Malaria, current treatment

Guerin, P. J. Olliaro, P. Nosten, F. Druilhe, P Laxminarayan, R. Binka, F. Kilama, W. L. Ford, N. White, N. J. Malaria Current status of control, diagnosis, treatment and a proposal agenda for research and development. Lancet Infec. Dis. 2002, 2, 564-573. 

GUERIN, P.J., OLLIARO, P., NOSTEN, F., DRUILHE, P LAXMINARAYAN, R., BINKA, F., KILAMA, W.L., FORD, N., WHITE, N.J., Malaria Current status of control, diagnosis, treatment, and a proposed agenda for research and development, Lancet Infectious Diseases, 2002,2, 564-573. 

THE CHEMOTHERAPY OF MALARIA The present status of antimalarial drugs Newer methods of therapy Other antimalarial compounds The current treatment of malaria... 

Introduction - The recent literature contains many citations to parasite-related diseases and problems pertaining thereto. In a recent paper several areas requiring intensified research and the development of new or improved drugs were identified. In the past year, a single periodical has carried papers on amebicides, anthelmintics, malaria,amebic and bacterial dysentery, intestinal helminths and filariasis, trypanosomiasis and leishmaniasis, schistosomiasis, and immunodiagnosis of parasitic diseases. Considerable information relating to current treatment of these afflictions may be found in these papers as well as in a report called "Drugs for Parasitic Infections. ... 

Four different protozoa of the genus Plasmodium -P. falciparum, P. vivax, P. ovale and P malariae - can cause malaria. P. falciparum is the most virulent, being responsible for virtually all fatal malaria cases. Humans are infected by a feeding female Anopheles mosquito (Fig. 2). The clinical symptoms of malaria are associated with the development of the parasite within human red blood cells, while the liver stages remain asymptomatic. The following dtugs (in alphabetical order) are currently in use for the treatment of malaria [5]. 

A large and rapidly growing number of clinical trials (phase I and phase II) evaluating the potential of DNA vaccines to treat and prevent a variety of human diseases are currently being performed ( http // clinicaltrials.gov) however, there is yet no licensed DNA vaccine product available for use in humans. The clinical trials include the treatment of various types of cancers (e.g., melanoma, breast, renal, lymphoma, prostate, and pancreas) and also the prevention and therapy of infectious diseases (e.g., HIV/ABDS, malaria, Hepatitis B vims, Influenza vims, and Dengue vims). So far, no principally adverse effects have been reported from these trials. The main challenge for the development of DNA vaccines for use in humans is to improve the rather weak potency. DNA vaccines are already commercially available for veterinary medicine for prevention of West Nile Vims infections in horses and Infectious Hematopoetic Necrosis Vims in Salmon. 

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

Antimalarial drugs are designed to prevent or treat malaria. Antimalarial drugs currently used for treatment for prophylaxis are mefloquine, primaquine, chloroquine, pyrimethamine, amodiaquin, quinine/quinidine, chloroguanide. 

Three currently-used artemisinin based combination therapies (ACT) artesunate-mefloquine, artemether-lumefantrine and dihydroartemisinin-piperaquine, have been proven highly simple, safe and effective in the treatment of multidrug resistant P. falciparum malaria. 

Sulfadoxine is the only long-acting sulfonamide currently available in the USA and only as a combination formulation with pyrimethamine (Fansidar), a second-line agent in treatment for malaria (see Chapter 52). 

The pharmaceutical properties of artemisinin are far from optimal it is insoluble in water and only marginally soluble in oil. It has poor oral bioavailability and has been administered for the treatment of Plasmodium falciparum malaria in humans at total doses of about 1 g (over 3 days). Early studies by Chinese scientists in 1979 led to the discovery of dihydroartemisinin 3, artemether 4 (Artenam), and sodium artesunate 5, oil and water soluble derivatives, respectively (Figure 9.1 ).6-7 These drugs are currently in clinical use in Asia in a number of preparations such as suppositories, i.v. injectables, oil depos, to name only a few.8 Capsules containing 0.5 g of artemisinin for oral administration are available in Vietnam. 

Malaria is one of the oldest parasitic diseases. The difficulty of malaria control is aggravated by the appearance of strains of Plasmodium falciparum resistant to antimalarials, as well as resistance of the vector mosquitoes to DDT and other insecticides. The molecule quinine isolated from the bark of the Cinchona sp. tree, represents the model for the synthesis of the majority of drugs currently used for malarial treatment [194], Davioud-Charvet et al [206] describe the screening of a library of... 

There was a high frequency of amphetamine abuse and withdrawal among patients from the Thai-Myanmar border area admitted to hospital with Plasmodium falciparum malaria (90). This co-morbidity can cause diagnostic confusion, alter malaria pathophysiology, and lead to drug interactions. Considering the potential neuropsychiatric adverse effects of mefloquine, an important component of current antimalarial treatment in Southeast Asia, it should be avoided in patients who abuse amphetamines. 

WHOPES is currently evaluating seven insecticide products for indoor residual spraying and insecticide treatment of mosquito nets for malaria and/or Chagas vector control, two insect repellents, and two insect growth regulator mosquito larvicides, with ongoing trials in 14 countries. 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

Atovaquone acts synergistically with proguanil, and the combination of these two drugs (Malarone ) is highly efficacious in the treatment of uncomplicated malaria (8), including that against multidrug resistant forms, and in prophylaxis (9). It has not yet been widely marketed, so data on rare adverse effects are currently sparse. 

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