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35 Cards in this Set
- Front
- Back
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What are the stages in Drug Discovery in the Pharmaceutical Industry? |
Basic research informatione.g. when body tissue is damaged itgenerates 'inflammatory mediators' -endogenous chemicals that are responsiblefor causing many of the symptoms ofinflammation. Some inflammatory mediatorsare from a family of chemicals calledprostaglandins ---->Idea: Prostaglandinsmediate painfulsensations ----->Hypothesis: A chemical that blocksthe synthesis ofprostaglandins will bean analgesic drug |
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What happens after the hypothesis? |
Natural products+ Compound libraries + combinatorial chemistry ----> startingchemicals ----> assay systems ----> active chemicals ----> animal models ----> drug candidate |
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What are some natural drug products? |
micro-organisms, animals, medicinal plants |
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What happens in Conventional Chemical synthesis? |
Known synthetic pathwayto an identified chemicalproduct |
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What happen in CombinatorialChemical synthesis? |
Known syntheticpathway(s) to multipleunidentified chemicalproducts |
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What are some other Assay Design requirements? |
Safety issues Ethical issues Cost Intellectual property |
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What are some examples of required assays? |
Usually robotic, cell basedcolorimetric or fluorimetricassays Radioligand binding, Isolated tissues Functional assays, Cellular electrophysiologyAnimal behavioural studies |
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What do small changes in chemical structure alter? |
Small changes in chemicalstructure alter both thepharmacokinetic and thepharmacodynamic propertiesof the drug |
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What is the pharmaceutical industry? |
The pharmaceutical industry sells drugs for use as therapeutic agents.Pharmaceutical companies fall into two overlapping categories. Firstly thereare those that only sell drugs that are not protected by patents. Thesecompanies usually sell cheap versions of commonly used drugs but do nothave extensive research and development facilities and do not discover ordevelop new drugs. Secondly there are the companies that discover, developand then sell new drugs. These companies have extensive research facilitiesand are usually global corporations. |
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What is the first step in pre-clinical drug development? |
From an idea originating from basic research an hypothesis will be developede.g. a simple hypothesis would be ‘cyclo-oxygenase inhibitors will haveanalgesic properties’. |
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What are assay systems used for? |
Assay systems (i.e. measurement systems) will bedevised to identify chemical tools to test the hypothesis e.g. in this examplethe scientists will try different chemicals to see if they can find one thatinhibits cyclo-oxygenase enzyme activity. |
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What may the test chemicals be? |
Test chemicals may be naturalproducts (extracted from plants, animals, other natural sources), may comefrom chemical libraries of compounds held or bought by the company or fromtechniques such as combinatorial chemistry (which is a chemical techniquethat generates large numbers of chemicals in the laboratory). |
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What else are beginnining to be used as starting chemicals? |
Increasingly,biological materials or their derivatives such as fragments of antibodies orreceptors are being used as starting materials – so-called ‘biologicals’. |
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What happens when they find a starting chemical that works in the assay system? |
When they find one that works in the assay system, then the hypothesis can betested in an animal model e.g. in our example to see if the substance thatinhibits cyclo-oxygenase shows any analgesic activity. |
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What do scientists then do to the active compound? |
If the hypothesis holdsup then chemists will change the chemical structure of the active compoundlittle by little until they find the most potent chemicals they can. |
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What then happens once promising comounds are found? |
If and when theyfind promising compounds they will be tested extensively for toxic effects andpharmacokinetic (see later) properties. A safety pharmacology program will bestarted to measure unanticipated effects of the drugs that , though not overtlytoxic, may nevertheless compromise the use of the chemical as a drug |
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When does the first phase of clinical development begin? |
Thebest compounds will go forward into the first phase of clinical development asdrug candidates. From original idea to drug candidate usually takes 5 to 10years or even longer |
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How is Clinical Drug development divided? |
Clinical Drug Development is divided into four phases (or 5 if ‘phase ‘0’ iscounted). At all stages patients are monitored for side effects and informationon drug safety is gathered as a priority. |
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What happens in phase 0? |
Phase 0 is a transitional phase between the pre-clinical testing stage and fullclinical trials. Sub-therapeutic doses are monitored for any unexpected effects.This ‘phase’ is most commonly used in development of chemotherapeuticagents for cancer treatment. |
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What happens in phase 1? |
Phase I is relatively small scale, usually involving around 20-80 healthyvolunteers (often undergraduate students) and is concerned primarily with dosefinding and tolerability. Volunteers are given progressively larger doses of druguntil an effect is registered. Information gathered during phase I will allowestimates to be made of the amount of drug the body will tolerate withoutcausing side effects and what side effects might occur. Several rounds of PhaseI trials may occur for any given drug, in different countries and patient groups |
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What happens in phase 11? |
Phase II trials are of medium size, involving 100-300 patient volunteers. At thisstage the drug is tested for effectiveness against a specific disease which willbe the intended ‘indication’ of the drug. Again, several phase II studies may beperformed for a given drug. |
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What happens in phase 111? |
Phase III are large scale trials involving 1000-3000 patients whereeffectiveness is tested again and comparison is made with other treatments thatare available. If a drug survives phase III then it may be registered and sold asa therapeutic agent. More than one pahse III trial may be performed. |
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How long does the transition from phase 1 to 111 take? |
Transition through phases I, II and III takes about 6-10 years. Of 100 drugsentering phase I only a few, maybe 10 or so, will survive to phase II and ofthese only 1 or 2 will make it to phase III. If a drug makes it to phase III then ithas a reasonable chance of success as a drug. |
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Where is most of the cost of drug development incurred? |
The costs of drug discoveryand development are enormous and most of the costs are incurred at phase IIIso companies have to be confident of a reasonable chance of success beforeallowing a drug candidate to proceed to this stage. |
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How long does the pre-clinical phase take? |
Drug Discovery in the Pharmaceutical Industry: Pre-clinicalphase; usually takes 5 to 10 years |
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How can phase 0 be described? |
‘first-in human’trial using subtherapeuticdosing inhumansubjects. Caninclude testson ‘humanized’animals ortissues |
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What is an overview of phase 1? |
Small scale:involving 20to 80 healthyvolunteers side-effectssafety Tolerability &dose finding |
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What is an overview of phase 11? |
Mediumscale: involvingabout 100 to300 side-effects safety effectiveness |
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What is an overview of phase 111? |
Large scale:involvingabout 1000 to3000 patientvolunteers side-effects safety effectiveness comparisonwith currentavailablemedicines |
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What happens to drugs that complete phases 1 to 111? |
Drugs that complete phases I toIII successfully can be submittedfor registration with governmentagencies that allow the drugs tobe used as medicines in thecountries concerned. |
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What is phase IV? |
Phase IV is essentially the ongoingmonitoring and collection of datapertaining to a particular drug wherethe effectiveness of the drug orproblems in different patient groups(e.g. different races or other geneticvariation) can be evaluated. |
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What is an overview of phase IV? |
Phase IV Postregistrationstudies Differentpopulations Long-termsaftey |
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What is the goverment agency in the UK? |
Medicines and HealthcareRegulatory Agency: MHRA |
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What is the goverment agency in europe? |
European Medicines Agency:EMA |
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What is the goverment agency in USA? |
USA:Food and DrugAdiministration: FDA |
