Module 3R    Pyrogen test in vitro Author: Stefanie Schindler
A new in vitro pyrogen test (IPT) A A A
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Module 3R
Draize test replacement
Sensitization in-vitro?
Pain
Tox receptor
Implementation of the 3Rs
Pyrogen test in vitro
Dangerous pyrogens
Rabbits with fever
Definitely afebrile?
Does it have a future?
Blue blood
Not very noble
How is fever induced?
Fever in a test tube
A new fever thermometer
More than replacement
Replacement
Receptor modeling
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Parenteral drugs are forbidden to contain any pyrogenic (fever inducing) substances. For this reason every lot of a parenteral drug has to be tested on pyrogens, before it is released into the market. A new in vitro pyrogen test developed at the University of Constance (Germany) has has a good chance of being recognised by the registration authorities, as a fully-fledged pyrogen test.
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Parenteral drugs have to be pyrogen free
Parenteral drugs can be lethal, if they contain pyrogenic impurities. For this reason scrutinious testing is an absolute must.
The «Golden Standard»: pyrogen test on rabbits
The pyrogen test on rabbits is considered as the «Golden Standard». Possible replacement methods must relate to this test and be at least as sensitive, when they are to have any chance of success.
A human being is not a rabbit
Commercially available medicines have passed the rabbit-pyrogen test. However who can guarantee, that a substance tested on a rabbit, doesn’t still result in causing fever in a human being? And who reacts more sensitively to pyrogens: humans or rabbits?
Every test has its limitations
The pyrogen test on rabbits cannot register every substance which causes fever. It is not possible with this test to examine many new medical products or chemical compounds which are present naturally in the environment. Also regarding ethics as well as cost, the test doesn’t have much of a future.
Can the horseshoe crab provide us with further help?
In the 70’s, the first in vitro test to detect pyrogenic material was developed: The Limulus-Amoebocyte-Lysate-Test (LAL).
Not everything that glitters is gold.
The LAL test is not only ethically problematic. It cannot even recognise many pyrogens.
A substance which triggers fever, and still is not a pyrogen
Around 1980 it was discovered that interleukin 1-beta acts as a substance eliciting fever.
Interleukin 1-beta – basis for a new IPT
The principle of the new IPT is easy : If a substance triggers the production of interleukin 1 in full blood, it must be a pyrogen.
How can a fever be measured in a test tube?
In rabbit-pyrogen tests fever is measured in the way that we are used to : with a thermometer. In the new IPT the thermometer is called ELISA.
The new IPT – so far only advantages
The new IPT developed in Constance, could in the future not only make unnecessary worldwide pyrogen testing on rabbits, but also make injectable medicines safer in general.