Preclinical Studies

Question 1

What is the common reason for attrition during the pre-clinical phase?

Answer 1

Toxicology.

Question 2

What are 5 R’s addressed during drug development?

Answer 2

1 - Right Target
2- Right Tissue
3- Right Safety
4- Right Patient
5- Right commercial potential

Question 3

What is the definition of a drug target?

Answer 3

These are targets which the molecule binds onto in order to produce a desirable effect.

Question 4

What is the common route taken for a drug target?

Answer 4

DNA - RNA - Protein

Question 5

What is the definition of tissues?

Answer 5

Group of specialised cells carrying out A specific function.

Question 6

What is the definition of organs?

Answer 6

Groups of specialised cells carrying out specific functions.

Question 7

What is the definition of IN - VIVO?

Answer 7

Experimentations inside an intact living organism.

Question 8

What is the definition of IN - VITRO?

Answer 8

Experimentations outside an organism in test tubes.

Question 9

What is the definition of EX - VIVO?

Answer 9

Experimentations of intact tissues / organs outside living organisms.

Question 10

What is the definition of IN - SILICO?

Answer 10

Experimentations using computer simulation.

Question 11

Name some advantages of in - vitro procedures.

Answer 11

High throughput screening = screening known compounds from libraries.
Reduced cost.
Less regulations.

Question 12

What does the in - vitro cell line based testing involve?

Answer 12

• Cell Biology
• Mechanism of action
• Toxicology

Question 13

Name some disadvantages of in - vivo procedures

Answer 13

Highly regulated
Low throughput screening.

Question 14

What does the in - vivo cell line based testing involve?

Answer 14

Small animals are used.
- Complex disease mechanisms
- Overall effects on intact living organisms
- Effect of other organ systems and counter - regulatory mechanisms
- Pharmacokinetics
- Safety
- Mandatory before human testing

Question 15

What is a cell line?

Answer 15

Permanently established cell culture which will proliferate indefinitely given appropriate fresh medium alongside space.

Question 16

What is the difference in lines from cell stains?

Answer 16

Lines are immortalised - meaning they keep on replicating and never die .

Question 17

What is the disadvantage of using in - vitro cell lines?

Answer 17

These are not reflective of the biology of living organisms.

Question 18

What is the purpose of an in - vitro cell line?

Answer 18

Studying physiology, pathology and cell growth.
Alterations in structure / function and genetic makeup of cell under controlled environments.

Question 19

What are the limitations of animal in vivo models?

Answer 19

• Not able to model all aspects of human diseases.
• Animal models are short term compared to the course of human disease.
• Species difference in biology.
• Limited genetic diversity and carried out in controlled environmental conditions.

Question 20

What are the 3 R’s in animal research?

Answer 20

Replace - Animal studies with non - animal studies.
Refine - Minimise stress of study animals.
Reduce - As few animals are required and necessary.

Question 21

Where can you find new targets?

Answer 21

• Genomics and Bioinformatics.
• Genetics.
• Phenotypic Arrays.
• Clinical Precedent.

Question 22

What is a genome?

Answer 22

An organism’s complete set of DNA.

Question 23

What does genomics mean?

Answer 23

Study of the genome, including gene - gene and gene - environment interactions.

Question 24

What does genetics means?

Answer 24

Heredity.

Question 25

What does epigenetic mean?

Answer 25

Heritable changes in gene expression without changes to genome.

Question 26

What does bioinformatics mean?

Answer 26

An interdisciplinary science of sorting, retrieving and analysing large amounts of biological information.

Question 27

Where do you find new targets in Genomics and Bioinformatics?

Answer 27

Comparing gene expression between disease and normal.
Pathway Analysis.

Question 28

What is a pathway analysis?

Answer 28

Finding out if differentially expressed genes are associated with certain biological processes or molecular functions.

Question 29

Where do you find new targets in Genetics?

Answer 29

Human mutation data linked to disease.

Question 30

Where do you find new targets in Phenotype Studies?

Answer 30

In - vivo and In - vitro phenotypic models.
Neutralising antibodies and gene knockdown.
Clinical compounds / Drugs

Question 31

Where do you find new targets in Clinical Precedent?

Answer 31

Information from existing drugs.

Question 32

What is fragment screening?

Answer 32

Screening small and fragment compounds to pick up LOW AFFINITY binding sites which can then be built upon.

Question 33

What is a rational subset screening?

Answer 33

Identification of chemical family / class known to hit target to increase hit rate.
Modification of existing active molecules.

Question 34

What are in vivo animal models used to test?

Answer 34

Pharmacodynamics
Pharmacokinetics
Safety Pharmacology (Toxicology).

Question 35

What is an investigators brochure?

Answer 35

Collection of summary information on the investigational medicinal product.
IE:
Physiochemical Properties.
- Storage Information (etc)
Pre - Clinical Pharmacology.
- Pharmacodynamics
- Pharmacokinetics
- Toxicology ( Safety Pharmacology)

Question 36

Name some strengths of animal studies.

Answer 36

IN - VIVO RESEARCH
- Predictive models of disease.
- Generate Hypothesis
- Knowledge of animal biology.
BIOREACTORS
- Produce materials for research and treatments.
- Surgical materials.
EDUCATION

Question 37

Name some limitations of animal studies.

Answer 37

Limited replicability in humans.
WHY?
- Disease
- Pharmacokinetics
- Pharmacodynamics
- Loss of biological variability
- Environmental stimuli
(lab conditions differ from natural environment).
Publication Bias
Methodological Deficiencies