History of Treatment and Prophylasix

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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.

Atehrin (mepacrane).

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.

Praguanil

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 Pneurnocystis 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 SOOmg. 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.

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