Plasmodium strains

Polymorphism in the human leukocyte antigen (HLA) s ystem also may be an obstacle to producing an effective vaccine. A potential model for this problem is the observation that T cells, including the cytotoxic T lymphocytes, in patients with HLA-B3S do not re.spond to certain. strains of the parasite. It appears that the combination of certain proteins produced by Plasmodium strains with HLA-B3S prevents a normal T-cell re.sponse. In other words, the immune system of these patients will respond to some Plasmodium strains and not others. The implication is that an effective vaccine will have to be very polyvalent. 

That an effective vaccine, even one that only responds to certain Plasmodium strains, has not been developed has been puzzling, in that the human immune system does adapt with immunoglohulin-pnxiucing B cells and T cells that respond to processed antigen. The innate side of the immune sy.stem also responds. In other words, the human immune system responds to the various forms of the Plasmodium paiusite just as it does to other parasites. It has been suggested that just as the Plasmodium genus has adapted to humans, humans have adapted to the parasite. The five human mutations mentioned above arc one example. There may be others. 

Plasmodium vivax, responsible for the most prevalent form of malaria (benign tertian), has an incubation period of 8—27 days (14 average). A variety seen in northern and northeastern Europe has an incubation period as long as 8—10 months. The disease can cause splenic mpture and anemia. Relapses (renewed manifestations of erythrocytic infection) can occur with this type of malaria. Overall, P. vivax is stiU susceptible to chloroquine however, resistant strains have been reported from Papua New Guinea and parts of Indonesia. Plasmodium malariae the cause of quartan malaria, has an incubation period of 15—30 days and its asexual cycle is 72 hours. This mildest form of malaria can cause nephritis in addition to the usual symptoms. It is a nonrelapsing type of malaria but the ted blood ceU infection can last for many years. No resistance to chloroquine by this plasmodium has been reported. Plasmodium ovale responsible for ovale tertian malaria, has an incubation period of 9—17 days (15 average). Relapses can occur in people infected with this plasmodium. No chloroquine resistance has been reported for this parasite. 

Plasmodium falciparum DHFR inhibitor, Ki = 0.9 jxM, Ki vs. different resistant strains = 0.6-2.1 xM... 

Craig, A.A. and Kain, K.C. (1996) Molecular analysis of strains of Plasmodium vivax from paired primary and relapse infections. Journal of Infectious Diseases 174, 373-379. 

A8. Alving, A. S., Johnson, C. F., Tarlov, A. R., Brewer, G. J., Kellermeyer, R. W., and Carson, P. E., Mitigation of the hemolytic effect of primaquine and enhancement of its action against exoerythrocytic forms of the Chesson strain of Plasmodium vivax by intermittent regimens of drug administration. Bull. World Health Organization 22, 621-631 (1960). 

Plasmodium (P.) falciparum, responsible for the most dangerous form of malaria, is particularly prone to develop drug resistance. The incidence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also for the combination pyrimethamine/ sulfadoxine. 

Malaria (doxycycline only) Prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. 

As adjunctive therapy because of chloroquine-resistant strains of Plasmodium falciparum. 

Malaria For the suppressive treatment and treatment of acute attacks of malaria caused by Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. 

The ozonide (176) was prepared as part of a synthetic study towards the antimalarial natural product artemisinin (177) <92JCS(Pl)325l>. It proved stable enough to allow x-ray crystal structure determination (see Section 4.16.3.1). Other, more complex, polycyclic ozonides were prepared in order to investigate possible antimalarial properties. Compounds were evaluated in vitro for antimalarial activity using a multiresistant strain of Plasmodium falciparum. Most were found to be weakly active although a thousand times less active than artemisinin. 

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. ... 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

Halofantrine, a 9-phenanthrenemethanol derivative, is a blood schizonticide and is active against Plasmodium vivax and chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum. As no parenteral preparation is available it cannot be used for severely ill patients. Oral absorption is slow and incomplete and is increased by a fatty meal. 

Artemisia annua L. A. apiacea Hance ex Walpers Qing Guo (Stinking artemisia) (aerial part) Dihydroartemisinin, artesunate, artemisinin, chloroquine, flavonoids, sesquiterpene.33-269-476 This herb is mildly toxic. A schizonticidal agent, antimalarial, treat infections of multidrug-resistant strains of Plasmodium falciparum, the cause of human malignant cerebral malaria. 

Figure 5-42 Intact DNA from the chromosomes of three strains of the malaria parasite Plasmodium falciparum, ranging from 750 Kb to 5 Mb, separated by pulsed-field gel electrophoresis. Courtesy of C. Smith and T. E. Wellems. Reproduced by permission of Amersham Pharmacia Biotech Inc.

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