Malaria and It's History

Malaria

While it was recognised that the Anopheles mosquito played a key role in the transmission of the disease it was not until 1948 that all the stages in its life cycle were identified. The parasite undergoes a development stage in the mosquito and the female of the species requires a blood meal to mature her eggs.

She bites a human and injects material from her salivary glands, which contains primitive malarial parasites called sporozoites, before feeding. These sporozoites circulate in the blood for a short time and then settle in the liver where they enter the parenchymal cells and multiply; this stage is known as pre-erythrocytic schizogony. After about 12 days there may be many thousands of young parasites known as merozoites in one liver cell, the cell ruptures and the free merozoites enter red blood cells.

The blood stages of the four species of malaria can be seen in the section on diagnosis. In the case of P. vivax, and P.ovale the liver cycle continues and requires a course of primaquine to eliminate it. P.falciparum on the other hand does not have a continuing liver cycle.

In the red blood cells the parasites develop into two forms, a sexual and an asexual cycle. The sexual cycle produces male and female gametocytes, which circulate in the blood and are taken up by a female mosquito when taking a blood meal. The male and female gametocytes fuse in the mosquito's stomach and form oöcysts in the wall of the stomach. These oöcysts develop over a period of days and contain large numbers of sporozoites, which move to the salivary glands and are ready to be injected into man when the mosquito next takes a meal. In the asexual cycle the developing parasites form schizonts in the red blood cells which contain many merozoites, the infected red cells rupture and release a batch of young parasites, merozoites, which invade new red cells. In P.vivax, P.ovale and probably P.malariae, all stages of development subsequent to the liver cycle can be observed in the peripheral blood. However, in the case of P.falciparum only ring forms and gametocytes are usually present in the peripheral blood. Developing forms appear to stick in the blood vessels of the large organs such as the brain and restrict the blood flow with serious consequences.

While all four species have a haemolytic component ie. when a new brood of parasites break out of the red blood cell this is usually of little consequence. The exception is falciparum malaria where the parasites multiply very rapidly and may occupy 30% or more of the red blood cells causing a very significant level of haemolysis. One reason for this is that P.falciparum invades red cells of all ages whereas P.vivax and P.ovale prefer younger red cells, while P.malariae seeks mature red cells.

History of Treatment and Prophylaxis

Antimalarial drugs fall into several chemical groups and it is 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, when drug resistant strains of malaria have become a major problem. It is not a comprehensive history nor does it include a number of drugs which are no longer used.

Quinine

Quinine has been used for more than three centuries and until the 1930's it 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 and is 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 known for people to take quinine when they thought they had "a touch of malaria" and the association of repeated infections with falciparum malaria and inadequate treatment with quinine, resulted in the development in some of acute massive intravascular haemolysis and haemoglobinuria ie. black water fever.

Atebrin (mepacrine)

This drug is a 9-amino-acridine developed in the early 1930's. It was used as a prophylactic on a large scale during the second world war (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. It is now considered to have too many undesirable side effects and is no longer used .

Chloroquine

A very effective 4-amino-quinoline both for treatment and prophylaxis. It was first used in the 1940s 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 in cost. Unfortunately most strains of falciparum malaria are now resistant to chloroquine and more recently chloroquine resistant vivax malaria has also been reported.

Proguanil

This drug falls into the biguanide class of antimalarials and was first synthesised 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.

Malarone

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. How long it will be before resistant strains of malaria appear remains to be seen. 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. At present it is a very expensive drug.

Maloprim

A combination of dapsone and pyrimethamine. Resistance to this drug is now widespread and its use is no longer recommended

Fansidar

This 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)

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 and this together with undesirable side effects have resulted in 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 1 in 10,000 to 1 in 20,000 of the people taking this drug. It usually develops about two weeks after starting mefloquine and generally resolves after a few days.

Halofantrin (Halfan)

This belongs to a class of compound called the phenanthrene-methanols and is not related to quinine. It is an effective antimalarial introduced in the 1980s, but due to its short half life of 1 to 2 days, is therefore not suitable for use as a prophylactic. Unfortunately resistant forms are increasingly being reported and there is some concern about side effects. Halofantrin has been associated with neuropsychiatric disturbances. It is contraindicated during pregnancy and is not advised in women who are breastfeeding. Abdominal pain, diarrhoea, puritus and skin rash have also been reported.

Artemisinins.

This 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.

Acknowledgements

The pictures of malarial parasites and the malarial cycle were taken from :- "The microscopical Diagnosis of Tropical Diseases" Farbenfabriken Bayer 1955.

The original slides from which the following pictures were taken were a gift to Richard Davis from the late Emeritus Professor H.E. Shortt -- liver exo-erythrocytic stage, oöcysts in an infected mosquito and section of brain showing P. falciparum in the capillaries.

Approximately 300 million people worldwide are affected by malaria and between 1 and 1.5 million people die from it every year. Previously extremely widespread, the malaria is now mainly confined to Africa, Asia and Latin America. The problems of controlling malaria in these countries are aggravated by inadequate health structures and poor socioeconomic conditions. The situation has become even more complex over the last few years with the increase in resistance to the drugs normally used to combat the parasite that causes the disease.

Malaria is caused by protozoan parasites of the genus Plasmodium. Four species of Plasmodium can produce the disease in its various forms:

P. falciparum is the most widespread and dangerous of the four: untreated it can lead to fatal cerebral malaria.

Malaria parasites are transmitted from one person to another by the female anopheline mosquito. The males do not transmit the disease as they feed only on plant juices. There are about 380 species of anopheline mosquito, but only 60 or so are able to transmit the parasite. Like all other mosquitos, the anophelines breed in water, each species having its preferred breeding grounds, feeding patterns and resting place. Their sensitivity to insecticides is also highly variable.

Plasmodium develops in the gut of the mosquito and is passed on in the saliva of an infected insect each time it takes a new blood meal. The parasites are then carried by the blood in the victim's liver where they invade the cells and multiply:

Animation: Lifecycle of a malaria parasite from mosquito to blood stages (needs Macromedia Shockwave Flash Player)

After 9-16 days they return to the blood and penetrate the red cells, where they multiply again, progressively breaking down the red cells. This induces bouts of fever and anaemia in the infected individual. In cerebral malaria, the infected red cells obstruct the blood vessels in the brain. Other vital organs can also be damaged often leading to the death of the patient.

Malaria is diagnosed by the clinical symptoms and microscopic examination of the blood. It can normally be cured by antimalalial drugs. The symptoms, fever, shivering, pain in the joints and headache, quickly disappear once the parasite is killed. In certain regions, however, the parasites have developed resistance to certain antimalarial drugs, particularly chloroquine. Patients in these areas require treatment with other more expensive drugs. Cases of severe disease including cerebral malaria require hospital care.

In endemic regions, where transmission is high, people are continuously infected so that they gradually develop immunity to the disease. Until they have acquired such immunity, children remain highly vulnerable. Pregnant women are also highly susceptible since the natural defence mechanisms are reduced during pregnancy.

Malaria has been known since time immemorial, but it was centuries before the true causes were understood. Previously, it was thought that "miasma" (bad air or gas from swamps - "mal air ia") caused the disease. Surprisingly in view of this, some ancient treatments were remarkably effective. An infusion of qinghao (Artemesia annua ) has been used for at least the last 2000 years in China, its active ingredient (artemisinin) having only recently been scientifically identified. The antifebrile properties of the bitter bark of (Cinchona ledgeriana ) were known in Peru before the 15th century. Quinine, the active ingredient of this potion was first isolated in 1820 by the pharmacists.

Although people were unaware of the origin of malaria and the mode of transmission, protective measures against the mosquito have been used for many hundreds of years. The inhabitants of swampy regions in Egypt were recorded as sleeping in tower-like structures out of the reach of mosquitoes, whereas others slept under nets as early as 450 B.C.

Systematic control of malaria started after the discovery malaria parasite by Laveran in 1889 (for which he received the Nobel Prize for medicine in 1907), and the demonstration by Ross in 1897 that the mosquito was the vector of malaria.

These discoveries quickly led to control strategies and with the invention of DDT during the World War II, the notion of global eradication of the disease. Effective and inexpensive drugs of the chloroquine group were also synthesized around this time.

The hope of global eradication of malaria was finally abandoned in 1969 when it was recognised that this was unlikely ever to be achieved. Ongoing control programs remain essential in endemic areas. Malaria is currently endemic in 91 countries with small pockets of transmission occurring in a further eight countries. Plasmodium falciparum is the predominant parasite. More than 120 million clinical cases and over 1 million deaths occur in the world each year.

Eighty per cent of the cases occur in tropical Africa, where malaria accounts for 10% to 30% of all hospital admissions and is responsible for 15% to 25% of all deaths of children under the age of five. Around 800,000 children under the age of five die from malaria every year, making this disease one of the major causes of infant and juvenile mortality. Pregnant women are also at risk since the disease is responsible for a substantial number of miscarriages and low birth weight babies.

Malaria thus has social consequences and is a heavy burden on economic development . It is estimated that a single bout of malaria costs a sum equivalent to over 10 working days in Africa.

The cost of treatment is between $US0.08 and $US5.30 according to the type of drugs prescribed as determined by local drug resistance. In 1987, the total "cost" of malaria - health care, treatment, lost production, etc. was estimated to be $US800 million for tropical Africa and this figure is currently estimated to be more than $US1,800 million.

The distribution of malaria varies greatly from country to country and within the countries themselves. In 1990, 75% of all recorded cases outside of Africa were concentrated in nine countries:

The significance of malaria as a health problem is increasing in many parts of the world. Epidemics are even occurring around traditionally endemic zones in areas where transmission had been eliminated. These outbreaks are generally associated with deteriorating social and economic conditions, and main victims are underprivileged rural populations. Demographic, economic and political pressures compel entire populations (seasonal workers, nomadic tribes and farmers migrating to newly-developed urban areas or new agricultural and economic developments) to leave malaria free areas and move into endemic zones. People are non-immune are at high risk of severe disease. Unfortunately, these population movements and the intensive urbanization are not always accompanied by adequate development of sanitation and health care. In many areas conflict, economic crises and administrative disorganization can result in the disruption of health services. The absence of adequate health services frequently results in a recourse to self-administration of drugs often with incomplete treatment. This is a major factor in the increase in resistance of the parasites to previously effective drugs.

In all situations, control programmes should be based on four objectives:

Malaria is complex but it is a curable and preventable disease. Lives can be saved if the disease is detected early and adequately treated. It is known what action is necessary to prevent the disease and to avoid or contain epidemics and other critical situations. The technology to prevent, monitor, diagnose and treat malaria exists. It needs to be adapted to local conditions and to be applied through local and national malaria control programmes.

Reviewed by Joel Klein, MD

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