Plasmodium berghei: Phase contrast and electron microscopical evidence that certain antimalarials can both inhibit and reverse pigment clumping caused by chloroquine

• Published in: Experimental parasitology Vol. 40; no. 1; pp. 52 - 61
• Main Authors: Einheber, Albert, Palmer, Douglas M., Aikawa, Masamichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.1976
• Subjects: Animals; Antimalarials; Antimalarials - pharmacology; Bioavailability, oral; Blood schizontocides; Chloroquine; Chloroquine - pharmacology; Cytoplasmic Granules - drug effects; Cytoplasmic Granules - ultrastructure; Erythrocytes - parasitology; Erythrocytes - ultrastructure; Female; Hemozoin; in vivo; Malaria; Malaria - parasitology; Malarial pigment changes; Mice; Microscopy, electron; Microscopy, phase contrast; Phenanthrenemethanols; Phenanthrenes - pharmacology; Pigments, Biological; Piperidines - pharmacology; Plasmodium berghei; Plasmodium berghei - drug effects; Plasmodium berghei - ultrastructure; Quinine; Quinine - pharmacology; Quinolinemethanols; Quinolines - pharmacology; Vacuoles - drug effects; Vacuoles - ultrastructure; WR 142,490; WR 171,669; WR 30,090; WR 33,063; WR 142,490; Quinolinemethanols; Malaria; Bioavailability, oral; Chloroquine; Hemozoin; Microscopy, electron; Antimalarials; WR 171,669; Malarial pigment changes; Quinine; Phenanthrenemethanols; Blood schizontocides; Microscopy, phase contrast; Plasmodium berghei; WR 33,063; WR 30,090; Mice; in vivo
• ISSN: 0014-4894; 1090-2449
• DOI: 10.1016/0014-4894(76)90063-1

Chloroquine given parenterally to mice infected with Plasmodium berghei induces clumping of malarial pigment in intraerythrocytic parasites, as viewed by light microscopy. Quinine and candidate antimalarials WR 33,063, WR 171,669, WR 30,090, and WR 142,490 were singly tested for their ability to influence this clumping process if administered by gavage either before or after chloroquine. Phase constrast and electron microscopical studies showed that these agents not only can inhibit pigment clumping induced by chloroquine when given before chloroquine but can also reverse this process when given afterwards. Such reversal may be effected even if these agents are given at a time after chloroquine when hemozoin configuration consists exclusively of clumps. Electron microscopy on chloroquine-induced pigment clumping reversal by WR 30,090 and WR 33,063 provided evidence that this process, i.e., malarial pigment disaggregation, as seen by light microscopy may result from vesiculation of the postchloroquine enlarged food vacuole containing an aggregate of pigment particles and a pinching off therefrom of vesicles containing individual pigment particles, with a resultant scattering of these throughout the parasite cytoplasm. These studies demonstrate that an antimalarial's in vivo chloroquine-induced pigment dumping-inhibiting and reversing properties can serve as indicators of its oral bioavailability. Therefore, it is proposed that these properties should find application in a bioassay (preclinical primary screen) designed to evaluate the relative oral bioavailability of various physical dosage forms of any candidate antimalarial possessing such properties.