animal tests Flashcards
why are animal models nessecary
The FDA and other regulatory agencies require both proof of efficacy and safety in animal models before they will allow a compound to be studied in humans.
_ 3 different species of animals must be tested
-In animal models, the net biological impact of a compound is the sum of the total of the compound’s effect on all of the macromolecules, tissues, and organs that it comes into contact with while in vitro is an incomplete model.
Pharmacokinetics
It is a profile of what happens to the compound when it enters the body
Pharmacodynamics
It is the study of what a compound does to the body. It includes both efficacy and potency
Efficacy
The capacity of a compound to produce a desired biological endpoint
Potency
The amount of compound required to produce an effect OF A GIVEN INTENSISTY.
Therapeutic window
It is the span of time when the beneficial aspect of the drug occurs from when it is ingested to when it is excreted.
Sources of animal models
-Insertion of non-native DNA or the suppression of normal gee function via transgenic technology: eg. create a transgenic mouse model to study Lou Gehrig’s disease (SOD1)
-Drug-induced animal models: Use MPTP to artificially induce Parkinson’s disease
-produced by physical means: eg: Ischemic events can be surgically created by limiting or blocking blood flow in order to study the impact of compunds on stroke survival
Categories of animal moedls
Homologous animal models
Isomorphic
Predictive
Homologous animal models
-The most desirable model as they have the same CAUSES, SYMPTOMS AND TREATMENT options availible for humans
-Rarest type as difficult to achieve
-Majority of animals are not homologous models
Example of homologous model
Non-obese diabetic mouse model of type 1 diabetes where pancreas does not produce insulin
Isomorphic animal models
-Have the same symptomology as humans and treatment options are the same
-However, the root cause of the disease or condition in the animal is not the same as humans
Example of Isomorphic animal models
Cardiac arrest or stroke is artificially induced in an animal but they still have the same symptoms and treatment
Predictive animal models
-Animal model has little or no obvious resemblance to human condition but there are facets of the model that allow the researcher to use it as a predictive tool
Example of predictive animal model
Schizophrenia
It is impossible for a rat to say it has it and so instead they put the rat in a cylinder with water. rats that give up trying to escape after a short time have low willpower and could have mental disorders
Species selection
Mice, rats or primates where non-human primates are closet to humans overall
Limitations of non-human primates
-very few non-human primates available to study
-Difficult and expensive to maintain
-Large size impacts compound supply issues as potential therapeutics are most often dosed on a milligram per kilo basis (have to synthesis drugs at a greater quantity)
-Larger animals require larger amounts of compounds which drives up expenses
-Additional ethical considerations
-Non-human primates are only used when there is no other option
-animals with longer lifespan take longer to develop diseases which makes study longer
-Hard to have a large sample as only a few large animals can be tested at a time
SCID mice
severely compromised immunodeficient mice
Mouse Xenograft tumor model
A tumor is established in an immunocompromised mouse using either patient-derived tumor cells or a stable tumor cell line
-Once the tumor is established, treatment with candidate compound or vehicle is initiated.
-Changes in the tumor size are monitored to determine efficacy of candidate compound
Patient derived xenograft model
Take tumor out of patient, cut it up and insert it into rat
then remove tumor that grows in rat and insert into other rats
limitations of xenograft model
-the use of cross-species transplantation (human tumor cells to a mouse host)
-The experiment requires the use of immunocompromised mice so that the tumor cells will not be rejected by the mouse’s immune response
-Problem: the above do not follow the natural progression of cancer in humans as rats have different physiologies
Solution: Use an allograft mouse model to study potential anti tumor agents in the presence of a normal immune system
Mouse allograft tumor model
Immunocompetent mice are subjected to experimental conditions
-Rats are injected with rat cancer cells so there is an intraspecies transplantation rather than an interspecies transplantation
-Candidate compounds can be introduced in the same manner as xenograft model and efficacy can also e measured by looking at changes in tumor size
Problem of allograft models
It use mouse cells instead of human cells and so is much less utilised method
Genetically engineered mouse models of cancer
In GEM models, genes that are suspected of participating in the transformation of normal cells into malignant cells and tumors are targeted for mutation, overexpression or deletion
Benefits of GEM model
-Various stages of tumor progression can be studied as cancer is naturally induced
-The impact of theraputic agents can be determined at different stages of cancer
-Tumor microenvironment of GEM models more closely mimics natural cancer progression
Disadvantages of GEM model
-Costly and time-consuming
-GEM tumors are typically the result of limited alteration of the mouse genome, human tumors are heterogenous in nature( Multiple mutations may be present in clinical setting)
-Tumors that develop in GEM models are mouse tumors, not human tumors
-As a result, efficacy in a GEM model is not necessarily predictive of what will happen in a clinical setting as rat physiology is not as complex as human.
MPTP function
-MTP crosses BBB (blood-brain-barrier) and leads to rapid destruction of dopamine-synthesizing neurons in the substantia nigra region of the brain when metabolized to MPP+
-This triggers rapid development of Parkinson’s disease symptoms in primates and mice
