Antimalarial therapies

The primary goal in the management of malaria is the rapid identification of the Plasmodium species by blood smears (both thick and thin smears repeated every 12 hours for 3 days). Antimalarial therapy should be initiated promptly to eradicate... 

Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy only. The pyrimethamine-sulfadoxine combination may be used for initial selftreatment. 

Currently, artemisinin (18)-based antimalarial therapies remain too expensive to be afforded by those in the developing countries who need them most, due to low yields from the plant of origin, Artemisia annua L., and also due to the high cost of the specialized processing involved in the purification of this compound. In order to solve this problem,... 

Mukherjee, P., Pradhan, A., Shah, F., Tekwanih, B.L. and Averya, M.A. (2008) Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1) A novel target for the development of antimalarial therapy. Bioorganic and Medicinal Chemistry, 16, 5254-5265. 

Experiments performed in vitro revealed that in contrast to DFO, which has a major cytotoxic effect only on trophozoites and early schizonts of P. falciparum, reversed siderophores have a cytotoxic effect on ring-stage and cytostatic effects on trophozoites and schizonts . These observations provided the basis for studying combinations of iron chelators for antimalarial therapy. When DFO is added to malaria parasites cultured in erythrocytes in combination with the more lipophilic and more permeate reversed siderophore 66, a strong synergistic inhibitory effect on parasite growth is observed. This effect may result from the different speeds of permeation of the two chelators... 

Therapy. Antimalarial therapy employs the same agents, in addition to the combinations of artemether plus lumefantrine or pyrimethamine plus sulfadoxine. 

Rahman P, Gladman DD, LFrowitz MB. Smoking interferes with efficacy of antimalarial therapy in cutaneous lupus. J Rheumatol 1998 25(9) 1716-19. 

However, in a later, randomized, placebo-controlled trial pentoxifyUine neither reduced tumor necrosis factor alfa serum concentrations nor affected the clinical course in 51 patients who received it as adjunctive treatment to standard antimalarial therapy in a dosage of 20 mg/kg/day over 5 days (8). 

Pyrimethamine and proguanil are used as oral antimalarials.and inhibit the utilization of folate by the malarial parasite, so are valuable in chemoprophylaxis and in preventing the transmission of malaria. (See ANTIMALARIALS.) Trimethoprim is a useful antibacterial, and as an antiprotozoal in antimalarial therapy. The selectivity of these agents derives, in part, from the fact that whereas mammals can obtain folic acid from the diet, bacteria and the asexual forms of the malarial parasite must synthesize it. Also, the dihydrofolate reductase enzyme in humans is less sensitive to these drugs than that of the parasites. 

Side effects of these drugs include CNS effects (e.g., headache, nervousness, insomnia, and others), rashes, dermatitis, pigmentary changes of the skin and hair, gastrointestinal disturbance (e.g., nausea), and reversible ocular toxicities such as cycloplegia and corneal deposits. Potentially serions retinal toxicity is uncommon when the currently recommended doses are used and is least common with hydroxychloroquine. However, because of the possibility of permanent damage associated with the retinopathy, an ophthalmologic evaluation should be done at baseline and every 3 months when chloroquine is used and every 6 to 12 months when hydroxychloroquine is used. If retinal abnormalities are noted, antimalarial therapy should be discontinued or the dose reduced. ... 

Wallace DJ. Antimalarial therapies. In Wallace DJ, Hahn BH, eds. Dubois Lupus Erythematosus, 6th ed. Philidelphia, Lippincott Williams Wilkins, 2002 1149-1172. 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

Vial s research has pinpointed a series of compounds that possess powerful anti-malarial properties. Whatever the future of these compounds holds, there is no doubt that lipid metabolism is of interest for the development of new antimalarial therapies and that designing a novel chemical scaffold for enzyme-shaped inhibitors represents a promising new avenue for plasmodial chemotherapy. 

It would be remiss if not impossible to discuss the status of antimalarial drug therapy without referring to natural products. Since the disease we call malaria has been recognized for millennia, a great number of plant species have been identified by various cultures as having antimalarial properties. While it is surely not possible to substantiate all of these claims in terms of modem therapeutic efficacy, it is certain that current antimalarial therapy consists substantially of natural products and related derivatives. 

A vestigial chloroplast is present in the malarial parasite Plasmodium. It codes for some of the enzymes involved in fat synthesis. Because mammals do not have chloroplasts, this plasmodial organelle is a potential target for selective antimalarial therapy. 

The human malaria parasite Plasmodium falciparum expresses two neutral zinc-aminopeptidases, PfA-Ml and PfA-M17, which function in regulating the intracellular pool of amino acids required for parasite growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. As a result of the rapid emergence of drug-resistant parasites, blocking these peptidases with potent inhibitors has been proposed as a potential new antimalarial therapy. The simple phosphinic dipeptide 61 (Table 1) was reported to inhibit PfA-M17 with a Ki value of 80 nM [130]. 

In summary, the high efficacy in vitro and in vivo of DU1302 (in particular on chloroquine-resistant strains), its easy synthesis, its chemical stability, and its absence of toxicity and genotoxicity make this trioxaquine a promising drug-candidate for antimalarial therapy. 

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