingly lyses eosinophils in tissue
397
Asthma mABs
| What stage is benralizumab AT?
Currently stage 3
398
Asthma mABs
| Which anti IL5 Mepo author showed ablation of blood eosins + no effect in EAR and LAR?
Leckie et al
399
Asthma mABs
| Which author showed anti-il5 mepo to be good in eosino asthma?
Pavord
400
Asthma mABs
| How was IL-4Ra antibody DUPILUMAB different in symptomatic eosinohilic asthma?
Appeared to increase FEV1 (small)
401
Asthma mABs
| What happened with AMGENs version of antiIL4Ra?
Ineffective
402
Asthma mABs
| How did anti-IL-13 do?
Was ineffective at reducing exacerbations in biomarker high pts (n=450)
403
Asthma mABs
| How did Anti-TSLP do?
n=450
Dec exacerbation rate by 66%
INDEOENDENT OF BLOOD EOSINOPHIL COUNT
404
Asthma mABs
| Which mAB was UNSAFE in severe asthma?
Anti-TNF golimumab
- serious infections
- in increased malignancy EVEN IN STUDY
- discontinued by week 24
405
COPD mABs
| Describe 6 parameters that can be measured in COPD studies [prm end points]
```
Spirometry / FEV1 post BD (+natural Hx prevention)
Exacerbation
Quadrants and risk
Emphysema via HRCT
Systemic COPD // symptom score
Biomarkers/personalised med
```
406
COPD mABs
| Amount of smokers WW vs biomass exposure?
1 billlion vs 3 billion
407
COPD mABs
| How many airway divisions?
23
408
COPD mABs
| What is an "ultra inhaler"
ONCE daily dosing
Triple or dual therapy
Ultra-LAMA/LABA
409
COPD mABs
| What did Fletcher and Peto discover (hammersmith hospital)?
FEV1 decline differs between individuals with COPD
- Susceptibility
- Smoking amounts
410
COPD mABs
| What did the Lung Health study [USA CANADA] discover?
FEV1 is recoverable to a degree in those who quit
| Benefits exist regardless of when cessation occurs
411
```
COPD mABs
What did multiple 3 year large scale studies discover?
Pauwels et al
Burge et al
J Westbo et al
```
ICS has NO effect on FEV1
412
COPD mABs
What did the seretide TORCH study discover?
WW GP study
Seretide has NO significant effect on mortality
413
COPD mABs
| What did the Tiotropium [spiriva] chinese study of 841 patients discover?
That in stage 1/2 COPD tiotropium does reduce FEV1 decline
414
COPD mABs
- Standardised self complete questionnaire
- HRQOL
- Symptoms
- Impact on daily life
- Activity
What is this questionnaire name?
St George's respiratory Questionnaire
SGRQ
Paul Jones
415
COPD mABs
| Questionnaire covering sleep, energy, hills/stairs, cough, phlegm, chest tightness.....
COPD Assessment Test
CAT
Paul Jones
416
COPD mABs
| Which COPD questionnaire is used within GOLD staging [new].
mMRC Dyspnoea scale
417
COPD mABs
| What is an exacerbation?
A change from the patients baseline state that is beyond normal day to day variations in terms of
- dyspnoea
- cough
- sputum
And may warrant additionaly medication / change
418
COPD mABs
| MoA PDE4 inhibitors
- Inhibit phosphodiesterase 4 which normally breaks down cAMP->AMP
- Increases intracellular cAMP
419
COPD mABs
| What did studies show with regards to PDE4 use in COPD patients? [REACT study] 1945 patients
OD oral did decrease exacerbations by 13%
420
COPD mABs
| What are the adverse effects of PDE4 inhibitors [why they are often not used]
Severe N+V
Headache
Diarrhoea
- also expensive
421
COPD mABs
| As a result of the [REACT] study, when are PDE4 indicated in COPD?
Stage 3+
| Symptoms of chronic bronchitis + FREQ exacerbations
422
COPD mABs
| What was the effect of statins on exacerbation rate?
NO EFFECT
423
COPD mABs
What does the BODE index predict? What are the facets?
Bart Celli
```
BODE - Mortality
BMI
Ob airfow - FEV1
Dyspnoea - MMRC
Exercise capacity - 6 min walk
10 point scale
Bart Celli
```
424
COPD mABs
| What happened with infliximab [anti-TNFa] in COPD trials?
- Inc malignancies 9/157
- No effect on biomarkers
- Can cause interstitial lung disease
425
COPD mABs
| What happened wit Remicade [anti-TNFa] in COPD trials? Rennard et al
increased malignancies (6/78)
NO clinical efficacy
Rennard et al
426
COPD mABs
| How did benralizumab do in trials in COPD? What is benralizumabs MoA?
No reduction in exacerbation rate with eosinophils
| Anti-IL-5R
427
COPD mABs
| How did mepolizumab do in COPD trials? What is mepolizumabs MoA?
TREND to decreasing annual exacerbation rate in eosinophilic COPD
- Not sig
428
COPD mABs
| How did anti-ILR1, CXCL8, IL17A do in COPD trials?
FAILED
| Small studies
429
COPD mABs
| What condition was Anti-TGF-b effective in?
SSc cutaneous systemic sclerosis
430
```
COPD mABs
How did:
Anti-IL-13
Anti CCL2/MCP-1
Anti-CTGF
Anti-LOXL2 do in IPF?
```
No efficacy
431
COPD mABs
| Which mAB provided some benefit for IPF?
Anti-B cell CD20
432
New Drugs For Asthma
| Discuss need for new asthma drugs
```
S/Es
Needs for SPECIFIC medicines
Oral med need - compliance
Most severe asthma = steroid resistant
Nothing that cures/modifies disease
```
433
New Drugs For Asthma
| What are the advantages of Oral administration asthma drugs?
```
Easier to develop
May treat concomitant diseases
Easier toxicology // pharmacology
~70% have rhinitis - similar mechanisms
Reaches small airways when given orally
```
434
New Drugs For Asthma
| Downsides of oral medications?
Much greater likelihood of SEs
435
New Drugs For Asthma
| What are the problems of inhaled drugs?
```
Difficult toxicology
Irritancy
More difficult development
Pharmacokinetics not well understood
feSmall particle sizes needed to reach small airways
```
436
New Drugs For Asthma
| What percentage of Pts are mild-mod
95%
| - Current inhaled therapies are highly effective for MOST when taken optimally
437
New Drugs For Asthma
What were Femipiprant (DP2 receptor antagonist) trials - results.
Who did it work on with subgroup analysis though?
Erpenback et al
Gonem et al
- No difference in ACQ
- No difference on FeNO
- No effect on blood eosinophils
- Small dec in sputum eosinophils
BUT BUT BUT
In pts with FEV1 <70% there was a sig increase in FEV1 + ACQ
- Entering large multidose trials at present
438
New Drugs For Asthma
| In general and briefly, what are the [4] mechanisms of corticosteroid insensitivity?
Neutrophilic Inflammation
Dec HDAC2
p38 MAPK phosphorylation of GR
Inc MIF
439
New Drugs For Asthma
| IL4/13 are released by Th2 cells and act upon which cells? What do these stimulate?
B cell IgE production
440
What cell type releases CCL4,17,22 which are chemotactic for TH2 cells?
Dendritic cells
441
New Drugs For Asthma
| TH2 release of IL9 stimulates what cell type?
Mast cells
442
New Drugs For Asthma
| What cell releases IL5, and what does it act on?
TH2 [chiefly] produces IL5
| Eosinophils
443
New Drugs For Asthma
| Epithelial IL-33 release stimulates which cell type?
TH2
444
New Drugs For Asthma
| Which cell type releases SCF, which acts upon mast cells?
Epithelial
445
New Drugs For Asthma
| Mast cell release of PDG2 acts upon which cell types?
Th2 cells
ILCs
Eosinophils
446
New Drugs For Asthma
| How did Omaluzimab [anti-IgE do]?
Safe but not effective
| Unsuitable for high IgE >700IU
447
New Drugs For Asthma
| How did Ligelizumab [higher affinity that omaluzimab] do?`
Red dose needed and more prolonged IgE than omaluzimab
| NO MORE EFFECTIVE THO
448
New Drugs For Asthma
| How did anti M1 prime membrane bound IgE do? Quilzumab?
```
Degree of IgE production inhibition for nearly 6 months
Dec Late challenge response by 36%
Dec sputum eosinophils by ~50%
Did not reduce IgE enough
Not effective
```
449
New Drugs For Asthma
What did the DREAM study show with anti-IL-5 [mepolizumab]?
Who was it trialled on?
Who was the author?
```
Sig dec in exacerbations of 50% IN PATIENTS SELECTED BY INC SPUTUM EOSINOPHILS + SEVERE ASTHMA
Pavord et al Lancet 2012
- Not any huge effects on ACQ/symptoms
- No effect on FEV1
- Able to reduce oral steroid dose 50%
```
450
New Drugs For Asthma
| What are the 3 anti IL5 + R drugs?
Mepolizumab
Reslizumab
Benralizumab - Anti-IL5Ra
451
New Drugs For Asthma
| What benefits over Mepolizumab is Benralizumab likely to confer?
Able to reduce eosinophils in tissue
452
New Drugs For Asthma
| IL4/13 regulate the production of...?
IgE production [B cells]
453
New Drugs For Asthma
| Main effects of IL-13?
```
IgE production
Fibrosis [fibroblasts]
Mucus hypersecretion
Eosinophilic Chemotaxis [eotaxin]
Some people believe it may be at the root of steroid resistance
```
454
```
New Drugs For Asthma
How did:
IL-13 soluble receptor mAB
IL-4 Mutein
Anti-IL-13 antibody [lebrikizumab, tralokinumab]
Stat-6 inhibitors
do in trials?
```
All sucked ass + failed
| - exacerbations, symptoms, ACQ, FEV NO CHANGES
455
New Drugs For Asthma
| Which patients group did lebrikizumab appear to work on?
Those selected by high periostin = a biomarker for IL-13 release
BUT PHASE 3 TRIALS STOPPED
456
New Drugs For Asthma
| What does Dupilumab act upon?
anti-IL-4R
| - common receptor for IL4/13
457
New Drugs For Asthma
| What was the design of WENZEL's first trial of dupilumab?
Mod-severe asthma
Withdrew ICS/LABA Rx
Selected by peripheral eosinophilia >300/ml or sputum >3%
S/c injection 300mg /week 12 weeks
458
New Drugs For Asthma
| What were the results of Wenzel's trial of dupilimab in mod-severe asthmatics?
87% reduction in comparison to placebo
| 52 vs 52
459
New Drugs For Asthma
| What was seen in the second dupilumab study, IN UNCONTROLLED asthma?
Near dose-response small improvement in FEV1
Dec severe exacerbations
Little effect on blood eosinophils
460
New Drugs For Asthma
| What TF is activated in TH2 lymphocytes POST dendritic cell costimulation via CD28/CD3 -> dendrite MHCII+b7.2
GATA3
| Regulates TH2 differentation and cytokine gene expression
461
New Drugs For Asthma
| Why may GATA3 inhibition confer even more benefits over dupilumab?
Inhibits production of IL4/13 and IL-5
462
New Drugs For Asthma
New Drugs For Asthma
What is the intracellular regulation of GATA-3?
CD3/28 binding results in p38 MAPK phosphoprylation of GATA3
| Enters nuclear envelope via importin-a
463
New Drugs For Asthma
| How could GATA-3 be targeted?
siRNA
DNAzymes (passes through nuclear envelope)
p38 MAPK inhibitors eg losapimob
464
New Drugs For Asthma
| How did inhaled GATA3 DNAzyme fair in clinical trials?
BADLY
11% inhibition of EAR
31% inhibition of LAR
- NOT NEARLY AS GOOD AS 1 WEEK OF STEROID WHICH WILL BE NEAR 100% after 1 week
465
New Drugs For Asthma
| Why may TSLP be a good target in asthma?
Upstream cytokine
| - released by Epithelial cells + mast cells
466
New Drugs For Asthma
| What does TSLP act upon?
Dendritic cells which activate TH2 cells which activate
Eos via IL5
B lymphocytes via IL4/13
467
New Drugs For Asthma
| What was the first anti-TSLP mAB called?
Tezepelumab
468
New Drugs For Asthma
| How did tezepelumab do in its first trial s/c 4 week injections 70mg IN SEVERE asthma?
```
Dec exacerbations by 60-70%
Response INDEPENDENT OF BLOOD EOSINOPHILS
Inc FEV1
Dec eNO
Inc AQLQ
Dec blood eosinophils
```
469
New Drugs For Asthma
| Athough tezepelumab acts against esoinophils (IL5), and IL13 (drives eNO), what are the future considerations?
Long term effect of such profound immuno-modulation is unknown
- May impact parasitic defense in poorer countries
470
New Drugs For Asthma
| What drives neutrophilic inflammation in asthma?
Direct viral/bacterial contact can cause epithelial TNFa/CXCL1/8 which are neutro chemotactics
Macrophage/DC contact with allergens can release IL23/1b which stimulates TH17 cells -> release IL17 which causes epithelial [aforementioned] cytokinitc release
471
New Drugs For Asthma
| What could be blocked in neutrophilic asthma?
```
Anti TNF
Anti IL17/23
CXCL1/8
CXCR2 (neutr Receptor) antagonists
p38 MAPK inhibitor
PDE4 inhibitor
Macrolides
```
472
New Drugs For Asthma
| What cytokine is increased in SEVERE asthma
IL17
473
New Drugs For Asthma
How did Brodalumab (anti-IL-17Ra) fair in studies? Busse et al
What did Busse et al do wrong........idiota
No inc in FEV1
No change in ACQ
Well tolerated
Busse did not select patients based on neutrophilia
474
New Drugs For Asthma
| What happened with macrolide Rx in asthma?
Dec sputum IL-8
Dec neutrophil numbers
Dec MMP9
Improved AQLQ score
475
New Drugs For Asthma
Why, USING THE AZITHROMYCIN SEVERE ASTHMA TRIAL, is it important to select the right patients?
Brusselle G et al
Trialled azithromycin, 1 per 3days
No dif in exacerbations/AQLQ/ACQ/FEV1/PEF
BUT WHEN SUBGROUP ANALYSIS WAS PERFORMED
it decreased exacerbations by 42% in NON-eosinophilic asthma
476
New Drugs For Asthma
| Why are non-steroidal GR agonists being investigated?
If you are able to target transrepression only, antiinflammatory properties are retained.
Reduced transactivation is thought to reduce SEs
477
New Drugs For Asthma
| What intracellular targets may be beneficial for severe neutrophilic mediated asthma?
```
PDE4
IKK2
p38 MAPK
JNK
PI3K
- Can form selective inhibitors of these
```
478
New Drugs For Asthma
What is the only approved [COPD] PDE4 inhibitor? Romi....
Why has it not been approved for asthma?
No real greater benefit than corticosteroids but much worse tolerance
Inhaled may be needed
479
New Drugs For Asthma
| What is seen with p38 activation in severe asthma? PANK BHAVSAR
Sig increased
PANK BHAVSAR
- Also a reduction in endogenous inhibitor (MKP-1) of p38 MAPK
480
New Drugs For Asthma
| When trialled what happened with p38 MAPK inhibitors?
Steroid resistance was reduced
| BUT severe SEs
481
New Drugs For Asthma
| What molecule keeps mast cells near to epithlium?
Stem Cell factor
| SCF
482
New Drugs For Asthma
| What is the mast cell receptor for stem-cell factor SCF?
cKit
| Syk kinase/Lyn kinase
483
New Drugs For Asthma
| Syk kinase/Lyn kinase are possible intracellular targets in asthma INSIDE which cells?
Mast cells
484
New Drugs For Asthma
What class of drug (chromo....) inhibited AHR LAR and cough on sensory neurones, alongside mast cell activation? MoA was unknown for ages...
Give an example of a common drug
Chromoglycates
Furosemide
- Could make one that is longer acting -> effect of chromoglycate was reduced after 1 hr
485
New Drugs For COPD
| What percentage is unrelated to CS?
20%
486
New Drugs For COPD
| WW mortality COPD
3rd most common cause of world wide deaths
487
New Drugs For COPD
| What was seen when comparing indacaterol (LABA) vs salbutamol (SABA)?
Increased TDI symptoms scoring with LABA alongside greater FEV1 (60mls)
488
New Drugs For COPD
| What drug did Bossman Barnes re-discover?
Rediscovered Glycopyrronium - was previously used in tablet form by anaesthetists to prevent dry mouth. Acted on same muscarinic receptors in the lungs.
Developed for nebuliser use.
Japanese company developed nebb-ed form and sold to novartis for 1bn dollars
489
New Drugs For COPD
What is seen when doubling the dose of indacaterol from 300ug to 600ug?
What happens when adding glycopyrronium to 300ug indacaterol?
WHY?
VAN NOORD Thorax 2010
Doubling dose of indacaterol has NO effect as patient is at the maximal response of D/R curve
Against everyones beliefs, it improved FEV1 further
Thought to be due to cross-talk between the intracellular signalling pathways
VAN NOORD Thorax 2010
490
New Drugs For COPD
| What is a MABA? eg Batefenterol
LABA at one end, LAMA at another joined by "linkage" molecule
- Not as good as both mixed
491
New Drugs For COPD
| What are the main problems in the DESIGN of studies assessing "triple" combinations?
Do not compare to LABA/LAMA alone, but often to ICS-LABA combinations
- Although exacerbation rate // FEV1 is more favourable triple vs ICS/LABA, it is unlikely there will be a significant difference between triple vs LABA/LAMA
492
New Drugs For COPD
| What did the FLAME STUDY show, which compared LABA/LAMA vs ICS/LABA?
ICS/LABA had increased exacerbations in comparison to LABA/LAMA
17%!!
- Alongside red FEV1
493
New Drugs For COPD
Despite the results of the FLAME study, which depicted ICS confers no benefit to COPD patients, which SUBGROUP may benefit from ICS?
Retrospective analysis depicted that patients with high blood eosinophils (>2%) DID have statistically significant fewer exacerbations per year.
Significance increased when FURTHER stratifying the HIGH blood eosinophils ie 2-4, 4-6, >6%
494
New Drugs For COPD
| What is the mainstay of COPD Rx?
LAMA-LABA combination
495
New Drugs For COPD
| List (6) unmet needs in COPD Rx?
```
Poor reduction in exacerbations
Poor Rx of exacerbations
No disease modifying drugs/progression
Little effect on mortality
Little effect on comorbidities/systemic manifestations
No affect of inflammatory cells
```
- Targeting specific mediators = too many mediators
- Broad spectrum anti-inflammatory = TOO MANY S/Es
- Reversing corticosteroid resistance eg theophylline - too expensive - 600million to do study but is a generic drug now
496
New Drugs For COPD
| Which two cell types release TGFb in COPD?
TGFb ME!!!
Macrophages
Epithelial Cells
497
New Drugs For COPD
| What chemokines released by macrophages act on TH1 cells and Tc1 cells?
CXCL9/10/11
| Act at CXCR3
498
New Drugs For COPD
| What chemokines released by macrophages act upon neutrophils?
CXCL1/8
| act on CXCR2
499
New Drugs For COPD
| Which chemokines, released by macrophages act on monocytes?
CCL2
| via CCR2
500
New Drugs For COPD
| What chemokines do macrophages release in COPD?
CXCL9/10/11 - Th1 cells, Tc1
CXCL1/2 -neutrophils
CCL2 - monocytes
TGFb - fibroblast
501
New Drugs For COPD
| What are the general approaches // types of treatment that could be used?
```
SMOKING CESSATION
Anti-inflammatory
Chemokine antagonists/Receptor
Mucoregulators
Anti-protease/oxidants
Fibrosis inhibitors
Alveolar repair - retinoids (VIT-A) + Stem cells
```
502
New Drugs For COPD
| What was the rationale for anti-TNF therapy in COPD?
Inc TNF in COPD sputum
TNF2 polymorphism = RF for COPD
Inc TNFa in COPD patients with cachexia
TNF induces apoptosis of skeletal muscles
503
New Drugs For COPD
| Name four anti-TNF strategies?
Humanised antibody - infliximab/adalimumab
Soluble receptor blocking - etanercept
Non-spec intracellualr signalling eg p38 MAPK, PDE4, IKK
TACE inhibitors - release of TNF is dependent on enzyme TACE
504
New Drugs For COPD
What happened with the infliximab trial in COPD.
6 months Rx
Rennard et al
```
No change in:
FEV1
Symptoms
Exercise tolerance
Dyspnoea
Exacerbations
MARKED INCREASE in lung cancer, and infection
Rennard at al
```
505
New Drugs For COPD
| What neutrophil receptor antagonist has been tried in COPD? What chemokines do this receptor bind to?
CXCR2
Binds to IL8 (CXCL8)
ENa-78 and GRO-a
506
New Drugs For COPD
| What other receptors have antagonists been developed for, but not trialled in humans?
```
CCR2 (Monocytes)
CXCR3 CCR5 (TH1 cells)
```
507
New Drugs For COPD
| What happened with Navarixin, CXCR2 antagonist, in INITIAL SMALL COPD studies?
In small initial study (n=22), there was:
- 50% decrease in sputum neutrophils
- 59% decrease in sputum MMP9
- 22% mean deacrease in blood neutrophils
Looked promising
508
New Drugs For COPD
| What happened with Navarixin, CXCR2 antagonist, in LATER LARGER COPD studies?
No clinical improvement
No dec exacerbations
MARKED neutropaenia in some patients -> risk of neutropaenic sepsis
509
New Drugs For COPD
| LTB4 antagonists fail/work?
Fail
510
New Drugs For COPD
| What leukotreine antagonist has not been tested yet?
5-LO inhibitors
| cPLA2 inhibitors
511
New Drugs For COPD
| List 2 failed cytokine inhibitors in COPD?
Anti-TNF infliximab
| Anti IL-1B
512
New Drugs For COPD
| Which cytokine inhibitors are hyet to be tested in COPD?
Anti-IL-6R
| Anti-IL-17
513
New Drugs For COPD
| Which chemokines/receptors antagonists have failed in COPD?
Anti-IL8
| CXCR2
514
New Drugs For COPD
| Which chemokine receptors have not been tested in COPD yet?
CXCR3
| CCR2
515
New Drugs For COPD
| Elastase activity is increased in macrophages in COPD. Which MMP is chiefly responsible?
MMP9
516
New Drugs For COPD
| What was the result of MMP9 inhibition?
TIMP1 incredibly expensive to produce.
Others eg Marmistat = too non-selective.
Astra-Zenica MMP9/12 inhibitor = too toxic
The search is on for SAFE selective inhibitors
517
New Drugs For COPD
| List possible broad spectrum anti-inflammatory inhibitors for the Rx of COPD.
```
PDE4 inhibitors
IKK2 (NFkB ) inhibitors
p38 MAPK inhibitors
Pi3K inhibitors
JAK inhibitors
```
518
New Drugs For COPD
| What are 2 possible problems with broad spectrum anti-infla Rxs in COPD?
Sig SEs
| Inhaled delivery needed
519
New Drugs For COPD
Why are PDE4 inhibitors an attractive prospect for COPD Rx?
Name a PDE4 inhibitor?
```
Inhibition of:
Macrophage chemokine release
Epithelial cell chemokine release
Protease release
Fibrosis/Emphysema/CMH
- Pretty much everything on Peter's COPD flow chart
```
- Romflumilast
520
New Drugs For COPD
What happened when Roflumilast was trialled in severe COPD patients with freq exacerbations and CMH? What was one of the caveats of this being a large trial? Why was this drug approved [in US]?
Calverley et al
Which patient group is ideal? [Q = Clue]
Studies depicted little effect when trialled on all COPD patients
Study in SEVERE, CMH + freq exacerbation patients depicted significant changes in FEV
BUT changes were only ~50mls. Significant because of large n number ~3000 total
- CHANGE of 50mls is tiny
- NO effect on QOL
- Nausea, headaches, diarrhoea, WL - NO PATIENT HAS EVER GONE BACK FOR A REPEAT PRESCRIPTION IN THE GERMAN STUDY
- Approved in US because of 17% reduction in exacerbations in this patient demographic
ORAL
521
New Drugs For COPD
| Which other drug has similar SEs + MoA to Roflumilast? What are these SEs?
```
Theophylline partly inhibits PDE4.
N+V
WL
Diarrhoea
Headaches
```
522
New Drugs For COPD
| Despite horrendous SEs with PDE4 inhibitors: WL, NV, Diarrhoea, what is the possible avenue of getting around these?
4 Subtypes of PDE4
It is believes that 4D = nausea
4B = anti-inflammatory
EVEN MORE SELECTIVE inhibitors
523
New Drugs For COPD
| Which PDE4 subtype is responsible for nauseas?
4D
524
New Drugs For COPD
| Which PDE4 subtype is responsible for anti-inflammatory effect?
4B
525
New Drugs For COPD
Why did 4B PDE4 inhibitors fail, despite subtype 4B being chiefly responsible for the anti-inflammatory effects? What is the next step in PDE4 inhibitor development?
Still had profound SEs - WL, NV, Diarr
Developing an inhaled form of the drug - even P-Barnes inhaled version was intolerable - individuals felt sick instantly
3 inhaled PDE4i have failed trials recently
526
New Drugs For COPD
| Name some stimulants of p38 pathway?
LPS, IL1b, TNFa, Viruses, Irritants -> TNFa + chemokine synthesis
527
New Drugs For COPD
| What kind of drug is Losmapimod?
P38 MAPK inhibitor
528
New Drugs For COPD
| Name a p38 MAPK inhibitor?
Losmapimod
529
New Drugs For COPD
| How have Losmapimod and other p38 MAPK inhibitors done in trials?
No effect on FEV1, RV
CRP/IL8/IL6/MMP9
Liver toxicity, skin rashes
Also a LOSS of efficacy with time -> other kinases take place of p38..redundancy
Could try inhaled?
530
New Drugs For COPD
| What is the molecular mechanism of ICS resistance in COPD?
Decreased HDAC2 activity
Corticosteroids switch off the inflammatory response by blocking the expression of inflammatory mediators through deacetylation of histones, an effect mediated via histone deacetylase-2 (HDAC2). Once deacetylated, DNA is repackaged so that the promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB that act to turn on inflammatory activity.
531
New Drugs For COPD
| What is the mechanism of dec HDAC2 activity in COPD patients?
Oxidative stress -> causes increased PI3K signalling -> inc phosphorylation of AKT -> inc phosphorylation of HDAC2 -> steroid resistance
532
New Drugs For COPD
| How does theophylline increase HDAC2?
Decreases PI3K signalling
533
New Drugs For COPD
| What drugs decrease PI3K signalling and may be useful in reducing ICS resistance in COPD patients?
Theophylline
Nortiptyline
Macrolides
PI3K inhibitors
Have NOT BEEN TESTED EXTENSIVELY IN PATIENTS
534
New Drugs For COPD
| Apart from PI3K inhibitors, what targets could reverse steroid resistance in COPD pts?
Akt-1 inhibitors
HDAC1 activators
GSK3b activators
535
New Drugs For COPD
| What does oxidative stress activate in COPD, which make it pivotal in the role of disease development?
```
NFkB activation
TGFb activation
Dec HDAC2
DNA damage
Decreases activity of antiproteases
```
536
New Drugs For COPD
| Why have thiol oxidants, eg NAC, glutathione-SH failed in the Rx of COPD?
Inactivated by oxidative stress
| Some hard to deliver via inhalation
537
New Drugs For COPD
| Which TF regulates the major antioxidants, and could be a target for therapy?
NRF-2
538
New Drugs For COPD
| "pan" inhibitor anti-inflammatory target that hasnt been investigated?
pan-JAK inhibitors
