Discovery and development of drugs

·        Preclinical drug development.

·        Techniques of discovery.

Preclinical drug development

1.    The study of new medicines (drugs) is an exercise in prediction from laboratory studies in vitro and in vivo (animals) which forecast what the agent will do to man.

2.       Medical therapeutics rests on:

a.       Sensitivity: the desired effect alone is obtained with a minimum of other side effects.

b.       Dose: the dose that is safe and without toxic effects on humans.

3.    For decades the rational discovery of new medicines has depended on modifications of the molecular structures of the increasing numbers of known natural chemical mediators.

4.    The evolution of molecular medicine in recent years – the study of signal transduction, have opened a new approach to the development of therapeutic agents that can target discrete steps in the body’s pathways of chemical reactions.

5.    New drug development proceeds:

a.    Idea or hypothesis.

b.       Design and synthesis of substances.

c.       Studies on tissues and whole animals (preclinical studies).

d.       Studies in man (clinical studies).

e.       Grant of an official licence to make therapeutic claims and to sell.

f.       Post-licensing (marketing) studies of safety and comparisons with other medicines.

Techniques of discovery

1.       Molecular modelling:

a.       Aided by three-dimensional computer graphics.

b.       Allows the design of structures based on new and known molecules to enhance their desired, and to eliminate their undesired, properties to create selective compounds.

2.       Combinatorial chemistry:

a.       Involves the random mixing and matching of large numbers of chemical building blocks to produce ‘libraries’ of all possible combinations.

b.       Generate new compounds that are initially evaluated using automated robotic high-throughout screening devices that can handle thousands of compounds a day.

c.       These screens utilize radio-labelled ligand displacement on single human receptor subtypes or enzymes on nucleated cells.

3.       Biotechnology:

a.       Involves the use of recombinant DNA technology / genetic engineering to clone and express human genes.

b.    The polymerase chain reaction (PCR) is an alternative to bacterial cloning.

4.       Genetic medicines: synthetic oligonucleotides are being develop to target defined sites on DNA sequences or genes or mRNA so that the production of disease-related proteins is blocked.

5.       Gene therapy: nucleic acid, in the form of DNA, is administered to modify the genetic repertoire for therapeutic purposes.

6.       Immunopharmacology.

7.    PET (positron emission tomography): allows non-invasive pharmacokinetic and pharmacodynamic measurements in previously inaccessible sites, e.g. brain.

Preclinical studies in animals

1.       Pharmacodynamics: to explore actions relevant to the propose therapeutic use, and other effects at that dose.

2.       Pharmacokinetics: to discover how the drug is distributed in and disposed of by the body.

3.       Toxicology: to see whether and how the drug causes injury in:

a.       single dose studies.

b.       repeated-dose studies.

4.       Special toxicology involves areas in which a particular drug accident might occur on a substantial scale:

a.       Mutagenicity: a bacterial mutagenicity test which demonstrates the induction of point mutations.

b.       Carcinogenicity tests: not often required prior to the early studies in man unless there is serious reasons to be suspicious of the drug.