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The ‘hot stage’ this phase coincides with schizont rupture. The patient feels intensely hot. The increase in temperature (to 41oC) may lead to hyperthermic brain damage as well as causing delirium. This stage usually lasts 2-6 hours.
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The finally stage is the ‘sweating stage’ there is marked sweating. The patient feels fatigued and exhausted but will usually fall asleep.
The other symptoms slow slight variation according to the type of plasmodium causing the disease, (Shulman, 1997).
P. Ovale & P. Vivax Disease
With this infection fever occurs every other day when established. Theses species of plasmodium give rise to a clinically mild infection. The presence of an exoerythrocytic stage in the liver is responsible for relapses and makes eradication of the infection more difficult.
P. Malariae Disease
This is usually a mild disease with a fever, but it usually runs a more chronic course. The nephrotic syndrome may well complete this type of malaria. Because of its chronic nature the patient is likely to develop marked muscle wasting, mild icterus and massive splenomegaly.
P. Falciparum Disease
This by far the severest form of malaria, overall severity is directly related to the number of red blood cells parasitized. Infected red blood cells develop peculiar knob like projections on their surface, these facilitate adhesion of red blood cells to the endothelium of blood vessels. These cause vascular occlusions, which leads to severe anoxic organ damage. This occurs mainly in the kidney, liver brain and gastrointestinal tract. The fevers follow no pattern and splenomegaly tends to occur late.
Cerebral malaria is life threatening and characterised by a marked elevation in body temperature, a rapid deterioration consciousness, convulsions, coma and death.
Black water fever is characterised by production of dark brown urine, which is due to intravascular haemolysis. It is, however only witnessed in P. falciparum infections.
For most people, symptoms begin 10 days to 4 weeks after infection, although a person may feel ill as early as 8 days or up to 1 year later. P. vivax and P. ovale can relapse; some parasites can rest in the liver for several months up to 4 years after a person is bitten by an infected mosquito. When these parasites come out of hibernation and begin invading red blood cells, the person will become sick.
Conventional Drug Therapies and Their Effectiveness
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 i.e. black water fever.
Chloroquine a 4-amino-quinoline with a structure related to quinine is also an effective anti-malarial 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 to chloroquine and more recently chloroquine resistant vivax malaria has also been reported.
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.
The Aminoquinolines work against the parasite by inhibiting proteolysis of haemoglobin in the food vacuole.
Fansidar. This is a combination drug, each tablet containing sulphadoxine 500mg. and pyrimethamine 25mg. Both drugs are antifolates and interfere with the synthesis of thymidylate and DNA. It acts by interfering with . Resistance to Fansidar is now widespread and serious side effects have been reported. It is no longer recommended.
Artemisinine or Quinhoasu is a sesquiterpene lactone derived from the plant Artemisia annua. This effective anti-malarial is used as extracts in traditional medicine in China for the management of fever resulting from malaria. To improve its bioavailability the derivatives and have been developed. When used by itself, a high rate of treatment failures has been reported and it is now being combined with mefloquine for the treatment of falciparum malaria. Its main value at present is in the treatment of multi drug resistant falciparum malaria. It is recommended only for treatment not for prophylaxis. Artemisinine and its derivatives are thought to work by binding to the iron in the malarial pigments to yield free radicals that damage parasite proteins close to the parasites food vacuole.
Fig.3 showing structure of some of the drugs used to treat malaria.
Novel Therapies
Researchers at the University of Washington have discovered a method of treating malaria with magnetic fields that could prove revolutionary in controlling the disease the World Health Organization calls one of the world's most complex and serious human health concerns.
Henry Lai, research professor of bioengineering, says the malaria parasite Plasmodium appears to lose vigour and can die when exposed to oscillating magnetic fields, which researchers thinks may cause tiny iron-containing particles inside the parasite to move in ways that damage the organism.
As previously mentioned the emergence of drug-resistant malaria parasites has created enormous problems in controlling the disease. This method has the added benefit that it could bypass those concerns because it is unlikely Plasmodium could develop a resistance to magnetic fields.
The theory takes advantage of how the parasites feed. Malaria parasites "eat" the haemoglobin in red blood cells of the host. They break down the globin portion of the haemoglobin molecule, but the iron portion, or the haem, is left intact because the parasite lacks the enzyme needed to degrade it. This causes a problem for the parasite because free haem molecules can cause a chain reaction of oxidation of unsaturated fatty acids, leading to membrane damage in the parasite. The malaria organism renders the free haem molecules non-toxic by binding them into long stacks - like tiny bar magnets,
He and three other researchers have exposed Plasmodium falciparum, the deadliest of the four malaria parasite species, to a weak alternating, or oscillating, magnetic field. Data sets showed that exposed samples ended up with 33 to 70 percent fewer parasites than unexposed samples. Measurements of hypoxanthine, a precursor for nucleic acid synthesis used by the parasite, indicated that metabolic activities had also significantly slowed in exposed samples. Such reductions would be enough to manage malaria, according to the researchers.
The oscillating magnetic field may affect the parasites in two ways, according to Henry Lai. In organisms still in the process of binding free haem molecules into stacks, the alternating field likely "shakes" the stacked haem molecules, preventing further stacking. That would allow harmful haem free reign within the parasite. If the parasite is further along in its life cycle and has already bound the haem into stacks, the oscillating field could cause the stacks to spin, causing damage and death of the parasite.
Further research is being done to make sure the technique poses no risk to the human host. This is unlikely as it's a very weak magnetic field, just a little stronger than the earth's. The difference is that it is oscillating.
Vaccine Development
Unlike life long immunity that is induced by many viral infections such as mumps and measles, immunity due to malaria is partial and transient. Unfortunately currently there is no effective vaccine. This has been partly attributed to factors such as, the complexity of the parasites life cycle and the fact that many antigens are not expressed at each stage of the life cycle. (Sherman, 1998)
For these reasons amongst others, researchers have concentrated on the use of parasite proteins produced by recombinant DNA technology, to develop a vaccine. Once the gene encoding a malarial surface antigen has been molecularly cloned, it can be introduced into bacteria and expressed in large amounts. The first such gene to be tested is mentioned in (Shulman, 1997). This is the gene that encodes the circum sporozoite protein. This is the protein found on the surface of the infective sporozoite stage of the parasite and is the protein that engages a specific receptor on the hepatocyte to permit invasion. Although it has been only partially effective, it is forming the basis of other vaccines.
The three main types of vaccine being developed are:
"Anti-sporozoite" vaccines, designed to prevent infection, (as mentioned above).
"Anti-asexual blood stage" vaccines, designed to reduce severe and complicated manifestations of the disease. Such vaccines could lower morbidity and mortality among children under five years of age in Africa, the main risk group, and their development is given priority by WHO. Several such vaccine candidates are currently undergoing clinical and field-testing.
"Transmission-blocking" vaccines, designed to arrest the development of the parasite in the mosquito, thereby reducing or eliminating transmission of the disease.
A cost effective vaccine must be capable of being incorporated into appropriate health delivery programmes, and to provide sufficient duration of immunity. At present, it is difficult to predict when such a vaccine will become available.
It is clear that to develop a multi component malarial vaccine all the genes in the parasite need to be identified. This is currently being done in the form of the malarial genome project.
Economic Burden
The estimated costs of malaria, in terms of strains on the health systems and economic activity lost, are enormous. In affected countries, as many as 3 in 10 hospital beds are occupied by victims of malaria. In Africa, where malaria reaches a peak at harvest time and hits young adults especially hard, a single bout of the disease costs an estimated equivalent of 10 working days.
Research indicates that affected families clear only 40 per cent of land for crops compared with healthy families. Knowledge about malaria is markedly low among affected populations. In one recent survey in Ghana, for example, half the respondents did not know that mosquitoes transmit malaria.
The direct and indirect costs of malaria in sub-Saharan Africa exceed $2 billion, according to 1997 estimates.
According to UNICEF, the average cost for each nation in Africa to implement malaria control programs is estimated to be at least $300,000 a year. This amounts to about six US cents ($.06) per person for a country of 5 million people.
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. The disease is endemic in 91 countries currently, with small pockets of transmission in a further eight. P.falciparum is the predominant species, with 120,000,000 new cases and up to 1,000,000 deaths per year globally. It is the P.falciparum species that has given rise to the formidable drug resistant strains emerging in Asia. In 1989, WHO declared malaria control to be a global priority due to the worsening situation, and in 1993, the World Health Assembly urged member states and WHO to increase control efforts.
Fig.4 Map showing where malaria is common.
In Africa, malaria accounts for up to a third of all hospital admissions, and up to a quarter of all deaths of children under the age of 5. There are up to 800,000 infantile mortalities and a substantial number of miscarriages and very low birth weight babies per year due to the disease. The cost of malaria in economic terms is also high; treatment ranges in cost between $0.80 and $US 5.30 depending on local drug resistance. In Africa it is estimated that an individual receives 40-120 infective mosquito bites per year, compared to only 2 per year in India.
References
Kumar, P., Clark, M., (1998). Clinical Medicine. 4th ed. London: W. B. Saunders.
Mandell, J., Douglas, R., (1995). Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingstone
Sherman, I., (1998). Malaria: Parasite, Pathogenesis and Protection. Washington: ASM Press.
Shulman, S., (1997). The Biologic and Clinical Basis of Infectious Diseases. 5th ed. London: W. B. Saunders.
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