Download Role of US Military Research Programs in the Development of US

INVITED ARTICLE
REVIEWS OF ANTI-INFECTIVE AGENTS
Louis D. Saravolatz, Section Editor
Role of US Military Research Programs in the Development
of US Food and Drug Administration–Approved
Antimalarial Drugs
Lynn W. Kitchen,1 David W. Vaughn,1 and Donald R. Skillman2
1
Military Infectious Diseases Research Program, US Army Medical Research and Materiel Command, Fort Detrick, and 2Walter Reed Army Institute of Research,
US Army Medical Research and Materiel Command, Silver Spring, Maryland
US military physicians and researchers helped identify the optimum treatment dose of the naturally occurring compound
quinine and collaborated with the pharmaceutical industry in the development and eventual US Food and Drug Administration
approval of the synthetic antimalarial drugs chloroquine, primaquine, chloroquine-primaquine, sulfadoxine-pyrimethamine,
mefloquine, doxycycline, halofantrine, and atovaquone-proguanil. Because malaria parasites develop drug resistance, the US
military must continue to support the creation and testing of new drugs to prevent and treat malaria until an effective
malaria vaccine is developed. New antimalarial drugs also benefit civilians residing in and traveling to malarious areas.
Development of drugs to prevent and treat malaria is a US
military priority for several reasons. The infection can render
military personnel unable to fight and can cause life-threatening
disease. Insect repellent and bednets do not guarantee protection. A protective vaccine does not exist. Troops may develop
malaria after leaving malarious areas because of inadequate
prophylaxis or poor prophylaxis compliance. Mosquitoes capable of transmitting malaria exist in the United States, and
returning troops can transmit it to others.
Malaria had a major impact in the Spanish-American War,
the Pacific and India-Burma-China theaters in World War II,
and the Vietnam War. Malaria also afflicted troops in the Korean War and Operation Restore Hope in Somalia [1, 2]. In
Liberia in 2003, of 290 troops who stepped ashore during peacekeeping operations, 80 (28%) developed malaria, and 69 (44%)
of the 157 who spent at least 1 night ashore were afflicted. Five
malaria-infected marines developed severe disease requiring intensive care unit support [3].
Received 27 December 2005; accepted 1 March 2006; electronically published 24 May
2006.
Reprints or correspondence: Dr. Lynn W. Kitchen, Military Infectious Diseases Research
Program, US Army Medical Research and Materiel Command, 504 Scott St., Fort Detrick, MD
21702-5012 ([email protected]).
Clinical Infectious Diseases 2006; 43:67–71
This article is in the public domain, and no copyright is claimed
1058-4838/2006/4301-0011
QUININE AND QUINIDINE
The first drug recognized with antimalarial properties by Western medical workers was quinine. Quinine occurs naturally in
the bark of cinchona trees, which were originally found at high
altitudes in South America. Peruvian natives chewed cinchona
bark, but probably not for the purpose of treating malaria
(which may not have been present in the New World before
the arrival of Columbus). The bark may have been ingested to
stop cold-induced tremors in Indians working in Spanishcontrolled mines via a direct effect on skeletal muscles and
neuromuscular junctions [4]. The trees were named after the
Countess of Cinchon, the wife of the Viceroy of Peru, who
reportedly recovered from a febrile illness after ingesting the
bark. Cinchona bark was introduced into Europe in the early
17th century as a treatment for fever and malaria by Jesuit
priests returning from Peru, long before the discovery of the
malaria parasite in the late 1800s. However, variation of quinine
content in different cinchona species led to inconsistent therapeutic results. In 1820, two French chemists, Pierre Pelletier
and Joseph Caventou, isolated the alkaloids quinine and cinchonine from cinchona bark. Several French physicians successfully used purified quinine to treat patients with intermittent fever, and a search for the cinchona species with the highest
quinine content began.
Quinine profoundly influenced history, because it enabled
missionaries, explorers, colonists, and militaries to travel and
live where malaria was endemic (including the United States
REVIEWS OF ANTI-INFECTIVE AGENTS • CID 2006:43 (1 July) • 67
until 1951) [5]. The drug was commonly used by the US military by 1830. During the Second Seminole War in Florida
(1838–1842), Dr. Benjamin Harney, a career army medical officer, demonstrated the efficacy of large doses of quinine to
treat remittent fevers [6]. This led to improved results with
quinine by military physicians around the globe. During the
US Civil War, the Union Army used 125,000 kg of quinine or
other cinchona products. Quinine was key to the completion
of the Panama canal, because it prevented malarial illness in
canal workers [7].
Efforts to synthesize quinine were started in 1856 by the
British chemist William Henry Perkins, but this goal was not
accomplished until 1944 and has never been achieved on a
commercially economic scale. Charles Ledger and Manuel Mamani found a variety of cinchona (Cinchona ledgeriana) with
a high quinine content and sold seeds of this tree to the Dutch
government in 1865 after the British rejected the offer. Dutch
plantations in Java were soon producing 97% of the world’s
supply of quinine, which was ∼10 million kilograms a year by
the 1930s [5]. Quinine was eventually approved in the United
States as an oral drug (after the US Food and Drug Administration [FDA] was created), but an intravenous form of quinine was never approved.
Quinidine is a natural component of cinchona bark that was
first described in 1848 by Van Heymingen and was prepared and
given its present name by Louis Pasteur in 1853. In approximately
1918, W. Frey noted that patients with auricular fibrillation taking
quinidine for malaria developed regular heart rhythms. The drug
was originally approved for use in the United States as a drug
to treat cardiac dysrhythmias and was manufactured by Lilly. The
intravenous formulation was noted to be a life-saving remedy
for severe malaria (ironically, quinidine must be given in intensive
care unit settings because of cardiotoxicity) [8]. In 1991, the FDA
granted labeling revision of quinidine for antimalarial purposes
[9]. Intravenous quinidine is the only approved drug for treatment of severe malaria available to US troops and civilians, but
continued availability is uncertain because newer cardiac drugs
are more frequently used [10]. The US Army is developing an
intravenous formulation of artesunate—another naturally derived drug with long-recognized antimalarial properties—to treat
severe malaria.
CHLOROQUINE
Quinine is an effective treatment, especially when given with
other drugs for certain types of malaria, but adverse effects
(“cinchonism”) and a short duration of action make it a suboptimal prophylactic agent. Synthetic antimalarial work was
pioneered by the German scientist Paul Ehrlich. In 1891, while
studying aniline dyes to develop tissue staining methods, he
observed that methylene blue not only stained malaria parasites
68 • CID 2006:43 (1 July) • REVIEWS OF ANTI-INFECTIVE AGENTS
but killed them. He cured 2 cases of malaria using methylene
blue—the first time a synthetic drug was used to treat humans.
During World War I, countries producing quinine were controlled by anti-German forces. Projected quinine shortages and
the need for long-acting prophylactic drugs prompted an effort
by German companies to synthesize antimalarial compounds.
Bayer, a German dye company, soon became a leading pharmaceutical company, at which chemists and biologists assembled to develop synthetic antimalarials using methylene blue
as a prototype. In 1932, German scientists Mietzsch, Mauss,
and Kikuth reported synthesis of an antimalarial based on another dye, 9-amino acridine, later known as atabrine. In 1938,
the US Army received samples of atabrine from Winthrop
Stearns, a sister company of the German conglomerate IG Farben. US service members in Panama participated in clinical
trials to test the efficacy of atabrine, but Germany controlled
the manufacturing of this drug until scientists in the United
States successfully manufactured it in 1941. Concerns about
skin yellowing and Japanese propaganda suggesting that atabrine caused impotence created noncompliance after it became
available for service members. Dosing studies were undertaken
with US military personnel at Fort Knox, and Neil Fairly, an
Australian military physician, showed that a daily atabrine regime was effective in preventing malaria in volunteer Australian
troops. Partial control of malaria (achieved via rigidly imposed
use of atabrine beginning in 1942 and use of the insecticide
dichlorodiphenyltrichloroethane [DDT] beginning in 1943)
was an important factor in Allied success in World War II.
The Allied push to synthesize antimalarial agents during
World War II was prompted by Japan’s seizure of Java in 1942.
At the time, 90% of the world’s quinine came from Java. Allied
interest in chloroquine followed the capture of German supplies
of an analogue called sontoquine in Tunis in 1943. Chloroquine
and sontoquine had been patented in the United States in 1941
by the Winthrop Company, which had a cartel agreement with
IG Farbenindustrie, their original manufacturer, but drug development had stalled [5]. Chloroquine (which can safely be
used by pregnant women and children) rapidly controlled clinical symptoms of susceptible malaria with minimal toxicity and
was useful as a once-weekly prophylactic drug. Chloroquine, a
4-aminoquinoline, was approved by the FDA in October 1949
[11]. Multiple pharmaceutical companies were involved in its
development, including Winthrop, Abbott, E. R. Squibb and
Sons, Sharp and Dohme, and Eli Lilly and Company. However,
the emergence of chloroquine-resistant Plasmodium falciparum
and Plasmodium vivax have rendered this drug less useful.
PRIMAQUINE
Primaquine, derived from methylene blue, is a structural analogue
of pamaquine, which was produced in Germany in 1926. Pamaquine is too toxic for clinical use. Primaquine (synthesized by
Robert Elderfield of Columbia University) is in the 8-aminoquinoline class of antimalarial agents. This class demonstrates potent
activity against hypnozoite and other liver forms of malaria.
The US Army began development of primaquine in 1944
and undertook large-scale safety and efficacy studies in the early
1950s, when relapsing P. vivax malaria emerged as a major
problem in veterans returning from the Korean War. Compliance with chloroquine prophylaxis was good, so malaria symptoms developed only after troops departed from Korea. Dr. Alf
Alving (University of Chicago) led a research team under contract to the US Army that evaluated the safety and efficacy of
new antimalarial agents in inmate volunteers at the Illinois State
Penitentiary. Primaquine prevents relapse from P. vivax and
Plasmodium ovale hypnozoites and therefore cures relapsing
malaria [12]. Primaquine’s short half-life (4–6 h) requires daily
administration for 14 days. During the Korean War, primaquine
was given as directly observed therapy during the voyage from
Korea to the United States. At the time of FDA approval (January 1952 for military use and August 1952 for civilians), it
was recognized that 15 mg/day would not cure malaria due to
all strains of P. vivax (e.g., the Chesson strain), but higher doses
were not recommended because of association with hemolytic
anemia in persons of African descent.
Subsequently, hemolytic anemia associated with primaquine
was attributed to glucose-6-phosphate dehydrogenase (G6PD)
deficiency (most common in persons of African, Mediterranean,
Middle Eastern, and Southeast Asian descent) [13]. Reliable tests
for measuring G6PD level are now available, and the present
primaquine dosage recommendation, according to the US Centers for Disease Control and Prevention (CDC), for non–G6PDdeficient patients is 30 mg/day for 14 days for presumptive treatment of relapsing malaria (terminal prophylaxis) [14].
Staff at the Walter Reed Army Institute of Research and the
Naval Medical Research Center reviewed extensive data and concluded that primaquine could be useful for malaria prophylaxis.
The Navy laboratory in Jakarta subsequently completed a pivotal
Phase 3 efficacy study. The CDC now recommends primaquine
as a possible option for prevention of malaria [15, 16].
Tafenoquine (WR 238605), an 8-aminoquinoline analogue of
primaquine with a half-life of 2–3 weeks, is under development
by the US Army in collaboration with GlaxoSmithKline for prevention and treatment of P. falciparum and P. vivax malaria [17].
tablished in 1961 to develop new antimalarial drugs. Chloroquine-resistant malaria was noted in Colombia in 1959 and
later in Thailand and Vietnam. US troops in Vietnam experienced ∼81,000 cases of malaria, with 1.4 million malarial sickdays and 133 deaths. Discontinuation of DDT use because of
insecticide-resistant mosquitoes and adverse environmental effects contributed to the problem.
Chloroquine-primaquine (commercial name: Aralen phosphate with primaquine phosphate; Winthrop-Stearns) was
given to troops during the Vietnam War, but it was ineffective
against chloroquine-resistant malaria. The combination drug
is no longer commercially available, although each drug component is still available separately.
SULFADOXINE-PYRIMETHAMINE
The antimalarial activity of sulfa drugs, which block nucleic acid
synthesis required for malaria parasite multiplication, was recognized in the 1940s [18]. Because sulfadoxine and pyrimethamine interfere with folic acid synthesis differently, the combination results in a higher degree of anti–folic acid activity,
compared with monotherapy. Pyrimethamine was first created
by George Hitchings and others at Burroughs Wellcome in the
United States in 1950 as part of an effort to develop anticancer
agents, and it was approved as an antimalarial drug in Britain
in 1951. Pyrimethamine was widely used with chloroquine in
the World Health Organization (WHO) control programs of the
1960s, and pyrimethamine-dapsone (Maloprim; Wellcome) was
used for treatment and prophylaxis of chloroquine-resistant malaria in Vietnam. However, use of dapsone was associated with
infrequent but severe agranulocytosis and methemoglobinemia
[19]. Therefore, US Army scientists explored other folic acid–
blocking drug combinations. Walter Reed Army Institute of Research participated in clinical trials and FDA approval for the
sulfadoxine-pyrimethamine combination (Fansidar; HoffmanLaRoche) for malaria prevention. After approval was granted in
other countries, Fansidar was approved by the FDA in 1983.
Although Fansidar is still used as malaria treatment in some
countries that lack alternative antimalarial drugs [20], use of
Fansidar is limited because of infrequent but serious adverse
reactions, including Stevens-Johnson syndrome, and the widespread emergence of Fansidar-resistant malaria strains.
MEFLOQUINE
CHLOROQUINE-PRIMAQUINE
Chloroquine-primaquine was used successfully by United Nations troops during the Korean conflict. Chloroquine and primaquine were not available in a single fixed-dose combination
tablet until December 1969, when regulatory approval of combination tablets manufactured by Sanofi-Synthelabo was the
first major accomplishment of the Division of Experimental
Therapeutics at Walter Reed Army Institute of Research, es-
US scientists discovered the prototype drug for mefloquine, SN
10275, during World War II. The first-generation synthetic
quinoline methanols caused unacceptable phototoxicity. Mefloquine (WR 149240) was developed by the Division of Experimental Therapeutics at Walter Reed Army Institute of Research in the late 1960s in collaboration with the World Health
Organization Special Programme for Training and Research in
Tropical Diseases (WHO/TDR) and Hoffman-LaRoche. MefloREVIEWS OF ANTI-INFECTIVE AGENTS • CID 2006:43 (1 July) • 69
quine, a synthetic 4-quinoline methanol (quinine analogue),
was approved by the FDA in May 1989 under the commercial
name Lariam (Hoffman-LaRoche) for the prevention and treatment of malaria. The mechanism of antimalarial action is unknown. Mefloquine is effective against P. vivax and P. falciparum, and its long half-life permits weekly dosing. Mefloquine
was not initially recommended for pregnant women. However,
some female service members who were unaware that they were
pregnant ingested mefloquine during US military operations
in Somalia. Follow-up revealed no congenital defects from fetal
exposure, although an unexpectedly high rate of spontaneous
abortions was observed [21]. Currently, mefloquine is recommended as an antimalarial prophylaxis in pregnant women
at risk of multidrug-resistant infection [22].
Mefloquine is an important antimalarial drug for the US
military. However, reports of neuropsychiatric effects negatively
impact compliance with treatment, and malaria parasites have
developed partial resistance to mefloquine, especially in Southeast Asia and East Africa. Walter Reed Army Institute of Research is currently investigating mefloquine analogues, seeking
one with similar efficacy but reduced neuropsychiatric toxicity.
HALOFANTRINE
Halofantrine (WR 171669) was developed at Walter Reed Army
Institute of Research in collaboration with SmithKline Beecham
and the WHO/TDR beginning in the late 1960s and early 1970s
as a backup drug to mefloquine to treat chloroquine-resistant
P. falciparum malaria. Halofantrine was created by replacing
the quinoline moiety of the quinoline methanols (quinine-type
compounds) with other aromatic groups, to form the aryl
(amino) carbinols. Of this class of compounds, halofantrine, a
9-phenanthrenemethanol, is the most potent. Commercial development began in the 1980s, and the drug (Halfan) was approved by the FDA in July 1992.
Although halofantrine is still used for treatment of P. falciparum malaria outside of the United States in areas where other
antimalarial drugs are unavailable, use of halofantrine is limited
by its short half-life (1–2 days), slow and variable absorption,
and adverse effects (especially potentially fatal cardiotoxicity related to prolonged electrocardiographic QT intervals and embryotoxicity). Its main metabolite appears to be a less toxic and
equally efficacious antimalarial, but this was not further developed [23].
DOXYCYCLINE
The antibiotic doxycycline (Vibramycin, manufactured by Pfizer) has slow-acting antimalarial properties via binding to malaria ribosomes, thereby inhibiting protein synthesis. Walter
Reed Army Institute of Research conducted Phase 2 challenge
trials and clinical trials with doxycycline in Thailand, and FDA
approval was granted to Pfizer in December 1992 for its use
70 • CID 2006:43 (1 July) • REVIEWS OF ANTI-INFECTIVE AGENTS
as prophylaxis for P. falciparum and P. vivax malaria [24, 25].
From June 1992 to November 1993, 12000 Dutch military
personnel serving in Cambodia used doxycycline for malaria
prophylaxis; only 59 developed malaria.
Although doxycycline is a valuable antimalarial, and although
it has an additive effect with quinine for treatment of P. falciparum, it requires daily administration and may cause phototoxicity, gastrointestinal discomfort, and diarrhea, all of which
reduce compliance with the regimen. Lodging of doxycycline
tablets in the esophagus may cause serious chemical damage.
Furthermore, doxycycline cannot be given to pregnant women
or children because of tooth discoloration in developing teeth.
ERYTHROMYCIN AND AZITHROMYCIN
The antibacterial drugs erythromycin and azithromycin have antimalarial effects related to inhibition of mitochondrial protein
synthesis [26]. Azithromycin’s excellent safety profile in children
and pregnant women prompted antimalarial prophylaxis evaluations in Kenya, Indonesia, and Thailand by military investigators in the mid-1990s. Prophylaxis efficacy was excellent (99%)
for P. vivax malaria, but for P. falciparum malaria, it ranged from
70% to 83%, even with daily dosing [27, 28]. The US military,
in partnership with Pliva Pharmaceuticals, is seeking azithromycin analogues with improved and more-selective antimalarial
activity and similar safety and pharmacokinetic characteristics.
Combination of azithromycin with other antimalarial agents for
malaria is also under investigation. Synergy is noted when azithromycin is combined with chloroquine [29].
ATOVAQUONE-PROGUANIL
Malarone (GlaxoSmithKline), approved by the FDA for prevention and treatment of P. falciparum malaria in 2000, is a
combination of atovaquone (a substituted 2-hydroxynaphthoquinone) and proguanil. These drugs act against blood forms
and early liver stages of malaria. The structure of atovaquone
differs markedly from other antimalarials. Atovaquone is marketed in the United States as a single agent under the trade
name Mepron (Glaxo Wellcome) for treatment of Pneumocystis
jiroveci (previously named “Pneumocystis carinii”) pneumonia.
Atovaquone inhibits the electron transport system of the malaria parasite at the level of the cytochrome bc1 complex, thereby
blocking pyrimidine biosynthesis, which is essential for Plasmodia mitochondrial function (in contrast, mammalian cells
are able to salvage pyrimidines). Atovaquone also causes collapse of the mitochondrial membrane potential in P. falciparum.
Proguanil (Paludrine; ICI), which interferes with folic acid synthesis via binding to dihydrofolate reductase (much like pyrimethamine), was identified by British scientists Curd, Davey,
and Rose in 1945 [30] as a drug with low toxicity and high
activity against avian malaria. Proguanil was approved by the
FDA in 1948 as an antimalarial agent, but it was not widely
used, and marketing its use as a single drug ended in the United
States in the 1970s. Proguanil is still used overseas as an antimalarial, especially in combination with chloroquine (malaria
parasite resistance to proguanil monotherapy has been recognized since the 1950s). However, the primary role of proguanil
in Malarone may not be as an antifolate. Although the mechanism is unclear, there is profound antimalarial synergy when
atovaquone and proguanil are combined.
Development of drug combination strategies, dose-ranging
preclinical and clinical studies, and pivotal efficacy trials were
organized by Walter Reed Army Institute of Research in partnership with GlaxoSmithKline. Atovaquone was consistently
effective in clearing parasitemia in uncomplicated P. falciparum
malaria, but recrudescence rates up to 25% precluded further
development as monotherapy. After studies at the Armed Forces
Research Institute of Medical Sciences confirmed synergy between atovaquone and proguanil, coadministration trials conducted at various sites, including Walter Reed Army Institute
of Research laboratories in Brazil and Kenya, demonstrated
99% efficacy for treatment of uncomplicated multidrugresistant malaria and 98% efficacy for prophylaxis in placebocontrolled trials. Additional prophylaxis studies were completed
by the Naval Medical Research Unit-2 in Jakarta, Indonesia.
Although Malarone has few adverse effects other than mild
gastrointestinal intolerance, experience with this expensive drug
is limited. Rapid development of drug resistance related to
mutations mostly arising in the cytochrome b gene of P. falciparum has been noted when Malarone has been used as malaria monotherapy [31].
Acknowledgments
Financial support. US Army Medical Research and Materiel Command.
Potential conflicts of interest. All authors: no conflicts.
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