Ways for testing new medicines/medical treatments?

When a drug is invented/discovered it must go through rigorous testing stages before it is released for public use.

PRE-CLINICAL:

These are in vitro/in vivo animal studies. Before you can give it to a human you have to prove that it will most likely be safe. These are mainly toxicity tests (toxicology) of the drug you'll be giving. You can use animals (whole animal model) or tissues for this stage. But you can be assured at some point in the preclinical testing the drug will be tested on at LEAST one animal model.

In preclinical studies we look at the pharmacology of the drug, we look at the principal pharmacological action in the animal model and try and figure out any secondary properties (e.g. addiction). We look at absorption, distribution, metabolism and excretion of the drug (pharmacokinetic parameters). Most importantly we're looking at the toxicology through the following tests:

Acute Toxicity Tests (performed first)

These are designed to determine the effects that occur within a short period after dosing. Usually only a single dose of compound is given, perhaps by differnt routes (e.g. oral, intravenous or intraperitoneal). They have been used to determine dose-response relationships and end points such as LD50 (lethal dose).

Sub Acute Toxicity Tests

These involve exposing the animals to the compound for 28-90 days. Exposure to the drug is frequent, usually daily. These tests provide information on the target organs and the major toxic effects. Toxic effects that have a slow onset are able to be detected. Measurements of compound in tissues can be made and correlated with any toxic effects observed. During the study, clinical chemical measuremtns may indicated the development of any pahtological lesions. Compete necropsy including histology of ALL organ systems in survivors (all animals are killed). Blood chemistry, urinalysis, haematology etc. are performed on any ill animals during the study. Data from the sub-acute toxicity tests also help in the design of chronic toxicity studies.

Chronic Toxicity Tests (big investment to drug companies... they take a long time)

These include lifetime exposure to the animals to the compound of interest. Changes in simple measurements such as body weight, food and water intake as well as clinical measurements can be made. Relatively non-invasive. The choice of dose, species, strain, ruote of expoure etc. are influenced by the type of chemical, expected exposure plus regulations of countries where the compound is to be marketed.

Often rats and dogs are used as the species of choice. For rats about 50 male and female per group (3 doses), plus 100 of each for control. For dogs, about 10 male and female per group. The drug/chemical is most often administered in the food, but if necessary, there may be other routes of administration.

This is the only way to test for carcinogenicity (potential to cause cancer)

After Pre-clinical studies comes Clinical studies. These are performed on humans and have four phases (I assume you don't want to know about these as you're studying animals, it's easy enough to look up)

Tetratogenicity tests are carried out on animals around Phase III of clinical trials. These are when the drug is given to a pregnant animal, blood of the embryo is tested to see how much drug crosses the placenta and to see what effects it has (i.e. is the foetus deformed?) These tests were bought in thanks to thalidomide.

Important things to consider when designing a Pre-Clinical study on animals:

- Does the test species have the same target as in the human? Do they have the same enzyme that the drug is working on? The same receptor?

- Is the test species subject to diurnal variation? This can affect the pharmacokinetic parameters (ADME). Lab animals must be kept in constant conditions so they maintain feeding/behavoural activity.

- Is what your testing going to be affected by the immune system of the animal. E.g. testing a human immune protein in a rat won't work. The rat's immune system will eliminate it.

It is important to define species variation (what is different in effects between different animals) and whether or not we can extrapolate the findings from animals to humans. Will the effects seen in a mouse be significant to that in a human? This part is risk assessment.

I hope this covers most of the stuff you need to know!!

EDIT: Before I forget... Addictiveness of a drug is tested in animals through using electric stimulators which are hooked up to the animals brain. When the animal pushes a lever the electrode stimulates the mesolimbic dopamine pathway, known as the reward pathway which is the main reason for "drug seeking" behaviour. The animal will continue pushing the lever which shows that this pathway is crucial to addictive behaviour. This experiment can be altered for drug testing by replacing the electrode with administration of the drug.

Also it can be tested by having a box with a parti

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