Antimalarial effects

The Plasmodium falciparum malaria PD model successfully described the antimalarial effect of artemisinin, mefloquine, and a combination of the two drugs... 

Andrews KT, Walduck A, Kelso MJ, Fairlie DP, Saul A, Parsons PG (2000) Antimalarial effect of histone deacetylation inhibitors and mammalian tumor cytodifferentiating agents. Int J Paarasitol 30 761-768... 

Primaquine is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline-quinone metabolite that inhibits the coenzyme Q-mediated respiratory chain of the exoerythrocytic parasite. 

In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections. 

Mechanism of Action. Although the drug s exact mechanism of action is unknown, mefloquine may exert antimalarial effects similar to chloroquine that is, these drugs inhibit hemoglobin digestion in malarial parasites, thus causing heme by-products to accumulate within the protozoa and cause toxicity and death of this parasite.65... 

Mechanism of Action. The exact mechanism of quinine is not known. This drug probably exerts antimalarial effects similar to those of chloroquine—that is, inhibition of hemoglobin digestion and subsequent accumulation of toxic heme by-products that lead to death in susceptible protozoa.22... 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

Artemisinin compounds clear parasites from the blood more rapidly than any other antimalarial agent, by a unique pharmacodynamic action. They are concentrated in parasitized erythrocytes, and structure-activity relations (see Chapter 2) suggest that their endoperoxide bridge is essential for the antimalarial effect. A critical step in the mechanism of action seems to be a hemin-catalyzed reduction of the peroxide moiety, which results in free radicals and reactive aldehydes that subsequently kill the malaria parasites. The hemin-rich internal environment of the parasites is assumed to be responsible for the selective toxicity of artemisinin toward these organisms. 

The intrinsic instability of235 makes its existence difficult to prove intramolecular closure to 4-hydroxy-1-deoxyartemisinin 236 or simple aqueous hydrolysis leads to its destruction. If 235 (and related structures) were the bottleneck through which the artemisinin class exerted its antimalarial effect, then replacement of 0-13 by CH2 might give an isolable intermediate epoxide of greater stability, but also with lesser activity. 

Primary drug Secondary drug ANTIMALARIALS Effect Mechanism Precautions... 

Dutta P, Pinto J, and Rivlin R (1985) Antimalarial effects of riboflavin deficiency. Lancet 2,1040-3. 

V. R. Gordeuk and M. Loyevsky, Antimalarial Effect of Iron Chelators, in Iron Chelation Therapy , 1st edn., ed. C. Hershko, Kluwer Academic/Plemnn Publishers, New York, 2002, Vol. 509, p. 251. 

Krugliak M, Deharo E, Shaimiev G, Sauvain M, Moretti C, Ginsburg H. Antimalarial effects of Cl8 fatty acids on Plasmodium falciparum in culture and on Plasmodium vinckei petted and Plasmodium yoefii nigeriensis in vivo. Exp. Parasitol. 1995 81 97-105. 

Artemisinin (152) is a sesquiterpene lactone with an unusual peroxide bridge. One of the earliest modifications involved catalytic reduction of the peroxide, resulting in loss of one oxygen and total loss of antimalarial activity (196) in the adduct (153). The role of the peroxide bridge in producing antimalarial effects was not fully understood, but it appeared essential for activity, so much of the early work on analogs conserved this structural feature as an empirical finding. The mechanism... 

Proguanil is one of the antimalarial drugs most widely used for prophylactic purposes, usually in combination with chloroquine or atovaquone in malaria prophylaxis, and with atovaquone in malaria treatment (SEDA-21, 297). A biguanide, it is rapidly absorbed in standard doses and mainly excreted by the kidneys. Its antimalarial effect is due to its metabolite cycloguanU. However, its metabolism varies individually, and this is reflected in a variable degree of efficacy (SEDA-17, 328). 

Nonclassical 2,4-diaminoquinazoline analogues of folic acid have been of interest as potential chemotherapeutic agents since the early 1970s. Some possess interesting levels of antibacterial activity and remarkable antimalarial effects. The drug trimetrexate (693) displays potent anti-malarial, antibacterial, and antitumor activities, and has been through clinical trials as an anticancer... 

Rosenthal, P. J., Wolfish, W. S., Palmer, J. T. and Rasnick, D. (1991) Antimalarial effects of peptide inhibitors of a Plasmodium falciparum cysteine proteinase. J. Clin. Invest. 88 1467-1472. 

A variety of factors have contributed to the resurgence of malaria, and continue to foster the disease (47). These include socioeconomic and political problems, as well as inadequacies in public health care. Two principal causes of malarial resurgence were (i) the emergence of insecticide-resistant strains of the anopheline mosquitos which are the vectors for transmission of the disease, and (ii) drug-resistant strains of the parasite responsible for the pathology of the most lethal form of the disease, Plasmodium falciparum. Due to the latter, P. falciparum strains which are resistant to the antimalarial effect of chloroquine are spread throughout most of the areas where the disease is endemic, and resistance to more recently introduced antimalarial... 

The range of taxonomic families which have demonstrated antimalarial effects in experimental systems suggests that many diverse natural products can inhibit the growth of the malarial parasite. The key to the discovery and development of clinically useful antimalarial drugs would appear to lie in our capacity to probe these resources and to identify the most potent and selective specimens. 

Zafar, M.M. etal. 1990. Screening oi Artemisia absinthium for antimalarial effects on Plasmodium berghei in mice A preliminary ttpotZ Journal ofEthnopharma-cology 30(2) 223—226. 

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