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A.History of Plasinodium Parasites
Malaria parasites have been with us since the dawn of time. They probably originated in Africa along with mankind. Fossils of mosquitoes up to 30 million years old show that the vector for malaria was present well before history was written. The Plasmodium parasites are highly specific; men are the only vertebrate host and Anopheles mosquitoes the vectors. This specificity of the parasites also points towards a long and adaptive relationship with our species.
Presently, at least 300,000,000 people are affected by malaria, and there are between 1,000,000 and 1,500,000 malaria deaths per years. Malaria is generally endemic in the tropics, with extensions into the subtropics. Travelers sometimes carry malaria into countries they travel to. Today it is an important cause of death in non-malarious areas; it is occasioned by the common ignorance or indifference of travelers to prophylaxis. Distribution varies greatly from country to country, as the flight range of the vector from a suitable habitat is fortunately limited to a maximum of 2 miles, not taking account of prevailing wind and others. The map below indicates the current distribution of indigenous malaria according to the World Health Assembly.
In 1990, 80% of cases were in Africa, with the remainder clustered in nine countries: India, Brazil, Afghanistan, Sri-Lanka, Thailand, Indonesia, Vietnam, Cambodia and China. Current data for Africa is unavailable. Currently the disease is endemic in 91 countries, with small pockets of transmission in a further height. Plasmodium falciparum is the predominant species, with 120,000,000 new cases and up to 1,000,000 deaths per year globally. It is the Plasmodium falciparum species, which has given rise to the formidable drug resistant strains emerging in Asia.
There are many control measures against malaria, such as spraying with DDT, coating marshes with paraffin (to block Anopheles mosquito larvae spiracles), draining stagnant water, and the widespread use of nets. Research into the biology and microbiology of malaria enables a methodical search for better vaccines and a possible cure in the fight against malaria.
B.Biology of Plasmodium Parasites and Anopheles Mosquitoes
The Plasmodium genuses of protozoal parasites (mainly P.falcipanim, P.vivax, P.ovale, and P. malariae) have a life cycle, which is split between a vertebrate host and an insect vector. The Plasmodium species,with the exception of P.malariae (which may affect the higher primates) are exclusively parasites exclusive to man. The mosquito is always the vector, and is always an Anopheline mosquito, although, out of the 380 species of Anopheline mosquito, only 60 can transmit malaria. Only female mosquitoes are involved, as the males do not feed on blood. A bite of mosquito transfers about 10% of its sporozoite loaded into the capillaries or perivascular tissue. Now the sporozoites must begin their evasion of the host defenses, possibly by binding serum proteins for "camouflage". Some are destroyed by macrophages, or by antigen-specific antibodies in immune individuals, but in non-immune individuals, they reach the hepatocytes and initiate schizogeny or become hypnozoites depending on their delayed triggered system. All sporozoites leave the peripheral circulation system within 45 minutes. The basic life cycle of the parasite is shown below.
- Sporozoites in salivary gland.
- Oöcysts in stomach wall.
- Male and female gametocytes.
- The liver phase is the release of merozoites from liver, which enters red cells where both sexual and asexual cycles continue.
C. Asexual blood stage and a brief illustrated guide of the ultra structure of plasmodium falciparum
The following pages show electron micrographs of the four principal stages in the asexual cycle of Plasmodium falciparum: the merozoite, the ring stage, the trophozoite and the schizont.
1. A merozoite, showing the apical prominence with a rhoptry, dense granules, and a very indented nucleus.
2. A ring stage of the cup-like form, showing the nucleus n surrounded by ribosomes and some endoplasmic reticulum. The species name falciparum means "crescent-shaped" and refers to the appearance of the ring stage.
3. Mid-trophozoite stage, showing the nucleus, the pigment vacuole and a cytostome with a forming food vacuole. "Trophozoite" means the maturing stage. Greek "tropho" means, "to mature".
4. A schizont, showing a series of nuclei and developing merozoites containing rounded early rhoptries around their perimeters. A lipid vacuole is present centrally. Note the irregular appearance of the red blood cell (RBC) surface and the presence of knobs. The name "schizont" comes from the Greek "schizo" meaning, "to tear apart".
Section of mosquito showing oöcysts (1) and sporozoites (2)
Section of liver showing a greatly enlarged parenchymal cell full of merozoites (see arrow)
Section of brain showing blood vessels blocked with developing P. falciparum parasites (see arrows).
D.History of Treatment and Prophylaxis
Antimalarial drugs fall into several chemical groups. It would therefore be useful to have some knowledge of their chemistry. The aim here is to give a brief outline of anti-malarial drugs and their usefulness today and when drug resistant strains of malaria have become a major problem.
Quinine has been used for more than three centuries and until the 1930's was the only effective agent for the treatment of malaria. It is one of the four main alkaloids found in the bark of the Cinchona tree. It is also the only drug, which over a long period of time has remained largely effective for treating the disease. It is now only used for treating severe falciparum malaria partly because of undesirable side effects. In Africa in the 1930's and 40's it was required for people to take quinine when they thought they had contracted the disease and noticed the association of repeated infections with falciparum malaria. The inadequate treatment with quinine resulted in the development in some of acute massive intravascular haemolysis and haemoglobinuria like black water fever. Atebrin (mepacrin drug) is a 9-amino-acridine developed in the early 1930's. It was used as a prophylactic on a large scale during World War 11(1939-45) and was then considered a safe drug. It had a major influence in reducing the incidence of malaria in troops serving in South East Asia. ft is now considered to have too many undesirable side effects and is no longer used.
Chloroquine (C18H26C1N3) is a very effective 4-amino-quinoline both for treatment and prophylaxis. It was first used in the 1940's shortly after the Second World War and was effective in curing all forms of malaria. With few side effects when taken in the dose prescribed for malaria and it was low sold at low cost. Unfortunately most strains of falciparum malaria are now resistant to chloroquine and more recently chloroquine resistant vivax malaria has also been reported.
Proguanil is a drug that falls into the biguanide class of antimalarials and was first synthesized in 1946. It has a biguanide chain attached at one end to a chlorophenyl ring and it is very close in structure to pyrimethamine. The drug is a folate antagonist and destroys the malarial parasite by binding to the enzyme dihydrofolate reductase in much the same way as pyrimethamine. It is still used as a prophylactic in some countries.
In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. When combined with proguanil there is a synergistic effect and the combination is at the present time a very effective antimalarial treatment. The drug combination has undergone several large clinical trials and has been found to be 95% effective in otherwise drug resistant falciparum malaria. It has been claimed to be largely free from undesirable side effects but it should be noted that proguanil is an antifolate. This is not likely to be a problem with a single treatment course of the drug but some caution should be exercised when using it for prophylaxis. It remains a very expensive drug.
Maloprim is a combination of dapsone and pyrimethamine. Resistance to this drug is now widespread and its use is no longer recommended.
Fansidar is a combination drug, each tablet containing sulphadoxine 500mg. and pyrimethamine 25mg. It acts by interfering with folate metabolism. Resistance to Fansidar is now widespread and serious side effects have been reported. It is no longer recommended.
Mefloquine (Lariam) was first introduced in 1971. This quinoline methanol derivative is related structurally to quinine. The compound was effective against malaria, resistant to other forms of treatment when first introduced and because of its long half life was a good prophylactic, but widespread resistance has now developed with undesirable side effects that resulted from a decline in its use. Because of its relationship to quinine the two drugs must not be used together. There have been reports of various undesirable side effects including several cases of acute brain syndrome, which is estimated to occur in I of 10,000 to 1 of 20,000 of the people taking this drug. It usually develops about two weeks after starting mefloquine and generally resolves after a few days.
Ilalofantrin (Halfan) belongs to a class of compound called the phenanthrene-methanols and is not related to quinine. It is an effective antimalarial drug introduced in the 1980s, but due to its short half-life of 1 to 2 days, it is not suitable for prophylactic use. Unfortunately resistant forms are increasingly being reported and there is some concern about side effects. Halofantrin has been associated with neuropsychiatric disturbances. It is forbided during pregnancy and is not advised to women who are breastfeeding. Abdominal pain, diarrhea, puritus and skin rash have also been reported. Artemisinins is derived from a Chinese herbal remedy and covers a group of products. The two most widely used are artesunate and artemether. While they are widely used in Southeast Asia they are not licensed in much of the so-called "Western World" including Australia. A high rate of treatment failures has been reported and it is now being combined with mefloquine for the treatment of falciparum malaria.
E.Symptoms of the disease
You may still contract malaria although prophylactic measures have been taken. If one has flu-like symptoms, up to eight weeks to six months after you visit any hot spots, he must tell his doctor and mention that he has been in a malarial area. Malaria symptoms include: Chills and shivers, Sweat, High temperature, abdominal pain, Splitting headache, Loss of appetite, Muscle and joint pains. Cough, Nausea, Slight jaundice, Diarrhea, enlarged liver and spleen and Fatigue. So when you exhibit any of these symptoms, and you have been exposed to malaria, immediately you must contact your licensed medical practitioner or local hospital.
F.Definition |
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