Drug discovery and development • Ian Hughes, [email protected]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 • know about the difficulties and dangers inherent in the drug development process.
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• know the processes involved in drug discovery and development
• see where pharmacologists/bioscientists may contribute
• know about the difficulties and dangers inherent in the drug development process.
What is a drug?
• Any chemical compound - sugar ???
• Anything which produces a change in the body - an axe ???
• Define by characteristics:
1. use or potential use in diagnosis or treatment of disease
2. selective in their actions
What costs what in Leeds? (GPs; 98/99)
• Omeprazole (anti-gastric acid) £3.5m
• Simvastatin (cholesterol lowering) £2.4m
• Beclomethasone (asthma) £1.8m
• Fluoxetine (antidepressant) £1.5m
• Lansoprazole (anti-gastric acid) £1.4m
• Ranitidine (anti-gastric acid) £1.3m
• Paroxetine (antidepressant) £1.2m
• TOP 7 TOTAL >£13m
• Total GP drugs for Leeds >£67m
Why are new drugs needed?
• unmet medical need; new diseases (BSE; AIDS, Alzheimer’s; obesity); low efficacy (dementia, cancer); side effects (antidepressants, antipsychotics)
• downstream health costs; (Alzheimer’s; spinal injury)
• cost of therapy; (Viagra, Interleukins)
• costs to individual/country; (depression)
• sustain industrial activity; pharmaceutical industry employs thousands and makes a massive contribution to overseas earnings); patent expiry
The changed context of drug discovery and development
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.
• PERSONAL LICENCE - competent, trained, procedures specified
• PROJECT LICENCE - allows a personal licence holder to carry out specified procedures for a specified project that cannot be done without animals and where severity justifies likely gain.
• GET INTO MAN EARLY
R R R
Reducing animal usage
• About 2.6m animals/y used in procedures in UK (11.6m in Europe)
• Likely to increase; more research, more targets, genetic capability
•3Rs -- 3Rs -- 3Rs• REPLACEMENT: use non-animal tests if possible (cheaper,
less trouble, less variable but not possible for everything at this time)
• REDUCTION: get the statistics right, don’t replicate work unnecessarily, don’t overbreed
• REFINEMENT: reduce suffering and severity of procedure, pay attention to housing, stress, husbandry and rich environments, proper analgesia and pre- and post- operative care
• BIOLOGICAL; acute pharmacological profile - LD50, ED50, binding data for many receptors, dose-effect relationships, open field tests, particular tests for different activities (e.g. CVS, CNS, GI tract)
Both positive and negative information is useful.
• Acute toxicity profile
• Chronic toxicity profile
-- 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.