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MALARIA

~          ~          ~

Treatment & Prevention

 

 

 

~History                         ~Early Remedies              ~Antimalarial Drugs

~Drug Resistance             ~Treatment Approaches   ~Challenges 

~Advances                      ~Research & Development ~Vaccine?

~Helpful Websites            ~Sources

 

 

 

 

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

http://www.who.int/tdr/

 

 

 

 

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