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Animal Models

John A. Budny jabudny at EARTHLINK.NET
Fri Apr 19 13:31:10 EST 1996

During the discussion on animal models that took place in the newsgroup
(bionet.toxicology) in February I remember a thought
that was expressed that the criteria for an animal model that is used in
pharmacology or therapeutic development should be held
to the same standards as the models used in toxicology.  If that is the
case, which I agree, then the reverse should be true, namely,
that the models used in toxicology should have the essential traits or
characteristics of models that are used in pharmacology or
therapeutic developments.

A recently published article in NATURE MEDICINE, Vol. 2, Number 2, April
1996, pages 430-436 entitled "The Philippine
cynomolgus monkey (Macaca fasicularis) provides a new nonhuman primate model
of tuberculosis that resembles human
disease".  The article states:
"The evaluation of new drugs and vaccines ultimately requires animal models
that develop a disease similar to that in humans. 
Old and New World monkeys are susceptible to tuberculosis, but studies of
naturally acquired tuberculosis have indicated that the
degree of susceptibility varies among the different species."  "...rhesus
monkey ... is highly susceptible ... develops an acute,
fulminant, highly fatal form of tuberculosis."  "...only established model
of tuberculosis...".  "[however] the Philippine
cynomolgus monkey ... [has] the possibility that its susceptibility to
tuberculosis more closely approximates that of humans ..."

The authors concluded:
1.  "Our study demonstrates unequivocally that the Philippine cynomolgus
monkey is susceptible to tuberculosis."
2.  "... cynomolgus monkey is less susceptible to TB than the rhesus."
3.  "The disease in the rhesus resembles the acute fulminating forms of
tuberculosis sometimes seen in infants and children.  In
contrast, cynomolgus monkeys ... develop a chronic, slowly progressive
4.  "Thus, our study indicates that the cynomolgus model of tuberculosis
more closely resembles human tuberculosis than the
rhesus model in two respects.  First, cynomolgus monkeys ... develop a
chronic, slowly progressive form of tuberculosis, akin to
that of adult humans, whereas rhesus monkeys challenged with comparable
doses develop an acute, rapidly progressive disease. 
Second, a significant proportion of cynomolgus monkeys administered a low
dose of M. tuberculosis are able to contain the
infection in a subclinical state, unlike rhesus but, again, akin to humans."

It appears that the rhesus monkey represents an animal model for acute forms
of tuberculosis seen in infants and children.  The
cynomolgus monkey, on the other hand, develops a chronic, slow progressive
disease seen in adult humans.

Time-course or pharmacokinetic similarity was suggested in the discussion
that took place in February for animal models with
reference to the toxicant.  No mention was made of the "time-course" of the
disease.  Here, we have an example of a time-course
with respect to the disease.

Should a criteria for an animal model for toxicology be that the time-course
and characteristics of the toxicologically-induced
disease state resemble, replicate or be identical to the toxicant-induced
disease condition in humans?

John A. Budny
jabudny at earthlink.net

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