“…Resistance to the commonly used drug chloroquine is most prevalent, while resistance to most other antimalarials such as alkaloids (e.g., quinine), sulfonamides (e.g., sulfadoxine), and diaminopyrimidines (e.g., pyrimethamine) have also been extensively reported. [33][34][35] The spread of multidrug resistance particularly with P. falciparum, 47,48 is responsible for the majority of deaths and most severe forms of disease, including cerebral malaria, whereas only sporadic cases of resistance have been reported in vivax malaria.…”
Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development.
“…Resistance to the commonly used drug chloroquine is most prevalent, while resistance to most other antimalarials such as alkaloids (e.g., quinine), sulfonamides (e.g., sulfadoxine), and diaminopyrimidines (e.g., pyrimethamine) have also been extensively reported. [33][34][35] The spread of multidrug resistance particularly with P. falciparum, 47,48 is responsible for the majority of deaths and most severe forms of disease, including cerebral malaria, whereas only sporadic cases of resistance have been reported in vivax malaria.…”
Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development.
“…5 However, the prevalence of splenomegaly during cerebral malaria varied widely. 6,7 These studies used different comparison groups and were conducted in areas of different transmission patterns. In Thailand, transmission is low and splenomegaly is much rarer in exposed populations.…”
Abstract. The role of the spleen during Plasmodium falciparum malaria in humans is unclear. In Thailand, malaria transmission is low and splenomegaly is rarer than in high transmission areas. We compared the prevalence of splenomegaly between 52 cerebral malaria patients and 191 patients without complications despite a high parasite biomass. We also measured concentrations of reactive nitrogen intermediates (RNIs) in a fraction of these cases recruited in 1998 (24 cerebral malaria and 56 controls). Splenomegaly was significantly associated with cerebral malaria (adjusted odds ratio ϭ 2.07 [95% confidence interval ϭ 1-4.2]; P ϭ 0.048). There was a linear trend for this association (P ϭ 0.0003). After adjusting for potential confounders, concentrations of RNIs were significantly lower in the presence of splenomegaly (P ϭ 0.01). These results suggest that in humans, as in animal models, the spleen may be involved in the pathogenesis of cerebral malaria. The relationship between RNI concentrations and the spleen suggest that nitric oxide may have a regulating role in the complex physiology of the spleen during malaria.
“…The chemotherapy of malaria has been aided by the relatively recent discovery and development of natural and synthetic endoperoxides. The parasites that cause this disease, genus Plasmodium , are becoming increasingly resistant to traditional therapies such as chloroquine and other alkaloids, sulfonamides (e.g., sulfadoxine), and diaminopyrimidines (e.g., pyrimethamine). , The spread of multidrug resistance is particularly troublesome with Plasmodium falciparum , which causes cerebral malaria , and other very serious consequences and is responsible for nearly all of the annual 1−3 million deaths attributed to malaria. , Research into endoperoxide antimalarials began with isolation of the 1,2,4-trioxane artemisinin (qinghaosu, 1 ) in 1972 as the active ingredient in a tea of Artemisia annua leaves used for thousands of years in China and southeast Asia to treat fever. , Subsequent work on semisynthetic derivatives of lactone-reduced dihydroartemisinin ( 2 ) produced artemether ( 3a ) and arteether ( 3b ) as oil-soluble analogues and yielded artesunate ( 3c ) and artelinate ( 3d ) as water-soluble formulations (Scheme ). , Several million doses of these compounds have been given in Asia, Africa, and Central America, and they are at various stages of formal clinical development as new malaria therapies. − 1 …”
Section: Introductionmentioning
confidence: 99%
“…The parasites that cause this disease, genus Plasmodium, are becoming increasingly resistant to traditional therapies such as chloroquine and other alkaloids, sulfonamides (e.g., sulfadoxine), and diaminopyrimidines (e.g., pyrimethamine). 1,2 The spread of multidrug resistance is particularly troublesome with Plasmodium falciparum, which causes cerebral malaria 3,4 and other very serious consequences and is responsible for nearly all of the annual 1-3 million deaths attributed to malaria. 5,6 Research into endoperoxide antimalarials began with isolation of the 1,2,4-trioxane artemisinin (qinghaosu, 1) in 1972 as the active ingredient in a tea of Artemisia annua leaves used for thousands of years in China and southeast Asia to treat fever.…”
Section: Introductionmentioning
confidence: 99%
“…16,38,39 Evidence gathered from these investigations indicates that oxygen-and carboncentered radicals, [40][41][42][43] one or more high-valent iron oxo species, and reactive electrophilic alkylating species, such as epoxides and dicarbonyl compounds, are formed during iron(II)-induced decomposition of these systems. 16 In this paper, we do the following: (1) report full details on a series of C 4 -alkylated trioxanes 4 and 5a-c (Figure 1) that demonstrated the central role of an intermediate carbon-centered radical in the mechanism of action of this class of compounds; (2) introduce C 4 -(hydroxyalkyl)trioxanes 5d and 5e that were designed to combine those structural characteristics of the first series that are associated with high antimalarial activity; (3) show that derivatization of C 4β diastereomers of two of these trioxane alcohols 4a and 5d produces potent antimalarials 6 and 7; and (4) make SAR generalizations related to the novel analogues reported herein.…”
Novel C4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two new pairs of C4-diastereomers against chloroquine-sensitive Plasmodium falciparum support conclusions about the importance to antimalarial activity of formation of a C4 radical by a 1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C4 beta-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transformation. Four of these new analogues, 6a-c and 7, are potent in vitro antimalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).
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