impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

Ferry along the Potomac River. The site was virtually
‘just down the road’ from the WRAIR headquarters
within commuting distant from the main research lab.
Klayman solicited the help of his colleague, Dr. Willis
Reid, Chief of the Department of Parasitology in
Experimental Therapeutics, who enlisted boy scouts
from his Scout troop to harvest the plant. Klayman
then set about the difficult process of trying to duplicate
the Chinese extraction process without the benefit
of any roadmap of the proper processes to use. It took
Klayman almost two years, but in 1984 he cracked it,
and was featured on the May cover of one of the most
prestigious U.S. journals, Science, with his announcement
that artemisinin was a poorly-water-soluble crystalline
compound. He revealed in his manuscript in
Science that these two oxygen atoms were like a small
nuclear weapon waiting to explode if given the right
trigger. This trigger turned out to be free iron, and
malaria-infected red blood cells are full of this free
iron. Malaria pigment, or haem, that the parasite produces
from the breakdown of hemoglobin served as the
perfect trigger for this bomb. When artemisinin enters
the free iron-rich haem in these red blood cells, the two
oxygen atom molecule falls apart violently and triggers
a cascade of free radicals that are toxic to the parasite.
The more free iron in a parasitized red blood cell, the
more artemisinin enters the cell, and the greater the
killing effect of the drug. This reaction is so rapid, and
artemisinin is so explosive, Klayman speculated the
parasite would have little time to recognize its structure
and develop resistance.
With Klayman’s discovery, work began rapidly on the
various extracts of the parent artemisinin structure.
Klayman’s work on the lipid soluble forms of
artemisinin, artemether and arteether, was rapidly followed
by work within the Parasitology and
Pharmacology groups at Experimental Therapeutics.
This work started to verify some of the Chinese claims
of efficacy of this remarkable group of drugs. Arteether
was selected by the U.S. Army and the WHO for development
as an intramuscular sesame oil solution principally
for the emergency treatment of severe malaria.
Unfortunately, the promising work and optimism about
this drug class was about to change. Dr. Thomas
Brewer was the principal investigator working on the
toxicology of this class and whose teams started to see
some disturbing results in work with rats and dogs
treated with both arteether and artemether. All animals
given high doses of these compounds developed a progressive
neurologic defect, with eventual cardiorespiratory
collapse and death in five of six animals studied.
These neurologic findings included gait disturbances,
loss of spinal and pain response reflexes, and prominent
loss of brain stem and eye reflexes. Pathologic
examination of rat brain sections showed a dose-related,
region-specific pattern of injury. The microscopic
examination even showed complete loss of some critical
brain cell bodies in these rats, but worse for the
progress in developing these drugs, the changes were
P. J. Weina - History of Artemisinins
27
also seen in a second animal model, dogs. The publication
of this work in 1994 effectively silenced the work
on the artemisinin drug development program for the
U.S. Army.
Development of the artemisinins continued in many
countries and along many fronts throughout the world
despite the red flag of neurotoxicity raised by the U.S
Army’s program. And despite this setback, even the
U.S. Army’s drug development program had believers
who refused to give up on this very promising group of
antimalarial drugs. Chemists like Dr. A.J. Lin in
Medicinal Chemistry at Experimental Therapeutics
worked tirelessly to try to find other artemisinin derivatives
that would not have this toxicity. It was his
team’s work that found water soluble extracts of
artemisinin that preserved the active site endoperoxidase
bridge but with some very different properties
than the lipid soluble forms. The lion’s share of the
work with the pharmacodynamics and pharmacokinetics
with virtually all of the artemisinin derivatives was
done either personally or under the direction of Dr.
Qigui Li. It was Dr. Li’s diligent and steadfast work
with the precise and exhaustive preclinical animal work
for most of the artemisinin derivatives that laid the
groundwork for future successful efforts in making
these important compounds available to those who
needed these drugs the most. It was quickly discovered
that the water soluble forms, while relatively unstable
compared to the lipid soluble forms, had little of the
toxicity noted in arteether and artemether.
The faith of those visionaries throughout the world
who did not give up on the artemisinins has since been
justified many times over. Today artemisinin drugs are
the main line of defense against drug-resistant malaria
virtually everywhere in the world. The most rapidly acting
of all is artesunate, a water-soluble derivative of
artemisinin originally isolated by the Chinese. But
although oral and intravenous forms of artesunate are
manufactured in China and Vietnam, no Western pharmaceutical
company were willing to make it. The reasons
are all too predictable. “Because the Chinese isolated
it first, artesunate is not patentable,” says
Milhous. “And without a patent no pharmaceutical
firm is willing to pick up the co-development costs.”
Much of this has changed recently with the predominance
of public-private partnerships and large grants of
money from donors such as the Bill and Melinda Gates
Foundation. This change has made these products
available in many parts of the world, but licensure in
the Western world, including the U.S. and the
European Union in general, has been lagging severely
behind the rest of the world. WRAIR took up the cause
and concentrated first on two other derivatives: artemotil
and artelinic acid, both of which were patentable.
In March 2000, the Dutch company ARTECEF registered
artemotil in Holland with work done by the
WRAIR on this compound. The significance of the
artemisinin drugs to parts of the world most heavily