Development of a drug Based on: a known active drug known receptor known endogenous ligand Of natural origin: microorganisms Plants Animals

Examples for naturally occuring drugs Procaryontes, Fungi: Antibiotics, Alcohol Plants: Atropine, Reserpine, Cocaine, Opium/Morphin/Heroin, Cannabis… Animals: Heparin, Spider toxins,

A candidate molecule will be synthesized in various forms/enantiomers in various derivatives Computer aided drug design Assessment of physical and chemical properties Development of analytical methods Stop of further development if: Problems with the Synthesis, isolation, stability, solubility

In vitro testing Testing in cell cultures Efects on various enzymes etc…. Mutagenesis: Ames-test: Test bacteria mutants with Histidin deficiency Which grow only in the presence of His. Under the influence of a mutagenic drug, They mutate to His-revertantes Which grow in the absence of His

Patent application The molecule is patented for 20 years During this time only the patent owner can use the patent commercially. But all competitors can do research on this Molecule.

In vivo testing Practically all tests are prescribed by laws Kinetics/plasma levels Plasma protein (albumin) binding Metabolism Accumulation in organs Elimination Cancerogenity Mutagenesis: The fur test in mice

Teratogenity Is the ability of a chemical drug, or of a physical influence, to damage the developing organism (foetus) The Thalidomid (Contergan®)-desaster Induction of limb malformations

Toxicity Acute and subchronic toxicity 1-2 month 2 species: one rodent and one non-rodent Chronic toxicity (in one species) >9 month

Galenics Auxilliary substances Protective substances (e. g. antioxidants) Forms for administration: Drops pills patches transdermal injection/infusion depot forms

Specific screening For example Behavioural Pharmacology: Profile of a drug leads to indication (e.g. Depression, Schizophrenia, M. Parkinson….)

Behavioural pharmacology Animal models 1.With predictive validity: The effects of a test drug in this model corresponds to that of clinically effective drugs. e.g. All neuroleptics reduce body temperature.

2. Face validity: Phenomenological similarities between the model and the clinic. e.g. haloperidol-induced catalepsy

3. Construct validity The primary cause of the disease is modeled

Genetic models Spontaneous mutants k. o. mutants, conditional k. o. k. i. mutants (transgenics) Transmitter based models Experimentally changed transmitter activity -By neurotoxic lesions -By pharmacological interventions

Clinical phase I About 5 years after start of development: 10 – 20 healthy human volunteers Tolerability, Pharmacokinetics, Pharmacodynamics, excretion

Clinical phase II 100 – 200 patients in the clinic Dosage finding Unwanted side effects

Clinical phase III >200 > 2000 patients inside and ouside of clinics Is the drug therapeutically effective? Rare side effects Allergic effects

Application for admission Application to the: BfArM 1) FDA 1 drug out of > CNS-drug development costs: 800 millions € After approval the drug can be maketed 1) Bundesinstitut für Arzneimittel und Medizinprodukte

Clinical phase IV 5 years strict surveillance by the authority. Asessment of side effects. Every 5 years the admission must be prolonged. Continuous studies in animals and humans