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Pharmacology => Drug => Malaria
Malaria
INTRODUCTION
Malaria, debilitating infectious disease caused by single-celled parasites, characterized by chills, shaking, and periodic bouts of intense fever. Malaria is transmitted from person to person by the bite of female mosquitoes.
Although malaria was once widespread in North America and other temperate regions, the last major outbreak of malaria in North America occurred in the 1880s. The disease today is limited mostly to tropical and subtropical countries, particularly sub-Saharan Africa and Southeast Asia. According to the World Health Organization, malaria is prevalent in over 100 countries. Each year, between 400 million and 600 million cases of malaria are diagnosed, and 1.5 million to 2.7 million people die of the disease. In recent years, malaria has become more difficult to control and treat because malaria parasites have become resistant to drugs, and mosquitoes that transmit the disease have become resistant to insecticides.
CAUSES AND SYMPTOMS
Malaria in humans is caused by four species of single-celled parasites, all members of the genus Plasmodium. Plasmodium falciparum is the most common species in tropical areas and is transmitted primarily during the rainy season. This species is the most dangerous, accounting for half of all clinical cases of malaria and 90 percent of deaths from the disease. Plasmodium vivax is the most widely distributed parasite, existing in temperate as well as tropical climates. Plasmodium malariae can also be found in temperate and tropical climates but is less common than Plasmodium vivax. Plasmodium ovale is a relatively rare parasite, restricted to tropical climates and found primarily in eastern Africa.
Malaria is transmitted by mosquitoes of the genus Anopheles. About 60 of the world's 390 species of Anopheles mosquito are known to transmit the malaria parasite. However, only a dozen species are important in the transmission of malaria worldwide, and usually just one or two species are responsible for transmission in each region where the disease is prevalent.
Malaria transmission begins when a mosquito bites an infected human and ingests blood containing the malaria parasite. Inside the mosquito's stomach, the parasites quickly develop into mature male and female gametes, or sex cells. The male gametes and female gametes fuse, producing a cell known as a zygote. The zygotes then enter the wall of the mosquito's gut and develop into oocysts. The oocysts multiply, each producing thousands of cells known as sporozoites. The sporozoites leave the wall of the gut and migrate to the mosquito's salivary glands. The mosquito phase of the malaria parasite's life cycle is normally completed in 10 to 14 days, but the process occurs more slowly at cooler temperatures. The development of Plasmodium falciparum is particularly sensitive to low temperatures, preventing transmission of this parasite in temperate climates except during summer.
Sporozoites in a mosquito's saliva are transmitted when the mosquito bites another human being. Once inside the human body, the parasites are carried by the blood to the liver, where they take up residence in liver cells. There, the parasites divide many times, producing 30,000 to 40,000 parasites over the course of one to two weeks. In Plasmodium vivax and Plasmodium ovale infections, some parasites can remain dormant in the liver for 3 months to 5 years. This phenomenon is responsible for the malaria relapses that often occur with Plasmodium vivax and Plasmodium ovale infections. Scientists believe that this dormancy allows these two species to survive in temperate climates, where mosquitoes are available to transmit the parasite during only part of the year.
After multiplying in the liver, the parasites enter the bloodstream. The intermittent fever that characterizes malaria is caused by this stage of the parasites' development. The parasites enter red blood cells and multiply until the red cells burst, releasing into the bloodstream a new generation of parasites that go on to infect other red cells and multiply yet again. The destruction of the red cells also spills wastes, toxins, and other debris into the blood, setting off an episode of fever. The episode begins with sudden, violent chills, which are soon followed by an intense fever and then profuse sweating that brings the patient's temperature down again. In a first infection, the episodes of fever frequently last 12 hours and usually leave an individual exhausted and bedridden. Chronic infections can lead to severe anemia, a decrease in the concentration of red cells in the bloodstream, because the malaria parasite consumes or renders unusable the proteins and other vital components of the patient's red cells.
The recurrence of intermittent fever depends on which species of Plasmodium is responsible for the infection. In fact, since early Roman times-long before scientists knew that malaria could be caused by four different species of parasite-people have distinguished different types of malaria by the frequency of the intermittent fever. Infections caused by Plasmodium falciparum and Plasmodium vivax are known as tertian malaria because the fever occurs approximately every 48 hours, so the episodes of fever develop every first and third day .
Infections caused by Plasmodium falciparum are known as malignant tertian malaria because of their severity and high fatality rate. Plasmodium falciparum malaria can also cause severe headaches, convulsions, and delirium, and sometimes develops into cerebral malaria. In cerebral malaria, red blood cells infected with parasites attach to tiny blood vessels in the brain, causing inflammation and blocking the flow of blood and oxygen. The disease caused by Plasmodium vivax is known as benign tertian malaria because it is usually less severe. Infections caused by Plasmodium malariae are called quartan malaria because the fever recurs every 72 hours, or every fourth day.
DIAGNOSIS AND TREATMENT
Malaria is difficult to diagnose based on symptoms alone. This is because the intermittent fever and other symptoms can be quite variable and could be caused by other illnesses. A diagnosis of malaria is usually made by examining a sample of the patient's blood under the microscope to detect malaria parasites in red blood cells. The different species of Plasmodium can be distinguished by their appearance under the microscope. Parasites can be difficult to detect in the early stages of malaria, in cases of chronic infections, or in Plasmodium falciparum infections because often in these cases, not many parasites are present. Recent advances have made it possible to detect Plasmodium proteins or genetic material in a patient's blood.
Malaria is treated with drugs that block growth of the Plasmodium parasite but do not harm the patient. Some drugs interfere with the parasite's metabolism of food, while others prevent the parasite from reproducing. Drugs that interfere with the parasite's metabolism are related to quinine, the first known antimalarial drug. Quinine is a chemical derived from the bark of the South American cinchona tree and was used as a fever remedy by the ancient Incas. This drug has a bitter taste; produces severe side effects, such as nausea, headache, ringing in the ears, temporary hearing loss, and blurred vision; and large doses can be fatal. However, quinine is still sometimes used in treating malaria today, particularly in developing nations, because it is inexpensive and effective.
Chloroquine is a synthetic chemical similar to quinine. It became the drug of choice for malaria when it was developed in the 1940s because it was effective, easy to manufacture, and lacked most of the side effects of quinine. However, in the last few decades, malaria parasites in many areas have become resistant to chloroquine. Presently, it is effective against malaria only in some parts of Central America and the Middle East. Mefloquine is another drug related to quinine that is still largely effective, but for many people, especially those living in developing nations, it is too expensive to use routinely.
The other important class of antimalarial drugs depends on a unique aspect of Plasmodium biology. In order to copy its genetic material and reproduce, the malaria parasite must obtain compounds similar to the vitamin folic acid from its human host. Drugs that prevent the parasites from properly metabolizing these compounds inhibit the reproduction of the parasites. In recent years the parasites have developed resistance that diminishes the effectiveness of these drugs, known as antifolate drugs, when they are used individually. Antifolate drugs can still be effective when given in combination with each other or with other types of antimalarial drugs, because an individual malaria parasite is not likely to be resistant to multiple drugs. Combination drugs are very expensive, however, and are only used in particularly severe cases of malaria.
IMMUNITY
After repeated infections, people who live in regions where malaria is prevalent develop a limited immunity to the disease. This partial protection does not prevent people from developing malaria again, but does protect them against the most serious effects of the infection. These individuals develop a mild form of the disease that does not last very long and is unlikely to be fatal.
Most of the deaths and severe illnesses caused by malaria occur in infants, children, and pregnant women. Infants and children are vulnerable because they have had fewer infections and have not yet built up immunity to the parasite. Pregnant women are more susceptible to malaria because the immune system is somewhat suppressed during pregnancy. In addition, the malaria parasite uses a specific molecule to attach to the tiny blood vessels of the placenta, the tissue that nourishes the fetus and links it to the mother. After exposure to this molecule during her first pregnancy, a woman's immune system learns to recognize and fight against the molecule. This phenomenon makes a woman particularly vulnerable to malaria during her first pregnancy, and somewhat less susceptible during subsequent pregnancies.
Some people have genetic traits that help them resist malaria by preventing the parasites from growing and developing normally, even in people who are infected with malaria for the first time. Sickle-cell anemia and thalassemia are two inherited blood diseases that are linked to malaria resistance. People with two sickle-cell or thalassemia genes become seriously ill and often die in childhood if their disease is untreated. But people who have only one sickle-cell or thalassemia gene do not develop the genetic disorder and are, in fact, resistant to malaria. Various sickle-cell or thalassemia genes are widespread among people in Africa, the Mediterranean region, the Middle East, India, and Southeast Asia.
Another genetic condition that results in an increased resistance to malaria is ovalocytosis. In ovalocytosis, a protein found in the membrane of red blood cells is abnormal, causing these cells to have an oval shape. This trait, which is common in Southeast Asia and the Pacific Islands, causes chronic anemia but protects people from developing cerebral malaria. Finally, Plasmodium vivax cannot infect people whose red cells lack the Duffy antigen, a protein that is usually found on the surface of red cells. This trait, known as Duffy negativity, is common in people of African ancestry and causes no apparent health problems.
PREVENTION AND CONTROL
Malaria can be prevented by two strategies: eliminating existing infections that serve as a source of transmission, or eliminating people's exposure to mosquitoes. Eliminating the source of infection requires aggressive treatment of people who have malaria to cure these infections, as well as continuous surveillance to diagnose and treat new cases promptly. This approach has been successful in areas such as North America and Europe where malaria is not common. However, it is not practical in the developing nations of Africa and Southeast Asia, where malaria is prevalent and governments cannot afford expensive surveillance and treatment programs.
Eliminating exposure to mosquitoes, the second strategy, can be accomplished by several means. These means are permanently destroying bodies of stagnant water where mosquitoes lay their eggs; treating such habitats with insecticides to kill mosquito larvae; fogging or spraying insecticides to kill adult mosquitoes; or using mosquito netting or protective clothing to prevent contact with mosquitoes. In 1947, the United States initiated a program to eliminate exposure to malaria-carrying mosquitoes. The program involved applying the insecticide DDT to the interior walls of homes, where female mosquitoes typically rest after feeding. Within five years, this program virtually eliminated illness and death due to malaria in the United States.
In 1950, the World Health Organization (WHO) adopted a similar indoor spraying program with the goal of eradicating malaria worldwide within eight years. However, budget considerations limited preliminary research, and the program did not take into account the complex differences in the patterns of malaria transmission in different parts of the world. The eradication program was very successful in some countries, particularly island nations such as Sri Lanka, but in other countries, it did not lead to a significant or sustained reduction of malaria cases.
By 1969 it had become clear that eradicating malaria altogether was out of reach, and WHO shifted its focus to malaria control. However, financial obstacles continued to limit the success of this effort. Many of the countries where malaria is prevalent are developing nations where even basic health care is unaffordable for many people and governments lack funds for public health programs. Some countries that had been willing to make short-term financial commitments for malaria eradication programs were unable to make the long-term commitments necessary to sustain malaria control programs. A shortage of health care workers trained in malaria surveillance and control further complicated the problem.
During the mid-1960s, insecticide-resistant mosquitoes began to emerge in some regions. Around the same time, malaria parasites developed resistance to chloroquine and other antimalarial drugs. By the late 1970s, malaria had reemerged in many countries, such as Sri Lanka and Mozambique, where eradication programs had virtually eliminated the disease just a few years before. This resurgence was particularly devastating because many people had not been exposed to the disease in years and no longer had protective immunity.
Today continuing difficulties with insecticide-resistant mosquitoes and drug-resistant parasites have led to the abandonment of community-wide mosquito control programs in many countries. In these areas, the primary means of preventing malaria is the use of insecticide-treated bed nets. Recent research has shown that these nets are one of the most effective malaria prevention strategies available, but even their modest cost is beyond the means of many families in developing nations. Lack of access to medical care and to effective antimalarial drugs is also a problem in these countries.
The resurgence of malaria and the widespread problems of drug and insecticide resistance have focused increasing attention on the need for a malaria vaccine. Developing such a vaccine has been difficult because the malaria parasite has hundreds of different strategies for evading the human immune system. Many of these strategies are not well understood, and it is difficult to develop a vaccine that will block all of the parasite's ways of getting past the immune system. To be successful, a vaccine will also need to target several different stages of the parasite's life cycle. Some pharmaceutical companies have been reluctant to work on a malaria vaccine because malaria is most prevalent in developing nations and the companies fear that sales of the vaccine may not be able to recoup the costs of its development. Progress has also been slow because the malaria parasite is difficult to raise in the laboratory and study, since it must live inside the cells of another organism. Despite these hurdles, scientists have developed several possible vaccines that are now being tested in humans.
HISTORY
Malaria is an ancient disease that has plagued humans throughout history. The Greek physician Hippocrates described malaria in his writings during the 400s BC. Documents from early civilizations in China, the Middle East, and Egypt also show evidence that malaria was known to these cultures. Throughout history-and even today-outbreaks of malaria have often been associated with warfare, migrations, and other societal disruptions. More soldiers have been lost to malaria than to bullets in the wars of the 20th century.
Historians believe that malaria was brought to the western hemisphere by European explorers. The first recorded malaria outbreak in the western hemisphere occurred in 1493, and the disease was common during the era of European exploration and settlement in the Americas. The first malaria treatment emerged in 1638, when Spanish Jesuit missionaries brought cinchona bark-the source of quinine-back to Europe from South America. Tonic water, which contains quinine, was developed in an attempt to make the drug more palatable.
Malaria's association with bodies of stagnant water has long been recognized, and civilizations as early as the Etruscans (1st millennium BC) drained marshes and swamps in an effort to combat the disease. However, the exact cause of malaria was not understood until the closing years of the 19th century. In 1880 the French surgeon Charles Alphonse Laveran identified the malaria parasite in the blood of a patient. In 1899 Sir Ronald Ross, a British physician, demonstrated that the parasite is transmitted from human to human by the female Anopheles mosquito. Ross was later awarded a Nobel Prize for this discovery. Efforts to develop a better understanding of the malaria parasite's biology continue today with an international program to decipher all the genetic material of Plasmodium falciparum.
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