Plasmodium falciparum, malarial parasite

A simple assay for the detection of the malarial parasite Plasmodium falciparum involves saponin lysis of blood sample and membrane filtration followed by amplification of the consensus sequence of eight 21-bp repeats. This procedure has been successfully used in the field (F2). A PCR assay targeting kinetoplast DNA sequences of Leishmania species was also successfully tested in the field (F2). Molecular methods for the detection of toxoplasma gondii and several other parasites have been reviewed (F2). 

The malarial parasite is a single-cell protozoan (plas-modium). Although more than 100 species of plasmodia have been identified, only four are capable of infecting humans Plasmodium malariae, P. ovale, P. vivax, and P. falciparum) the rest attack a variety of animal hosts. P. falciparum and P. vivax malaria are the two most common forms. 

Mecfianism of Action A quinolone-methanol compound structurally similar to quinine that destroys the asexual blood forms of malarial pafhogens, Plasmodium falciparum, P. vivax, P. malariae, P. ovale. Therapeutic Effect Inhibifs parasite growth. Pharmacokinetics Well absorbed from fhe gasfroinfesfinal (GI) tract. Protein binding 98%. Widely distributed, including cerebrospinal fluid (CSF). Metabolized in liver. Primarily excreted in urine. Half-life 21-22 days. 

It has been established that DXS catalyzes the first step in a novel biosynthetic pathway leading to isoprenoids in bacteria, algae, plant chloroplasts, and in the malaria parasite, Plasmodium falciparum. DXS is therefore a novel target for antibiotics, herbicides, or anti-malarials. Our work has contributed to an understanding of the novel biosynthetic pathway and could further open new perspectives on how to inhibit the pathway in pathogenic bacteria, protists, or weeds. 

Krungkrai SR, Learngaramkul P, Kudan S, Prapunwattana P, Krungkrai JP (1999) Mitochondrial heterogeneity in human malarial parasite Plasmodium falciparum. Science Asia 25 77-83... 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

Kanaani J, Ginsburg H (1989) Metabolic interconnection between the human malarial parasite Plasmodium falciparum and its host erythrocyte. Regulation of ATP levels by means of an adenylate translocator and adenylate kinase. J Biol Chem 264(6) 3194-3199... 

Ulschmid JK, Rahlfs S, Schirmer RH, Becker K (2004) Adenylate kinase and GTP AMP phosphotransferase of the malarial parasite Plasmodium falciparum. Central players in cellular energy metabolism. Mol Biochem Parasitol 136(2 ) 211-220... 

Scientists at the University of Michigan Medical School, in collaboration with those at the Indian Institute of Science in Bangalore, have carried out tests on curcumin that show it to inhibit the drug-resist-ant forms of malaria and reported their findings in the Journal of Biological Chemistry in December 2004. Mice infected with the related parasite, Plasmodium falciparum, which causes rodent malaria, were fed curcumin and this reduced the number of parasites in the blood by as much as 90%, and completely protected more than a quarter of mice to whom it was given. Whether it could be a treatment for human malarial infection remains to be seen. 

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... 

The malarial parasite, Plasmodium falciparum, was grown in red blood cells to the late trophozoite stage. Cells isolated by centrifugation were lysed with saponin, and the intact parasites were resuspended in 10 mM Hepes-KOH buffer (pH 8.0) at a dilution of 1 3. 

Several compounds derived from these libraries were identified as Hsp70 modulators and were further evaluated in cell proliferation assays such as the SK-BR-3 and MCF-7 breast cancer cell lines and the HT29 colon cancer cell line (Fig. 6) [26]. Compounds 22-24 were potent against all three cell lines. The dihydro-pyrimidinone libraries were also tested for replication inhibition of the malarial parasite, Plasmodium falciparum, where Hsp70 chaperones are believed to play an important role in the parasite s homeostasis [24]. Nine compounds that inhibit replication of the parasite were identified. Among them, compounds 25 and 26 were the most potent (Fig. 7) and were prepared by direct couplings of dihydropyrimidone acids 19 with a pyrrolo amine. 

Chiang AN, Valderramos J-C, Balachandran R et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg Med Chem 17 1527-1533... 

Alphonse Laveran, a French Army physician working in North Africa in the 1880s, was the first to observe malarial parasites in human blood. Their mode of transmission was not understood, however, until Ronald Ross, a British medical officer in India, found the organisms within the bodies of Anopheles mosquitoes. Malaria is caused by four species of parasitic protozoa Plasmodium vivax, P. ovale, P. malariae, satid P. falciparum. These organisms have complex life cycles involving several different developmental stages in both human and mos-... 

The Scientific American (www.sciam.com, 2001) reported a study at the National Institute of Allergy and Infectious Disease (United States) in which two mouse strains were genetically engineered to produce large quantities of a malarial parasite surface protein from Plasmodium falciparum. The malaria vaccine secreted in their milk was able to contain the disease in monkeys vaccinated with the same. This study has now been extrapolated to target livestock as the source animals. GTC is currently... 

Sickle cell gene mutation offers partial protection against serious malarial infection. Abnormal red blood cells (RBCs) are less easily parasitized by Plasmodium falciparum than normal RBCs. Consequently, persons with heterozygous sickle gene (SCT) have a selective advantage in regions (tropical areas) where malaria is endemic. The incidence of the sickle gene in a population correlates with the historical incidence of malaria. 

Perlman, H., Berzins, K., Wahlgren, M., Carlsson, J., Bjorkmin, A., Patarroyo, M. E., and Perlmaann, P. (1984) Antibodies in malarial sera to parasite antigens in the membrane of erythrocytes infected with early asexual stages of Plasmodium falciparum J. Exp. Med. 159,1686-1704. 

Among the fungal and protozoal lectins only a few have been studied in detail. One of these is the galactose-specific lectin of the protozoa Entamoeba histolytica. It mediates adhesion of the parasite to human colonic mucin glycoproteins and has a central role in the contact-dependent cytolysis or histolysis for which the parasite is named. A sialic-acid-speeific lectin has been isolated from merozoites of the human malarial parasite, Plasmodium falciparum. An unusual lectin is that of the protozoan Giardia lamblia, specific for mannose-6-phosphate, which is activated by trypsinization. 

Rather uniquely, ICAM-1 is also subverted as receptor by human pathogens in at least three different ways. Major group rhinoviruses and A-type coxsackieviruses use ICAM-1 to release their RNA into the host cell cytoplasm. Erythrocytes infected by the malarial parasite Plasmodium falciparum, are able to bind ICAM-1 in the surface of endothelial cells (Berendt et al., 1992 Ockenhouse et al., 1992), and use this cytoadherence to sequester themselves in deep vascular beds, including the brain, minimizing exposure of the parasite to immune surveillance. Finally, human immunodeficiency virus-1 (HIV-1), uses ICAM-1 as a coreceptor (Bastiani et al., 1997 Fortin et al., 1997 Rizzuto and Sodroski, 1997). HIV-1 acquires several host cell membrane proteins when it buds from infected cells, making it possible for ICAM-1 to be incorporated into the envelope of the virions. This results in an increase of subsequent virus-cell interactions, enhancement of virus infectivity, and extension of the host cell range. 

Allred, D. R., and Sherman, I. W. (1983). Developmental modulation of protein synthetic patterns by the human malarial parasite Plasmodium falciparum. Can. ]. Biochem. Cell Biol. 61,1304-1314. 

Assaraf, Y. G., Golenser, J., Spira, D. T., and Bachrach, U. (1984). Polyamine levels and the activity of their biosynthetic enzymes in human erythrocytes infected with the malarial parasite, Plasmodium falciparum. Biochem. ]. 222, 815-819. 

Becker, K., Rahlfs, S., Nickel, C., and Schirmer, R. H. (2003b). Glutathione-functions and metabolism in the malarial parasite Plasmodium falciparum. Biol. Chem. 384,551-566. 

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