The present status of malaria chemotherapy: Mefloquine, a novel antimalarial

Sweeney, T. R.

doi:10.1002/med.2610010304

Cited by 43 publications

(23 citation statements)

References 47 publications

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“…On the other hand, the smaller affinity of Q and MQ for FP may preclude the formation of complexes in the presence of cellular FP ligands, implying that the mode of antimalarial action of these drugs could be altogether different from that of CQ. Furthermore, MQ is 100 times more active than Q as an antimalarial drug [20,40]. Such difference in activity is inconsistent with the similar effects that these two drugs exert on phospholipid monolayers.…”

Section: Discussionmentioning

confidence: 97%

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Ginsburg

Demel

1984

Chemistry and Physics of Lipids

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Hemin, antimalarial drugs and complexes formed between them, have demonstrable effects on biological membranes. Using the phospholipid monolayer model, we show that hemin intercalates into the membrane and increases its surface pressure, depending on the lipid composition and the initial surface pressure: negative surface charges and particularly looser compaction of the phospholipids reduce the effect of hemin. With increasing surface pressure hemin tends to intercalate as a monomer, and the half-saturation concentration of its effect increases exponentially. The antimalarial monovalent drugs quinine and mefloquine, but not chloroquine, also penetrate into the membrane and expand it. All three drugs markedly increase the effect of hemin, but chloroquine reduces the effect in monolayers composed of unsaturated phospholipids. The drugs' effect is mostly due to an increase in the maximal surface pressure and suggests a complexation of heroin and drug within the membrane phase. Preformed hemindrug complexes decrease the half-saturation concentration of the effect and suggest that the complexes adsorb to the membrane, releasing the hemin through an apolar continuum into the phospholipid phase. The implications of the results to the membrane toxicity mechanism proposed for the molecular mode of action of antimalarial drugs are discussed.

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Section: Discussionmentioning

confidence: 97%

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Ginsburg

Demel

1984

Chemistry and Physics of Lipids

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“…An important finding was that mefloquine (MQ), an arylamino alcohol (4-quinoline-methanol), developed by the Walter Reed Institute of Research in the early 1970s (Sweeney, 1981) and now marketed for the prophylaxis and treatment of malaria, showed promising anti-schistosomal activity in mice. Single oral doses of 200-400 mg/kg to mice infected with either juvenile or adult stages of S. mansoni or S. japonicum resulted in high total or even complete reductions in female worm burdens ).…”

Section: Introductionmentioning

confidence: 99%

Morphological effects and tegumental alterations induced by mefloquine on schistosomula and adult flukes ofSchistosoma mansoni

2009

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There is a pressing need to develop novel anti-schistosomal drugs, as current treatment relies largely on praziquantel (PZQ). To further strengthen current evidence of the anti-schistosomal properties of mefloquine (MQ), we studied the temporal effect of this compound in vitro and in vivo, and examined alterations on the tegumental surface of schistosomula and adults of S. mansoni by means of scanning electron microscopy (SEM). Schistosomula and adults were each incubated in vitro using MQ over a wide concentration range (1-100 mg/ml). In addition, mice infected with adult S. mansoni were treated with a single oral dose of 400 mg/kg MQ, and worms were recovered 24, 48, 72, 96 and 120 h following treatment. MQ showed a rapid onset of action on schistosomula in vitro ; 100 and 75 mg/ml of MQ killed schistosomula immediately ; the minimal lethal and effective concentrations of MQ on schistosomula after 1 h were 25 and 5 mg/ml, respectively. Adult worms incubated with 100 and 10 mg/ml of MQ were dead after 1 h and 24 h of incubation, respectively. A hepatic shift of adult schistosomes was observed in mice already 24 h after treatment, and 120 h following treatment >98 % of all worms had translocated to the liver. SEM observations revealed extensive tegumental destruction, including blebbing, shrinking and sloughing, particularly following in vitro incubation and on the tegument of female worms.

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“…Quinoline containing compounds, such as the potent and inexpensive chloroquine (CQ) [2,3,4] have a long tradition in the treatment of malaria, and systematic modification has led to a variety of antimalarial drugs with diverse substitutions around the quinoline ring [5,6]. However, the spread of chloroquine-resistant Plasmodium falciparum strains has dashed hopes of global malaria eradication and has complicated the clinical management of malaria in endemic areas.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

D’hooghe

Kenis

Vervisch

et al. 2011

European Journal of Medicinal Chemistry

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A variety of 2-(aminomethyl)aziridines was prepared and converted into the corresponding 1,2,3-triaminopropanes through a novel, microwave-assisted and regioselective ring opening by diethylamine in acetonitrile. Antiplasmodial assays revealed antimalarial activity for 2-[(1,2,4-triazol-1-yl)methyl]aziridines and 2-(N,N-diethylaminomethyl)aziridines, as well as for the corresponding 1-(diethylamino)propanes obtained through ring opening, pointing to the relevance of both the 2-(aminomethyl)aziridine and the 1,2,3-triaminopropane unit as novel antimalarial pharmacophores.

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The present status of malaria chemotherapy: Mefloquine, a novel antimalarial

Cited by 43 publications

References 47 publications

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

Morphological effects and tegumental alterations induced by mefloquine on schistosomula and adult flukes ofSchistosoma mansoni

Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

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