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Treatment Options and Drug Resistance
In 1955, the World Health Organization (WHO) implemented a program to eradicate malaria through the use of the new drug chloroquine and widespread spraying of the insecticide DDT. By 1970, the majority of North America, southern Europe and the former Soviet Union were malaria-free, and many parts of Asia and South America were well on their way to becoming so. Just as WHO was on the brink of success, however, Plasmodium became resistant to chloroquine at the same time that Anopheles mosquitoes became DDT-resistant (DeSalle, 1999). Although there are several antimalarial drugs in existence today, they are all slowly failing due to the quick spread of drug resistance. Though the disease is certainly exacerbated by poverty and inadequate health systems in these countries, the main cause of its severity the failure of antimalarial drugs due to the spread of resistance (Hoffman, 2000).
For centuries, quinine has been the most common drug used in treating malaria. Quinine interrupts Plasmodium’s life cycle at the merozoite stage, when it emerges from the liver and begins invading red blood cells. As the parasite devours hemoglobin found in the red blood cells, it releases toxic hemazoin. To protect itself from the hemazoin, the merozoite stores it as malaria pigment. Quinine prevents merozoites from producing the malaria pigment and causes the parasites to essentially "choke on the products of their own digestion” (Honigsbaum, 2002).
While there has not been any documented resistance to quinine, the drug has several limitations that prevent it from being a permanent solution for malaria treatment (White, 1999). First, and most importantly, quinine has no effect on Plasmodium’s gametocytes and therefore is cannot completely prevent tranmission of malaria (Honigsbaum, 2002). In addition, many side effects develop after quinine is used for extended periods of time: headaches, nausea, ringing in the ears, and, in the case of severe falciparum malaria, blackwater fever, an autoimmune disease in which the body’s supply of hemoglobin suddenly breaks down (Honigsbaum, 2002).
Chloroquine became the drug of choice for malaria treatment during World War II, and it soon came to be known as the “magic bullet,” a “fast-acting, easy-to-administer prophylactic that afforded complete protection against all forms of malaria.” Like quinine, chloroquine is primarily a blood schizontocide that destroys the parasite as it invades the red blood cells. But unlike quinine, it can also prevent transmission of Plasmodium gametocytes. However, by the end of the 1960s, the malaria parasite developed resistance to the chloroquine (Honigsbaum, 2002).
P. falciparum resistance first developed in Southeast Asia and South America in the late 1960s, and since then, it has spread to virtually every corner of the world. Despite this widespread resistance, chloroquine is still the most commonly used antimalarial drug in the world, with between 200 and 400 million people taking it each year (White, 1999). The situation is especially serious in sub-Saharan Africa, as chloroquine is still widely used throughout the majority of the area. The development of chloroquine resistance is particularly serious because for decades, it served as the cheapest and most reliable treatment for malaria. As a result, the medical community has been hard-pressed to develop new antimalarial drugs that are effective against chloroquine-resistant parasites (Rathod et al., 1997).
During WHO’s malaria eradication campaign, DDT was the primary drug used to kill Anopheles mosquitoes. This was successful until the 1970s, when DDT-resistant strains of Anopheles mosquitoes began to appear in South and Southeastern Asia, South and Central America, and Africa. DDT spraying essentially ended when the United States banned it in 1982, following a “vociferous campaign” by environmentalists (Honigsbaum, 2002).
Several common antibiotics can confer protection from malaria. This works because Plasmodium has an apicoplast, an organelle associated with enzymes in plant and bacterial metabolic pathways that is essential for the malaria parasite to function. The apicoplast has its own circular DNA, similar to that found in mitochondria and chloroplasts, which encodes proteins needed for transcription and translation. This activity makes malaria susceptible to antibiotics such as doxycycline and azithromycin, which hinder protein synthesis in bacteria (Ridley, 1999).
Mefloquine has been primarily used in Southeast Asia and South America since the 1980s to treat uncomplicated multi-drug-resistant falciparum malaria, as there seems to be an inverse relationship between mefloquine and chloroquine resistance.” Although mefloquine had only been used since 1984, where it was first deployed in Thailand, resistance developed very rapidly, especially in comparison to chloroquine resistance. Despite careful use, a significant decline in sensitivity to mefloquine was noticed a mere six years after it was first used (White, 1999).
One of the newest drugs to enter the market is atovaquone, which is usually used in combination with proguanil, as the two drugs are synergistic (White, 1999). Although atovaquone-proguanil is not widely available, it has been shown to be highly effective on all parasites and is manufactured by GlaxoSmithKline as Malarone (Honigsbaum, 2002)
Atovaquone works differently from the majority of antimalarial agents in use today, in that it inhibits Plasmodium’s mitochondrial activity rather than attacking the parasite in a specific stage of its life (Rathod et al., 1997). However, commonly found point mutations in Plasmodium’s cytochrome b gene greatly reduce the parasite’s susceptibility to atovaquone, as it allows the electron transport chain mechanism to continue. In addition, experiments have shown that it is easy to create resistance to atovaquone. While the atovaquone-proguanil combination increases the chances of eliminating resistant parasites, the protection is limited because proguanil is a very weak antimalarial (White, 1999).
5-Fluorooroate is one of the most potent new drugs, as it has been effective against all strains of malaria. Like atovaquone, it acts differently from all other antimalarials currently in use, and because it has never been tested in the field, there is no resistance to it whatsoever. However, because 5-fluorooroate must undergo at least five metabolic transformations before it arrives at its toxic form, there is high probability that resistance will develop (Rathod, 1997).
Although artemisinin has been used in China for over 2,000 years, it was only recently “discovered” by the rest of the world. However, it is being used increasingly in malaria endemic areas and has the potential to become the most potent antimalarial in decades (White, 1999; Marshall, 2000). Artemisinin and its derivatives come from the plant Artemisia annua and are effective against all strains of malaria, including multi-drug-resistant falciparum malaria (White, 1999).
Artemisin's effectiveness comes from its water-insoluble, crystalline structure, which includes two oxygen atoms that are “like a bomb waiting to explode.” The iron found in the heme Plasmodium releases when it invades red blood cells triggers the explosion of this bomb. Therefore, when the malaria parasite comes into contact with artemisinin, it essentially falls apart. Artemisinin reduces the number of malaria parasites in the body by almost 10,000 times more than the other drugs in use, even though it is only used for three days. At the end of this three-day regime, usually only 0.01% of the parasites remain (White, 1999).
Artemisinin has the additional benefit of having few side effects, which encourages compliance to treatment, and unlike many antimalarials, it can reduce gametocyte transmission from humans to mosquitoes. This reduced transmission translates into reduced incidence of malaria, and therefore less drug use, which eventually results in a decrease in drug resistance (White, 1999).
Thus far, no resistance to artemisinin has been documented, either in the lab or in the field. Consequently, artemisinin and its derivatives are the first-line drugs used in Southeast Asia, especially in Vietnam and Thailand, where they have been in use for almost ten years. If artemisinin is used carefully, resistance should not develop in the near future (White, 1999)
Artesunate, the most rapidly-acting artemisinin derivative, clears falciparum parasites from the blood faster than any other antimalarial, according to researchers at the U.S. Naval Medical Research Center (Marshall, 2000). While the drug is used extensively in China, Vietnam, and Thailand, it has been difficult to find a Western pharmaceutical company to manufacture artesunate, as it is no longer patentable because it was first isolated in China (Honigsbaum, 2002). However, WHO has finally taken artesunate under its wing and is working with researchers to provide a “rectocap,” or rectal artesunate suppository, which they hope to distribute to rural areas for use in emergencies (Marshall, 2002).
P. falciparum home
DeSalle, Rob. 1999. Epidemic! The World of Infectious Diseases. New York: The New Press.
Hoffman, Stephen L. 2000 “Research (genomics) is crucial to attacking malaria.” Science, New Series 290: 1509.
Honigsbaum, Mark. 2002. The Fever Trail: In Search of the Cure for Malaria. New York: Farrar, Straus, & Giroux.
Marshall, Eliot. 2000. “Reinventing an ancient cure for malaria.” Science, New Series 290: 437-39.
Rathod, P. K., T. McErlean, P. Lee. 1997. “Variations in frequencies of drug resistance in Plasmodium falciparum.” Proceedings of the National Academy of Sciences of the United States of America 94: 9389-9393.
Ridley, Robert G. 1999. “Planting the seeds of new antimalarial drugs.” Science, New Series 285: 1502-03.
White, Nicholas. 1999. “Antimalarial drug resistance and combination chemotherapy.” Philosophical Transactions: Biological Sciences 354: 739-49.
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