MALARIA
~ ~ ~
Treatment & Prevention
~History ~Early Remedies ~Antimalarial Drugs
~Drug Resistance ~Treatment Approaches ~Challenges
~Advances ~Research &
Development ~Vaccine?
History
For
as many thousands of years as humans have been falling sick with malaria,
remedies have been used in all corners of the world to treat the symptoms of
the disease. In China, the herb qinghao (Artemesia annua) was used to bring down malarial fevers,
while the bark of the Peruvian cinchona tree was used to cure malaria in the Americas well before the
arrival of Europeans on the continent.
Jesuit missionaries in South America recognized the effective
antimalarial use of cinchona
bark and brought their newly borrowed remedy back to Europe in the mid-1600s,
which then appeared in India only decades later. By the 19th century, this miraculous medicine was
grown commercially on colonial Dutch plantations in Indonesia, where the Dutch
maintained a monopoly over the drug, by then known as quinine, until they lost the colony to the Japanese
during World War II. A subsequent
shortage of quinine during the war made apparent the need to develop alternate
antimalarial drugs, a scientific process that began in the 1940s and continues
today with integrated control programs incorporating both treatment and
prevention.
Early Remedies
The
roots of this process of scientific discovery began in the 1880s when French
and Italian researchers first identified the Plasmodium parasite, then established the mosquito
transmission hypothesis, proving that human malaria is transmitted by the Anopheles mosquito. Syphilis-curing properties of malaria were discovered and
employed early in the 20th century and led to an improved
understanding of the life cycle of the parasite. With the quinine shortage of World War II, an increased
demand for antimalarials, and a better understanding of the malaria parasite in
the human host, scientists in the 1940s developed the first synthesized
antimalarial drug which was marketed as chloroquine.
Malaria control programs began soon after and combined mosquito control,
using the toxic pesticide DDT, with treatment and prevention programs, using
chloroquine and quinine. The
United States, along with international organizations such as the World Health
Organization and the United Nations Development Program, embarked upon a series
of global malaria eradication projects in the 1950s and 1960s, but hesitated as
soon the obstacle of widespread chloroquine resistance in the malaria parasite
appeared. The projects aimed at
malaria eradication then became projects aimed at comprehensive malaria
containment and control.
In the last decade,
malaria control has been based on four principles:
· early diagnosis and treatment
· selective and sustainable preventive
measures, including vector control
· detection, containment and prevention of
epidemics
· building up of local capacity
Antimalarial Drugs
Since the development
of chloroquine, scientific advancements have resulted in a wide selection of
antimalarial drugs that are now used for both malaria prevention and treatment
of malaria already in the human host.
The most pressing challenge to malaria treatment and prevention is the
development of Plasmodium resistance to many antimalarial drugs in many
parts of the world. Changing
resistance patterns provide a constant motivation for researchers to develop
new drugs and prevention strategies.
These resistances must be taken strongly into account when browsing the
antimalarial pharmacy shelf.
Currently, there are three stages of therapy that go along with
advancing stages of malaria infection and disease:
· Suppressive therapy
· Chemoprophylaxis that attempts to destroy
the parasite in its erythrocytic stage as it enters blood stream
· Clinical cure:
· When suppressive therapy has failed and
larger doses of prophylactic drugs are used to eliminate erythrocytic parasites
· Radical cure
· When clinical cure has failed and stronger
drugs are used to eliminate blood stream infection and tissue stages in the
liver
The
available drugs are used for all three types of therapy and treatment and target
various stages of Plasmodium
development. Different Plasmodium species respond differently to each drug,
so it is impossible to say which drug should be used across the board for any
stage or species. Blood
schizonticides are
widely available and are used most frequently, targeting the asexual
reproduction stage of the parasite.
Tissue schizonticides
target the parasite’s developmental stage in the liver and are less
available and less effective in most species. Gametocyticides target parasite immature and mature gametocytes, but are not
widely effective in most species.
Most commonly used antimalarial drugs are blood schizonticides that
destroy the erythrocytic parasite during the stage when clinical symptoms
result. They generally target the
lysosomal food vacuole, the apicoplast, or an acrystate mitochondrion of the
erythrocyte.
The
categories and uses of antimalarial drugs can be confusing, but an overview
should set things straight. This
list is not complete but includes the most common drugs. Almost all are used as chemoprophylactics, that is to say that they are taken prior
to mosquito exposure to prevent disease symptoms from manifesting themselves,
especially in travellers to endemic areas. They are also used at various doses to treat people with
already developing disease, and are then given in full doses as soon as
symptoms appear. These drugs are
essential to save the lives of millions of people with malaria. In endemic regions where money is
scarce, drugs range in price from US$ 0.13 for a full adult preventive course
of chloroquine to US$1-$3 for artemisinin-based drugs. Though the pharmacy is extensive, few
of the people at risk have access to quality health care services that provide
them. Keep in mind where drug resistance appears:
· QUINOLINES
· From Peruvian Cinchona bark
· Have a long history of antimalarial use
· Originally extracted and used as quinine, the only known antimalarial until the
1940s
· Synthetic forms are 4-aminoquinoline
antimalarials, including chloroquine and amodiaquine, the safest, most effective, and cheapest
antimalarials available
· Amodiaquine is sometimes used when there is
chloroquine resistance
· Mefloquine, also known as Lariam, and halofantrine are structurally related and are active
against chloroquine resistant strains, but resistance to these can also develop
rapidly
· Mefloquine has potential neuropsychotic side
effects and halofantrine is bad for history of heart disease
· PROBLEM: Quinine, mefloquine, halofantrine, and amodiaquine have
strong side effects, especially during pregnancy, chloroquine has widespread
resistance, while the others have limited and increasing resistance
· ARTEMISININS
· From Chinese Qinghao herb (Artemesia annua)
· Have a long history of antimalarial use
· Synthetic forms are artemether, arteether, and artesunate
· Fast-acting against gametocytes, the sexual
stage parasites that infect mosquitoes
· Used in combination with other drugs to be
more effective and to reduce chance of developing resistance to either drug
· No significant drug resistance
· PROBLEM: Significantly more expensive than other antimalarials and
complex drug regimens are costly and difficult to administer
· ANTIFOLATES
· No plant origin
· Synthesized as sulphadoxine and pyrimethamine
· Used in combination because the two act
synergistically and reduce chance of developing resistance
· PROBLEM: Drug resistance develops rapidly and drugs can have strong
side effects
· ATOVAQUONE/PROGUANIL
· Similar to antifolates
· Used in combination because the two act
synergistically and reduce chance of developing resistance
· PROBLEM: Drug resistance develops rapidly and synthesis is
complicated, so drug is very expensive and not widely used as a prophylactic
· ANTIBIOTICS
· Common multi-use drugs that act against
bacterial protein synthesis
·
Tetracycline, doxycycline, and clindamycin are used increasingly in combination with
other antimalarials to improve their efficacy
For
those people already showing symptoms of malaria, a drug regimen is chosen
based on a variety of criteria and given the local malaria conditions:
· Drug resistant parasite
· Prior chemoprophylaxis
· Other illnesses
· Allergies
· Cost and availability of drugs
· Age
· Pregnancy
· Likely compliance
· Risk of reexposure
Drug Resistance
Despite this wide variety of antimalarial
drugs, malaria control using drug treatments has not been widely successful in most endemic
areas. When chloroquine was
developed and distributed along with quinine in the 1950s and 1960s, global
incidence of malaria dropped sharply, so much so that eradication seemed
possible. The drugs were very
effective for many years, but drug resistance eventually appeared as the Plasmodium parasite no longer responded to the
antimalarial drugs, particularly in South America and Southeast Asia. Around the same time, resistance to
insecticides began to appear in certain species of the Anopheles mosquito, increasing pressure for
alternative control methods.
Development of drug resistance in parasites is likely due to overuse of
the antimalarials in certain areas, especially areas of low transmission. The most common form of resistance is
in the most common malaria species, P. falciparum, to chloroquine. Today, chloroquine resistant P. falciparum exists in all areas except the Middle East,
Egypt, Central America west of the Panama Canal, Mexico, Haiti, and the
Dominican Republic. Chloroquine
resistant P. vivax exists in India, Papua New Guinea,
Indonesia, Myanmar, and the Solomon Islands. Resistance to sulphadoxine and pyrimethamine, the other
most-commonly used drug regimen, has appeared more recently in many areas.
A map shows
resistance to these two drugs compared to endemic malaria zones. Notice that resistance to at least one
of the two common drugs exists in almost every endemic zone:
Map: Global status of resistance to chloroquine
and sulphadoxine/ pyrimethamine, the two most widely used antimalarial drugs.
Data are from the WHO.
Source: Ridley, Robert G. “Medical need, scientific
opportunity and the drive for antimalarial drugs.” Nature 415, 686 - 693 (2002).
The
following chart illustrates the effects of chloroquine resistance based on a
study in all affected African countries:
Source: Roll Back Malaria 2003
Report, http://mosquito.who.int/cgi-bin/rbm/dhome_rbm.jsp?ts=3231124769&service=rbm&com=gen&lang=en
These
charts illustrate the effects of the increase of chloroquine resistance in
recent decades on child mortality and the positive results of training mothers
in chloroquine administration:
Source: Roll Back Malaria 2003 Report, http://mosquito.who.int/cgi-bin/rbm/dhome_rbm.jsp?ts=3231124769&service=rbm&com=gen&lang=en
Mefloquine,
a frequently used alternative drug to chloroquine where chloroquine resistance
exists, has resistance of its own, particularly in along the Thailand-Myanmar
border, on Irian Jaya, in the Philippines, and in some parts of Africa. The drug is not as cheap, safe, or
effective as chloroquine, but is often the best alternative in chloroquine resistance
areas. Also knows as lariam, this
drug can have neuropsychotic side effects that range from so-called
“vivid dreams” to acute psychoses and convulsions and is unsafe
during early months of pregnancy.
However, these side effects are not common and the Centers for Disease
Control maintains that “mefloquine prophylaxis is safe, is well
tolerated, and has saved thousands of lives.”
Treatment Approaches
One of the critical elements of malaria control is prompt and
effective treatment. In Sub-Saharan Africa
where most malaria is potentially fatal, early treatment could save millions of
lives. As soon as symptoms appear,
patients should start treatment immediately to prevent development of severe
and cerebral malaria, which often leads to death. The major obstacle to rapid and effective treatment is the
lack of health care infrastructure and medication in most malaria-endemic
areas. When health care systems
are weak, access to drugs for both treatment and prevention is limited and
often dependent on non-state actors.
Even where services and medications are available, early diagnosis is
not always possible because symptoms do not always appear and can be confused
with other illnesses. As a
precautionary measure, the WHO recommends that all children under 5 years with
fevers be treated with antimalarials, an increasingly common practice in many
countries. However, problems arise
when resistance to those antimalarials develops. The following chart present this data:
Source: Roll Back
Malaria 2003 Report, http://mosquito.who.int/cgi-bin/rbm/dhome_rbm.jsp?ts=3231124769&service=rbm&com=gen&lang=en
Increasing
resistance to many of the available antimalarial drugs presents a tremendous
challenge to public health and pharmaceutical sectors. With continually changing resistance
patterns, treatment of the 500 million people already sick with the disease is
as much of a dilemma as preventing new infections in the 2 billion people at
risk and taking measures to prevent even more drug resistance from
developing. In addition to
preventive public health measures such as bednet protection and mosquito control
(see PUBLIC HEALTH section, link on Homepage), innovative treatment methods and
drug and vaccine research and development hold the hope for an effective
solution to the global malaria crisis.
Robert Ridley from Medicines for Malaria Venture comments that:
“Unfortunately, malaria
is a disease of poverty, and despite a wealth of scientific knowledge there is
insufficient market incentive to generate the competitive, business-driven
industrial antimalarial drug research and development that is normally needed
to deliver new products.
Mechanisms of partnering with industry have been established to overcome
this obstacle and to open up and build on scientific opportunities for improved
chemotherapy in the future.”
This
challenge has recently been undertaken by a handful of large-scale partnering
efforts between pharmaceutical companies, non-governmental organizations, and
international governmental organizations.
These include the World Health Organization’s three main projects
that bring together innovative research with public health efforts:
· Multilateral Initiative on Malaria
http://www.who.int/tdr/diseases/malaria/mim.htm
· Medicines for Malaria Venture
http://www.who.int/tdr/diseases/malaria/mmv.htm
· Roll Back Malaria
http://mosquito.who.int/cgi-bin/rbm/dhome_rbm.jsp?ts=3231124769&service=rbm&com=gen&lang=en
Challenges
The
problems regarding malaria treatment and prevention are many and are only
compounded by the increasing drug resistance of the parasite. Without even accounting for resistance,
over half the population in endemic parts of Africa does not have access to
health care services, which means that they have no access to antimalarial
treatment. The reasons for this
lack of access are the same as in many developing countries:
· Inadequate financing
· Poor health care delivery systems
· Weak drug regulation
Where
health care facilities are accessible, stocks of antimalarials drugs often run
dry:
Source: Roll Back Malaria 2003
Report, http://mosquito.who.int/cgi-bin/rbm/dhome_rbm.jsp?ts=3231124769&service=rbm&com=gen&lang=en
Unlike
treatments for other diseases like HIV/AIDS, malaria treatments are relatively
inexpensive, even for poor countries:
Average
cost of a full course of adult outpatient treatment:
Chloroquine US$
0.13
Sulphadoxine/pyrimethamine US$
0.14
Amodiaquine US$
0.20
Artemisinin-based combinations US$ 1-3
As these prices indicate, antimalarial
treatments are generally highly cost-effective, often more so than preventive
measures like insecticide-impregnated bednets. Note that the three cheapest drugs, which are the most
commonly used in endemic areas, are also the main drugs to which drug
resistance is rapidly developing.
This is not a coincidence, seeing as resistance develops due to the
overuse of antimalarial drugs. Artemisinin-based drugs have less resistance but
are also significantly more costly, perhaps too much to be useful in
resource-poor countries. Public
health sectors now face a serious dilemma in which they are hesitant to use
antimalarials to prevent malaria and treat patients because resistance will
likely develop and make the situation worse, but they cannot afford to purchase
multiple and expensive alternative drugs.
If more drugs were available, specific drug combinations could be used to effectively treat malaria
and avoid development of resistance.
The severity of this dilemma calls for effective, affordable, and appropriate drugs to meet the challenge of new
resistance.
Research & Development
Where do we go from here? The goals of the global campaign to
control malaria from a pharmaceutical perspective are many:
· Continue to pursue increased treatment and
prevention
· Develop existing technologies
· Pursue new research and development
Unfortunately, pharmacuetical commitment to these goals is not as
strong as it could be. Because resistance
poses such an obstacle to drug sales and development and because malaria is
worst in poor countries that often do not offer an attractive market,
pharmaceutical companies commit less money and resources to malaria control
than they have the potential to do.
According to Jeffrey Sachs, who claims that NO major pharmaceutical
company is committed to malaria drug development:
“Total
worldwide spending on malaria drug and vaccine research is less than $100
million, which is less than one-seventh of 1% of the $70 billion or more of
annual worldwide biomedical R&D, for a disease that accounts for about 3%
of the worldwide disease burden as measured by disability-adjusted life
years.”
Advances
The beacon of hope
for malaria control is the potential for the development of a vaccine. A breakthrough came in 2002 with the
complete mapping of the Anopheles gambiae and Plasmodium falciparum genomes. This is a tremendous step that opens
many doors for drug and vaccine development targeting both the mosquito vector
and the human host. It is the most
recent development in a series of breakthroughs in understanding parasite
biology, host-parasite interactions, immunity, and drug resistance.
Potential
vaccines draw upon many different approaches using DNA genomic technology,
reverse immunogenetics to target the malarial blood stage, pre-erythrocytic
stage, and vector to human transmission.
Before any potential vaccine can be administered, it will have to go through
a standard period of testing and trials that can take up to 10 years.
Vaccine?
An
effective malarial vaccine will need to combine many approaches and be
multicomponent, but is expensive to develop. Potential innovative vaccines include oral immunization to
induce host immunity and use of transgenics to incorporate the vaccine into an
edible plant form. Despite the
high and often prohibitive cost of vaccine development, a recent study suggests
that an effective vaccine is more cost effective than other control methods
such as insecticide-impregnated bednet use because the cost per death averted
with the vaccine is lower than with use of bednets. For more information on vaccine research, see http://www.blackwell-synergy.com/links/doi/10.1046/j.1365-3083.2002.01160.x/full/.
FOR
MORE INFORMATION CONTACT eflynn@stanford.edu
Helpful Websites
Centers for Disease Control
http://www.cdc.gov/ncidod/diseases/submenus/sub_malaria.htm
World Health Organization
http://www.who.int/health_topics/malaria/en/
Tropical Disease Research
Sources
Desowitz,
Robert S. The Malaria Capers (More Tales of Parasites and People, Research and
Reality). W.W. Norton & Company, New York, 1991..
Graves,
PM. “Comparison of the
cost-effectiveness of vaccines and insecticide impregnation of
mosquito
nets for the prevention of malaria.” Annals of Tropical Medicine & Parasitology, Vol. 92, No. 4, 399-410
(1998).
Hastings
IM. “Malaria control
and the evolution of drug resistance: an intriguing link.” Trends
Parasitol.
2003 Feb;19(2):70-3.
Kager PA. “Malaria control: constraints and
opportunities.” Trop Med
Int Health. 2002
Dec;7(12):1042-6.
Markell,
E, John, and Krotoski, Medical Parasitology, WB Saunders Co, 1999, p.
109-121.
Miller, Louis H. and Brian Greenwood. “Malaria—a shadow over
Africa.” Science 298 (5591): 121.
Provisional
Data Report on Malaria Surveillance, Centers for Disease Control, http://www.cdc.gov/ncidod/dpd/parasites/malaria/malarone.htm.
Ridley,
Robert G. “Medical need,
scientific opportunity and the drive for antimalarial drugs.” Nature 415, 686 - 693 (2002).
http://www.pnas.org/cgi/content/full/99/21/13362.
Roll
Back Malaria, http://mosquito.who.int/cgi-bin/rbm/dhome_rbm.jsp?ts=3231132306&service=rbm&com=gen&lang=en
Sachs,
JD, “A New Global Effort to Control Malaria.” Science 2002 Oct 4; 298 (5591):
122-4.
Tropical
Disease Research Malaria Project, http://www.who.int/tdr/diseases/malaria/default.htm.
Wang, L., et al. “Oral Immunization with a Recombinant Malaria Protein
Induces Conformational Antibodies and Protects Mice against Lethal
Malaria.” Infection and
Immunity, May 2003, pp 2356-2364, Vol. 71, No. 5.
Images
Borrowed from
the following websites:
http://www-nt.who.int/tropical_diseases/databases/imagelib.pl (many images)
http://news.bbc.co.uk/1/hi/sci/tech/2288795.stm
http://www.brown.edu/Courses/Bio_160/Projects1999/malaria/ph.html
www.who.int/tdr/publications/
tdrnews/news59/genome.htm
http://www.malariasite.com/malaria/Res.jpg
http://flora.huh.harvard.edu/china/mss/plntmedi.htm
http://sres.anu.edu.au/associated/fpt/nwfp/quinine/c-pubescens2.jpg
http://scarab.msu.montana.edu/historybug/references/h-o.htm
http://w3.whosea.org/malaria/19.htm