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Titolo:
MODE OF ANTIMALARIAL EFFECT OF METHYLENE-BLUE AND SOME OF ITS ANALOGSON PLASMODIUM-FALCIPARUM IN CULTURE AND THEIR INHIBITION OF P-VINCKEIPETTERI AND P-YOELII NIGERIENSIS IN-VIVO
Autore:
ATAMNA H; KRUGLIAK M; SHALMIEV G; DEHARO E; PESCARMONA G; GINSBURG H;
Indirizzi:
HEBREW UNIV JERUSALEM,INST LIFE SCI,DEPT BIOL CHEM IL-91904 JERUSALEMISRAEL HEBREW UNIV JERUSALEM,INST LIFE SCI,DEPT BIOL CHEM IL-91904 JERUSALEMISRAEL MUSEUM NATL HIST NAT,CNRS,URA 114,LAB BIOL PARASITAIRE F-75231 PARIS 05 FRANCE MUSEUM NATL HIST NAT,EPHE,LAB PROTOZOOL & PARASITOL COMPAREE F-75231 PARIS 05 FRANCE UNIV TURIN,DIPARTIMENTO GENET BIOL & CHIM MED I-10126 TURIN ITALY
Titolo Testata:
Biochemical pharmacology
fascicolo: 5, volume: 51, anno: 1996,
pagine: 693 - 700
SICI:
0006-2952(1996)51:5<693:MOAEOM>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
FERRIPROTOPORPHYRIN-IX; OPTICAL-PROPERTIES; AQUEOUS-MEDIUM; COMPLEXES; DRUGS; ERYTHROCYTES; TROPHOZOITES; CHLOROQUINE; MEMBRANES; PARASITE;
Keywords:
PHENOTHIAZINES; METHYLENE BLUE; ANTIMALARIAL ACTION; PLASMODIUM FALCIPARUM; MURINE MALARIAS; HEXOSE-MONOPHOSPHATE SHUNT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
46
Recensione:
Indirizzi per estratti:
Citazione:
H. Atamna et al., "MODE OF ANTIMALARIAL EFFECT OF METHYLENE-BLUE AND SOME OF ITS ANALOGSON PLASMODIUM-FALCIPARUM IN CULTURE AND THEIR INHIBITION OF P-VINCKEIPETTERI AND P-YOELII NIGERIENSIS IN-VIVO", Biochemical pharmacology, 51(5), 1996, pp. 693-700

Abstract

The antimalarial action of methylene blue (MB) was first noted by Paul Ehrlich in the late 19th century. Although it has only sporadically been adopted as a serviceable drug, the resolution of its antimalarialaction seems warranted, as it is currently used for the treatment of various methemoglobinemias. In this work we have used MB, and its analogues Azures A (AZA), B (AZB), C (AZC), and thionin (TH), as well as the oxazine Celestine blue (CB) and the azine Phenosaphranin (PS). All MB analogues inhibit the growth of various strains of Plasmodium falciparum in culture with IC(50)s in the 2 . 10(-9)-1 . 10(-7) M range, with the rank order MB approximate to AZA > AZB > AZC > TH > PS > CB. The IC(50)s for a mammalian cell line were in the 3 . 10(-6)-4 . 10(-5) M range, and the rank order was TH approximate to AZB > AZA approximate to PS > AZC approximate to CB > MB. As IMB could affect cell growth through the oxidation of NADPH, we tested the action of the various compounds on the hexose-monophosphate shunt activity. Appreciable activation of the shunt was observed at 1 . 10(-5) M in both cell types, thus accounting for inhibition of growth of mammalian cells but not of parasites. All compounds were found to complex with heme in a rank ordersimilar to their antimalarial effect. It is therefore suggested that MB and its congeners act by preventing the polymerization of heme, which is produced during the digestion of host cell cytosol in the parasite food vacuole, into hemozoin. In this respect, these compounds seem to act similarly to the 4-aminoquinoline antimalarials. All compounds effectively suppressed the growth of P. vinckei petteri in vivo with IC50 in the 1.2-5.2 mg/kg range, and MB and AZB suppressed P. yoelii nigeriensis in the 9-11 mg/kg range (i.e. at doses similar to those of chloroquine). The potential toxicity of these compounds may restrict their clinical use, but their impressive antimalarial activities suggestthat the phenothiazine structure could serve as a lead compound for further drug development.

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Documento generato il 30/11/20 alle ore 19:52:24