Reversal of chloroquine resistance in falciparum malaria independent of calcium channels.
Racemic verapamil and close structural derivatives gallopamil and devapamil completely reverse chloroquine-resistance in falciparum malaria at 1-2 micromolar concentrations. If the R-(+) isomers of these calcium channel inhibitors are used, chloroquine-resistance is again completely reversed at similar doses. However, these R-(+) isomers do not bind to cardiovascular calcium channels which are stereospecific for the S-(-) isomer of the drugs. Further since calcium channel inhibition is not involved, toxicity associated with this activity can be avoided. Therefore it is possible that a series of R-(+) isomers could be found that alter the resistant state without possessing significant toxicity. It is postulated that these lipophilic drugs are interacting with the mechanism of resistance, possibly a multidrug resistance glycoprotein pump.
Ye
Z G
ZG
Dept. of Pharmacology and Toxicology, West Virginia University Health Sciences Ctr., Morgantown 26506.
Van Dyke
K
K
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002738:Chloroquine; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects*; D005711:Gallopamil / Q000633:toxicity; D007473:Ion Channels / Q000187:drug effects*; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D014700:Verapamil / Q000031:analogs & derivatives / Q000633:toxicity
D007473:Ion Channels; D005711:Gallopamil; D002738:Chloroquine; D014700:Verapamil; C055885:devapamil; D002118:Calcium