Drug discovery and development. Ian Hughes, firstname.lastname@example.org Objectives of next 5 lectures: you will: be aware of why/how new drugs are discovered know the processes involved in drug discovery and development see where pharmacologists/bioscientists may contribute
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Objectives of next 5 lectures: you will:
1. use or potential use in diagnosis or treatment of disease
2. selective in their actions
The 1800s: natural sources; limited possibilities; prepared by individuals; small scale; not purified, standardised or tested; limited administration; no controls; no idea of mechanisms.
The 1990s: synthetic source; unlimited possibilities; prepared by companies; massive scale; highly purified, standardised and tested; world-wide administration; tight legislative control; mechanisms partly understood.
Animal insulin (pig, cow)
growth hormone (man) (Creutzfeldt-Jakob)
Plant digitalis (digitalis purpurea - foxglove)
morphine (papaver somniferum)
Inorganic arsenic mercury
Synthetic chemical (propranolol)
biotechnology (human insulin)
discovery; refinement; chemical & biological characterisation
safety & toxicity in animals; formulation development
volunteer studies; patient studies
Discovery=find new active structure : Development=convert it to a useful drug
DRIVER IS UNMET MEDICAL NEED IN A VIABLE MARKET
USE iterative approach
DRUG + receptor
ISOLATED TISSUE EXPERIMENTS
WHOLE ANIMAL EXPERIMENTS
How predictive is the model?
exact replica = 100% predictor
mechanism same = good predictor
mechanisms different = poor predictor
Animal (Scientific Procedures) Act (1986)
Both positive and negative information is useful.
-- 14 day toxicity test in one rodent and one non-rodent species before use in man.
-- 3 month study read out at 28 days
-- longer studies (12 & 24 month)
Three dose levels (below, about, well above human dose).
It is insufficient to to use doses which are not toxic; the doses producing toxic effects and the nature of these effects MUST be established.
Additive:filler, lubricant, coating, stabiliser, colour, binder, disintegrator
Dosage form:capsule, tablet, injection, other?
Manipulate duration/profile: e.g. sustained release
Ease of use
phases can also be defined by the information you are trying to get out of the testing
indication for use; type of patient; severity of disease;
dose range, schedule and increment;
pharmacokinetic studies in ill people;
nature of side effects and severity;
effects in special groups.
Drug action depends on:
Clinical trial controls these variables and examines action of drug in defined set of circumstances
controlled or uncontrolled
open or blind
others:-- matched pairs; combinations; ++
serious side effects
balanced view of
no side effects
appreciate where best
used and risks
eg. PROPRANOLOL (beta adrenoceptor blocker)
antidysrhythmic >>> antianginal >>> antihypertensive >>> relieve hyperthyroid symptoms >>> antihypertensive with diuretic >>> prolonged release formulation
precipitate asthma attack > beta1 selective - ATENOLOL
Similar to drugs already on market