Malaria infection

Malaria. Malaria infection occurs in over 30% of the world s population and almost exclusively in developing countries. Approximately 150 X 10 cases occur each year, with one million deaths occurring in African children (87). The majority of the disease in humans is caused by four different species of the malarial parasite. Vaccine development is problematic for several reasons. First, the parasites have a complex life cycle. They are spread by insect vectors and go through different stages and forms (intercellular and extracellular sexual and asexual) as they grow in the blood and tissues (primarily fiver) of their human hosts. In addition, malaria is difficult to grow in large quantities outside the natural host (88). Despite these difficulties, vaccine development has been pursued for many years. An overview of the state of the art is available (89). 

Malaria is transmitted by the bite of an infected female Anopheles mosquito, one of the few species of the insect capable of carrying the human malaria parasite. The responsible protozoa ate from the genus P/asmodium of which only four of some 100 species can cause the disease in humans. The remaining species affect rodents, reptiles, monkeys, birds, and Hvestock. The species that infect humans are P/asmodium falciparum Plasmodium vivax Plasmodium malariae and Plasmodium ovale. Note that concomitant multiple malaria infections are commonly seen in endemic areas, a phenomenon that further compHcates choice of treatment. 

CA C1 C01.046 Falcipain-2 Potential drug target for malaria infection... 

The resurgence of malaria since the 1970s pitted environmentalists against international health officials over the continued use of DDT in poor countries. Each year, malaria infects and enervates half a billion people, roughly 10 percent of Earth s population. It kills up to 2.7 million people annually, mostly small African children and pregnant women. DDT is still used for spraying inside houses in more than two dozen poor countries, including China, India, and Mexico, where approximately 40 percent of the world s population lives. 

Figure 8.5 Monitoring the in vivo time course of P. yoleii malaria infection in mice inoculated with live parasites at day 0.15 (Upper trace) Parasite count obtained by microscopy of blood smear, folded with anemia model from the literature (para-sites/vol) = (parasites/RBC) x (RBC/vol). (Lower trace) Integrated LDMS heme signal from 300 shots across three consecutive sample wells each sample (30 pil) is processed following protocol C, and examined on a commercial LD TOF instrument. Infection is more easily and more rapidly discerned both at earlier and later times by LDMS, compared to the traditional optical microscopy examination.

Kirk, K. Membrane transport in the malaria-infected erythrocyte. Physiolog. Rev. 2001, 81,495-537. 

Rosenthal AS, Chen X, Liu JO, West DC, Hergenrother PJ, Shapiro TA, Posner GH. (2009) Malaria-infected mice are cured by a single oral dose of new dimeric trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells. JMed Chem 52 1198-1203. 

Large quantities of IgM are produced in response to particulate antigens like malaria, trypanosomiasis, helminths, and immune complexes and IgM malarial antibodies have been found associated with thrombocytopenia in patients with malaria infection (B4). 

It now appears certain that destruction of malaria parasites in vivo depends in part, if not wholly, upon the presence of humoral antibodies, and this must explain the success achieved with the passive transfer experiments. The exact role of the T and B lymphocytes in immunity in malaria infection in man still needs clarification. In rats the ability to resist P. berghei infection seems to be thymus dependent, and higher parasitemias were encountered in the thymectomized rats, which also developed severe anemia (B6). 

B6. Brown, I. N., Immunological aspects of malaria infection. Advan. Immunol. 11, 267-349 (1969). 

Pesticides were also valuable in bringing about the control of many insect-transmitted diseases. The use of DDT against the anopheles mosquito in the 1950s and 1960s, for example, was responsible for dramatic decreases in malaria infection rates in many parts of the world. The number of malaria cases in Venezuela dropped from more than 8 million in 1943 to 800 in 1958. Comparable results were reported in Italy, where the number of malaria cases dropped from 411,502 in 1945 to 37 in 1968, and in Taiwan, where the incidence dropped from more than 1 million cases in 1945 to just nine in 1969. 

Similiar animal studies using a malaria model system have also proved successful. Using a strain of mice for which malaria infection is normally lethal, scientists have found that administration of low doses of IL-12 (10-30 ng/day for 5 days) to infected mice offered effective protection against the disease. 

Iron(n) is known to decompose hydrogen and dialkyl peroxides to free radicals by reductive cleavage of the 0—0 bond and early investigations established the parasite s sensitivity to these species. When treated with radiolabelled C-artemisinin, the hemin-hemozoin fraction of the lysed malaria-infected erythrocytes was shown to contain a radiolabel, though the mechanism of incorporation is not clear. Meshnick and coworkers demonstrated that uninfected cells did not contain radiolabelled proteins whereas six radiolabelled proteins were isolated from cells infected with the Plasmodium falciparum (P. falciparum) strain of the parasite. It was suspected that one of the alkylated proteins was the Histidine Rich Protein (HRP) that was known to bind multiple heme monomers and therefore thought to be instrumental to the parasite s detoxification process. Moreover, iron chelators were found to inhibit the lethal effects of peroxides on the parasite. ... 

Most cases of malaria in the United States result from individuals who have contracted the disease before they entered this country. It is also possible to contract malaria during a blood transfusion if the transfused blood has been taken from a malaria-infected individual. Additionally, hypodermic needles previously contaminated by blood containing malarial parasites can be the source of an infection this has occurred when needles are shared among drug addicts. 

In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is... 

Infectious diseases are largely responsible for the health inequalities between developing nations and developed nations. More than 70 per cent of the world s HIV/ AIDS cases and 90 per cent of the world s malaria infections occur in Africa. Ninety per cent of the deaths from TB and diarrhea each year occur in the developing world (lOWH 2005). The average HALE at birth was 38.7 in Chad, 33.2 in Ethiopia, 29.8 in Malawi,... 

The marine environment clearly holds an enormous amount of potential to provide new leads for the development of treatments for infectious disease and antimalarial compounds in particular. The identification of new structural classes active against the malaria parasite will provide new mechanisms of action and better treatments for resistant strains. Since most malaria-infected regions also possess coastal areas rich in diverse marine invertebrate life, marine natural products provide an opportunity for these areas to utilize endemic resources to combat this devastating disease. 

Florens, L., Liu, X., Wang, Y.F., Yang, S.G., Schwartz, O., Peglar, M., Carucci, D.J., Yates, J.R. and Wu, Y.M. (2004) Proteomics approach reveals novel proteins on the surface of malaria-infected erythrocytes. Molecular and Biochemical Parasitology 135, 1-11. 

In/ falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that... 

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