Potent Plasmodicidal Activity of a Heat-Induced Reformulation of Deoxycholate-Amphotericin B (Fungizone) against Plasmodium falciparum

Abstract

The emergence and spread of drug-resistant Plasmodium falciparum continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against P. falciparum was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 ؎ 0.03 g/ml for strain K-1 and 0.33 ؎ 0.03 g/ml for strain FCR-3. In the presence of 1.0 g of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 g of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.Malaria infection due to Plasmodium falciparum is a major public health problem in many tropical and subtropical areas. Sporozoites, the infective form of the parasite, are transferred to the human host during a bite by female Anopheles mosquitoes, invade hepatocytes, and develop into liver schizonts, which contain large numbers of merozoites. The asexual bloodstage cycle of P. falciparum commences when the merozoites released from hepatocytes enter the blood circulation and invade red blood cells (RBCs). In this phase of the cycle merozoites initially develop within RBCs as ring forms and then progress to trophozoites and eventually to schizonts, which rupture and release a new wave of merozoites that invade a new batch of RBCs. Chloroquine (CQ), a blood-stage schizonticidal drug, has been the drug of choice for the treatment of falciparum malaria for several decades, but its clinical utility has been greatly reduced in most areas where CQ-resistant malaria is endemic (1, 22). However, CQ remains the most widely used first-line antimalarial drug because it is well tolerated, safe for pregnant women and young children, efficacious against susceptible strains of P. falciparum and the other three human malaria species, and inexpensive. At present, the development of new antimalarial drugs and the use of preexisting drugs in combination are the most important approaches to overcoming the problem of drug resistance.Amphotericin B (AMB) is a heptaene macrolide antibiotic that is active against fungi and yeasts. Fungizone, the commercially available deoxycholate salt for...

In Vitro Activity of Artemisinin in Combination with Clotrimazole or Heat-treated Amphotericin B against Plasmodium falciparum

“…Heat-treated AMB has an enhanced in vitro antiplasmodial effect than AMB against both chloroquine-resistant and chloroquine-sensitive P. falciparum strains. 7 The IC 50 of AMB or HT-AMB on 3D7 strain was found to be similar to that reported for other strains. Heat treatment of AMB forms a 'superaggregated form' having significantly increased stability, marked decrease in hemolytic efficiency, improved therapeutic index for mycoses treatment with reduced toxicity to mammalian cells, and decreased renal cytotoxicity.…”

“…6 HT-AMB is less toxic than AMB, and has been reported to posses potent antiplasmodial activity in vitro. 7 Clotrimazole (CLT) is also an antifungal agent with proven antiplasmodial activity in cultures. 8 Both CLT and AMB are FDA-approved synthetic compounds and abundantly available.…”

In vitro activity of antifungal drugs against Plasmodium falciparum field isolates

“…Th is fi nding is in contrast to other reports for ketokonazol and amphothericin B [5,[7][8][9][10][11][12][13]. Methodological issues including the use of specifi c solvents may explain at least partly these diff erences and confi rmation of our results is therefore necessary.…”

“…Th e evaluation of new compounds against fi eld isolates is of major importance for drug development. For some antimycotic agents like clotrimazole, ketoconazole and amphothericin B, preliminary reports indicate relevant activity against P. falciparum [3][4][5][6][7][8][9][10][11][12][13]. However these drugs have low bioavailability, unfavourable pharmacokinetics or a negative side eff ect profi le when taken as oral drugs [14].…”

Effect of Amphotericin B on Parasitemia and Survival of <i>Plasmodium Berghei</i>-infected Mice

“…As a matter of fact, administration of amphotericin B has indeed been suggested to positively influence the course of malaria [33][34][35][36], an effect, however, attributed to lysis of host erythrocytes in the trophozoite stage of Plasmodium falciparum [36] rather than to accelerated eryptosis.…”