impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

26
treatment of ‘intermittent fevers’, it is Mao and the
malaria problem the Vietnamese were having that is
credited with providing the primary push needed for
qing hao to be rediscovered by the Chinese scientific
community. Working diligently on the issue, by 1972
the Chinese succeeded in crystallizing the active principle
– qinghaosu, or artemisinin – and Mao’s scientists
quickly moved to begin testing it on humans. Seven
years later they reported their findings to the world.
According to the Chinese, artemisinin cured falciparum
malaria more rapidly and with less toxicity than either
chloroquine or quinine, and it was even effective
against strains that were chloroquine-resistant. Much
of this work has been extensively documented in the literature
of late and can be found in various well written
and engaging writings. Only a portion of this fascinating
story will be recounted below.
What is little known though is the role of the U.S.
Army’s Division of Experimental Therapeutics in the
development of the artemisinins. The reports of
artemisinin’s success came as somewhat of a surprise to
the U.S. military drug development community.
Current drug developers within the WRAIR doubted
the Chinese claims about artemisinin and resisted the
idea that a natural product worked so well. Their skepticism
was reminiscent in many ways of classic
European physicians who knew all about the treatment
of malaria but were resistant and reluctant to accept
the claims of the “Jesuit bark” 300 years before. The
Chinese, many of these skeptics pointed out, had made
similar claims in the past, most conspicuously when
they said they could cure malaria with acupuncture,
only to be proven wrong later when this was clinically
tested. Many believed that these studies, some dating
back nearly ten years, offered proof that the Chinese
could not be trusted in this case either.
What the skeptics in the U.S. Army did not know at the
time was that the discovery of qing hao came as a direct
result of the Vietnam War. Ho Chi Min asked Mao Tsetung
to assist Vietnam in its war with the Americans by
providing new treatments for malaria. Unknown to
most of the world, malaria was responsible for exceedingly
high mortality in Vietnamese troops. By May
1969, the China Science Institute set up “Office 523”
where the initial re-discovery of artemisinin was first
made. It is reported that it was Zhenxing Wei, a professor
of Chinese Traditional Medicine at the Research
Institute of Shandon Province in China, who laid claim
to having made this re-discovery. Apparently, it first
appeared in a Chinese recipe book dated 168 BC as a
treatment for hemorrhoids. Later it appears in The
Handbook for Emergency Treatments, a book written
by Ge Hong in 340 AD, where he recommends using it
as a treatment for ‘intermittent fevers’, although some
claim the translation is a recommendation specifically
for chills and fevers. Regardless, Ge Hong in his writing
instructs fever-sufferers to soak qing hao in one
sheng (about 1 liter) of tea, squeeze out the juice and
P. J. Weina - History of Artemisinins
drink the remaining liquid. Following Hang’s recipe,
scientists prepared the concoction described and fed it
to mice infected with Plasmodium berghei, a lethal
rodent malaria parasite. Incredibly, they found that
qing hao was as good as chloroquine and quinine at
clearing the parasite and also cured chloroquine-resistant
strains of the rodent malaria. Wei, with his knowledge
of general traditional medicine and his previous
knowledge of Hong’s book describing anti-fever prescriptions,
most of which contained artemisina leaves,
had an advantage in finding the active compound. He
had made two prior attempts during his career at trying
to find these active compounds from these preparations,
in 1958, and again in 1963, but failed in both of
these attempts. Finally, working in Office 523, he succeeded
in October of 1970 in obtaining 30mg of a pure
crystalline product that was not toxic. There are detractors
from the Wei claim that assert the re-discovery of
the properties of qing hao is properly attributed to
Professor Tu Youyou working at the same Office 523 in
the early 1970s. They contend that it was Youyou’s
group that showed the efficacy of this product in mice
had a cure rate in the 95-100% range. What is known
though in spite of the initial re-discovery of Ge Hong’s
work is that in August of 1972, this extract was eventually
shown to have remarkable efficacy in 21 patients
suffering with malaria in Beijing.
In another part of the world, back on the campus of the
WRAIR, it was Dr. Dan Klayman, Chief of the
Department of Medicinal Chemistry in WRAIR’s
Division of Experimental Therapeutics, who decided to
take a closer look at what was known of the Chinese
study. The more he looked at the available data, the
more his interest grew. Artemisinin was an endoperoxide,
a molecule consisting of two oxygen atoms, but in
a form he had never seen before in a drug. On exposure
to air, endoperoxides normally become unstable and
fall apart, yet the Chinese were claiming that
artemisinin could be crystallized into a compound that
would persist in the body long enough to destroy the
parasite. China’s refusal to share their techniques left
others with nothing to compare to or to even attempt
to reproduce their work. The Chinese refusal to assist
even the WHO was understandable in retrospect given
the presence of multiple WRAIR representatives on the
WHO chemotherapy and malaria steering groups.
Rightly or wrongly, the Chinese feared that if they
handed over the formula for artemisinin, WRAIR
would patent it for the benefit of “capitalist” pharmaceutical
firms. Under these circumstances, Klayman
really had no choice but to gather his own samples of
the plant if he wished to pursue this promising lead.
Klayman recruited botanists from Experimental
Therapeutics and the Smithsonian Institute in
Washington to determine whether A. annua existed in
North America. Astonishingly, they found it growing
right in the back yard of the Nation’s Capital, near a little
town steeped in Civil War history called Harper’s