PRINCIPLES OF TOXICOLOGY

17.8 TOXIN AND VENOM THERAPY 431
One traditional disadvantage of immune therapy of venomous animal bites and stings is the lack
of effectiveness of the IgG antibody in neutralizing venom constituents once they have entered the
interstitial fluid space. It has recently been found that preparation of truncated antibody molecules,
such as the F(AB)2 fragments, is one way to enhance neutralization of tissue bound toxins.
One of the major problems associated with the use of antivenins is the high incidence of serum
sickness, which is a human immune response to the intravenous administration of horse serum
antivenin. One method of reducing the problem would be to enrich the antigenic mixture used to
produce the antivenin with the major toxins or other proteins that are most dangerous. This may permit
a reduction in the total amount of freeze-dried horse serum required for therapy. Monoclonal antibodies
have not yet gained much acceptance for immunotherapy of intoxications or envenomations, probably
for a combination of reasons: (1) monoclonals are so specific they would only work on single
components of a venom, (2) they would be less likely to be of use against envenomation by a different
species, and (3) they are considerably more expensive to produce. Expense is a factor; most pharmaceutical
firms view the production of antivenins more as a responsibility, due the rather small market
for antivenins. In the future it is likely that better antivenins will become available, as the costs of
preparing “humanized” monoclonal antibodies decreases.
In Australia, it is routinely recommended that intramuscular epinephrine be administered prior to
injection of the antivenin, in order to reduce the intensity of any immediate hypersensitivity reaction
to the antivenin, and then oral corticosteroids be taken for several days afterwards in order to reduce
the delayed hypersensitivity response to administration of antivenin. With these precautions, the
incidence of serum sickness has been less than 10 percent, compared to the almost 30 percent estimated
for U.S. victims.
Toward a Rational Pharmacotherapy Based on Knowledge of the Toxic Constituents of a
Venom
Probably most envenomation victims are not treated rapidly enough with antivenins to fully respond
to immunotherapy, particularly when envenomation occurs outside a geographic area in which
envenomations are frequent. Other patients cannot tolerate the antivenom because of allergic sensitivity.
While recognizing the therapeutic power of the immune approach, it seems prudent to develop
rational pharmacotherapies based on a scientific knowledge of the chemistry and biological actions of
the toxins involved. Small toxins that act on receptors may be antagonized by using antagonists if the
toxin is an agonist and vice versa. This is most common when receptors to neurotransmitters are
involved (e.g., atropine can counteract the actions of the mushroom toxin muscarine). When a
competitive antidote is unavailable, it may be possible to physiologically antagonize the intoxication,
based on a knowledge of the opposing system. Of course, the very basis of rational therapy is the
biochemical and pharmacological understanding of the most active constituents.
For a rational therapy to succeed, it must be based not only upon scientific knowledge of the separate
actions of venom constituents, but must also take into account the synergistic actions of many of the
constituents. After all, a venom has usually evolved rather than just a single toxic substance! That is
why toxicological studies must also be carried out with whole venoms as well as their purified
constituents, in order to detect such interactions between venom constituents.
Toxins as Drugs
Besides serving as chemical defenses and offenses for the organisms that create them, some naturally
occurring toxins are also being used as chemical tools for investigating biomedical problems and as
models for designing novel new drugs. The use of toxins and venoms as therapeutic agents is not a
new phenomenon, but rather, an activity that is probably as old as the most primitive humanoid species.
In the nineteenth century, drug development based on natural products was made possible by the
emergence of organic chemistry. In recent years, the availability of radioligand binding and molecular
biological techniques for investigating drug receptors in vitro has further accelerated drug develop-