Malaria medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, it causes disease in approximately 650 million people and kills between one and three million, most of them young children in Sub-Saharan Africa. Malaria is commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development. Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete cure.[1]
Medical Therapy
Antimalarial drugs
There are several families of drugs used to treat malaria. Chloroquine is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of Plasmodium falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world. In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine.[2]
There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs may be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used. One drug currently being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the beta blocker propranolol. Propranolol has been shown to block both Plasmodium's ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role in combination therapies.[3]
Currently available anti-malarial drugs include:[4]
- Artemether-lumefantrine (Therapy only, commercial names Coartem® and Riamet®)
- Artesunate-amodiaquine (Therapy only)
- Artesunate-mefloquine (Therapy only)
- Artesunate-Sulfadoxine/pyrimethamine (Therapy only)
- Atovaquone-proguanil, trade name Malarone (Therapy and prophylaxis)
- Quinine (Therapy only)
- Chloroquine (Therapy and prophylaxis; usefulness now reduced due to resistance)
- Cotrifazid (Therapy and prophylaxis)
- Doxycycline (Therapy and prophylaxis)
- Mefloquine, trade name Lariam (Therapy and prophylaxis)
- Primaquine (Therapy in P. vivax and P. ovale only; not for prophylaxis)
- Proguanil (Prophylaxis only)
- Sulfadoxine-pyrimethamine (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)
- Hydroxychloroquine, trade name Plaquenil (Therapy and prophylaxis)
The development of drugs was facilitated when Plasmodium falciparum was successfully cultured.[5] This allowed in vitro testing of new drug candidates.
Extracts of the plant Artemisia annua, containing the compound artemisinin or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand.[6] One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted. [7] Since 2001 the World Health Organization has recommended using artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent WHO treatment guidelines for malaria recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that SERCA, a calcium pump in the endoplasmic reticulum may be associated with artemisinin resistance.[8] Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.[9] However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.[10]
In February 2002, the journal Science and other press outlets[11] announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25".[12] It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3".[13] As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available.
In 1996, Professor Geoff McFadden stumbled upon the work of British biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts[14], an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realisation that any number of herbicides may in fact be successful in the fight against malaria, and so he set about trialing large numbers of them, and enjoyed a 75% success rate.
These "apicoplasts" are thought to have originated through the endosymbiosis of algae[15] and play a crucial role in fatty acid bio-synthesis in plasmodia[16]. To date, 466 proteins have been found to be produced by apicoplasts[17] and these are now being looked at as possible targets for novel anti-malarial drugs.
Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles. Médecins Sans Frontières estimates that the cost of treating a malaria-infected person in an endemic country was between US$0.25 and $2.40 per dose in 2002.[18]
Counterfeit drugs
Sophisticated counterfeits have been found in Thailand, Vietnam, Cambodia[19] and China,[20] and are an important cause of avoidable death in these countries.[21] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.
References
- ↑ If I get malaria, will I have it for the rest of my life? CDC publication, Accessed 14 Nov 2006
- ↑ Tinto H, Rwagacondo C, Karema C; et al. "In-vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemsinin and quinine in an area of high chloroquine resistance in Rwanda". Trans R Soc Trop Med Hyg. 100 (6): 509&ndash, 14. doi:10.1016/j.trstmh.2005.09.018.
- ↑ Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K (2006). "Erythrocyte G protein as a novel target for malarial chemotherapy". PLoS Med. 3 (12): e528. PMID 17194200. Unknown parameter
|month=ignored (help) - ↑ Prescription drugs for malaria Retrieved February 27, 2007.
- ↑ Trager W, Jensen JB. (1976). "Human malaria parasites in continuous culture". Science. 193(4254): 673&ndash, 5. PMID 781840.
- ↑ Senior K (2005). "Shortfall in front-line antimalarial drug likely in 2005". Lancet Infect Dis. 5 (2): 75. PMID 15702504.
- ↑ Rwagacondo C, Karema C, Mugisha V, Erhart A, Dujardin J, Van Overmeir C, Ringwald P, D'Alessandro U (2004). "Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria". Trop Med Int Health. 9 (10): 1091–8. PMID 15482401..
- ↑ Eckstein-Ludwig U, Webb R, Van Goethem I, East J, Lee A, Kimura M, O'Neill P, Bray P, Ward S, Krishna S (2003). "Artemisinins target the SERCA of Plasmodium falciparum". Nature. 424 (6951): 957–61. PMID 12931192.
- ↑ Uhlemann A, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga F, East M, Lee A, Brady L, Haynes R, Krishna S (2005). "A single amino acid residue may determine the sensitivity of SER`CAs to artemisinins". Nat Struct Mol Biol. 12 (7): 628–9. PMID 15937493.
- ↑ Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier J, Zhou B (2005). "Yeast model uncovers dual roles of mitochondria in action of artemisinin". PLoS Genet. 1 (3): e36. PMID 16170412.
- ↑ Malaria drug offers new hope. BBC News 2002-02-15.
- ↑ One step closer to conquering malaria
- ↑ Salom-Roig, X. et al. (2005) Dual molecules as new antimalarials. Combinatorial Chemistry & High Throughput Screening 8:49-62.
- ↑ "Herbicides as a treatment for malaria". Retrieved 2007-09-25.
- ↑ Khöler, Sabine (1997). "A Plastid of Probable Green Algal Origin in Apicomplexan Parasites". Science. 275 (5305): 1485–1489. Unknown parameter
|month=ignored (help) - ↑ Gardner, Malcom (1998). "Chromosome 2 Sequence of the Human Malaria Parasite Plasmodium falciparum". Science. 282 (5391): 1126–1132. Unknown parameter
|month=ignored (help) - ↑ Foth, Bernado (2003). "Dissecting Apicoplast Targeting in the Malaria Parasite Plasmodium falciparum". Science. 299 (5607): 705–708. Unknown parameter
|month=ignored (help) - ↑ Medecins Sans Frontieres, "What is the Cost and Who Will Pay?"
- ↑ Lon CT, Tsuyuoka R, Phanouvong S; et al. (2006). "Counterfeit and substandard antimalarial drugs in Cambodia". Trans R Soc Trop Med Hyg. 100 (11): 1019&ndash, 24. doi:10.1016/j.trstmh.2006.01.003.
- ↑ U. S. Pharmacopeia (2004). "Fake antimalarials found in Yunan province, China" (PDF). Retrieved 2006-10-06.
- ↑ Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. (2006). "Counterfeit anti-infective drugs". Lancet Infect Dis. 6 (9): 602&ndash, 13. PMID 16931411.