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Flashcards in 2 - CML and Imatinib Deck (47):
1

cml

chronic myelogenous lukemia

2

cause of cml

uncontrolled proliferation of myeloid cells

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chronic phase

3-5 years
proliferation occurs but diseases controlled

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acute/blast phase

extreme proliferation

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treatment for cml

imatinib

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3 steps of translational pipeline

1. discovery
2. development
3. delivery

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delivery

regulatory approval

8

imatinib pre clinical trials

1. test on pure protein (kinase assay)
2. test if it inhibits proliferation of BCA-Abl +ve cell lines
3. test in primates

9

phase 1 trials

- interested in toxicity, tolerated dose and pharmokinetics of drug
- either on healthy people or cml patients
- dose is slowly increased
- no. of people trialled slowly increased

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phase 2 trial

- test patients with disease
- small study
- interested in finding biological response
- finding optimum dose

- sometimes randomised control trial

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biological response to imatinib

found in phase 2 trials

haematological and cryogenic response
- no more Philadelphia chromosome

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phase 3 trial

we know drug is safe and how it is processed by the body

full scale RCT
e.g. 1000 cml patients
cost effectiveness tested by NICE

13

rct

randomised control trial

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how do observational studies generate hypothesis

they identify patterns and trends in populations

15

rational drug design

designing small molecules that are complementary to biomolecular target
better than trial and error
requires knowledge of disease mechanism

16

which phase of trials tests to find the optimum dose fo drug

phase2

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advantages of randomisation

eliminates bias in treatment assignment
facilitates blinding/masking
maximises statistical power

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3 types of randomisation

simple - use random no. generator
blocked
stratified

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which types of randomisation do you use if you have a small smaple size

blocked or stratified

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advantages of blinding/masking

prevents patients/care-givers knowing which intervention was recieved

21

3 types of blinding

open-label
single-blind
double-blind

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define bias

unintentional adjustment in design/conduct of a trial

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how do you avoid bias

blinding/randomisation
allocation concealment
standardised procedure
standardised equipment

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problems with bias

may cause unreliable results

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what is 'intention to treat' (ITT) analysis

'once randomised, always analysed'
all patients allocated to original groups are included accordingly in analysis

even if they drop out

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advantages of ITT analysis

provides unbiased comparisons
avoid effects of cross-over and drop-out

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what is NICE

a rationing body to reduce variation in access to new interventions

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what does NICE stand for

national institute for health and care excellence

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how does NICE evaluate economic considerations for new drugs

NHS cost savings
HTA - health technology assessment
CEA - cost effective analysis

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how is HTA for

to calcute if the money for the drug production is really worht it

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how do you calucate HTA

life expectancy in years x HR-QoL

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how is QoL measured

EQ-5D questionnaire

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what are the 5 domains of health

mobility
self-care
usual activities
pain/discomfort
anxiety/depression

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what does QUALY stand for

quality adjusted life years

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'currency' of health

QUALYs

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QUALYs

length of life combined with quality of life
(life expectancy x HR-QoL = QUALYs)

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ICER - incremental cost effectiveness ratio
what is it and what is it used for

statistic used in CEA to summarise cost effectiveness of a health care intervention

38

how do you calculate ICER

cost of new intervention - cost of old intervention
divided by
QUALYs of new intervention - QUALYs of old intervention

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how does ICER tell you how cost-effective a treatment is

if the ICER is less than £20,000 per QUALY gained, then the NHS deem it cost effective

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what is CEA

cost effective analysis

the comparative analysis of alternative courses of action in terms of both cost and consequences for health

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describe the CEA graph

HR-QoL on y-axis
time on x-axis

area between curves for treatment A and B = QUALYs gained

42

transgenes

introduction of genes from a different source into a cell

43

techniques used to create transgenes

transfection
transduction

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uses of transgenes

researching function of gene/protein
gene editing
gene therapy

45

what kind of sequences are introduced into cells

cDNA
CRISPR constructs
promoters

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steps for creating transgenes

1 - purify mRNA from target cell
2 - convert mRNA --> cDNA using RT
3 - selectively amplify gene of interest (PCR)
4 - add restriction enzyme sequence
5 - use plasmid --> promoter sequence drives transcription of cDNA
6- GFP used to show localisation of gene in cell
7- transfection/injection/infection into nucleus

47

3 ways to transfect cDNA into nucleus

electroporation
lipid-mediated transfer
CaPO4 transfer