Plasmodium chabaudi: association of reversal of chloroquine resistance with increased accumulation of chloroquine in resistant parasites.
The effects of tricyclic antidepressants, desipramine and imipramine, and phenothiazines, chlorpromazine and trifluoperazine, on chloroquine (CQ)-resistant and CQ-sensitive lines of P. chabaudi were examined in vivo. In mice that received daily injections of these drugs the growth of CQ-resistant and CQ-sensitive parasites was unaffected or affected very slightly, if at all. A combination of CQ and each drug suppressed the growth of CQ-resistant parasites in a dose-dependent manner. In addition, in CQ-sensitive parasites each drug also increased the susceptibility to CQ. Measurements of CQ levels by high-performance liquid chromatography showed that CQ accumulated in sensitive parasites to more than twice the level in resistant parasites at 2 to 4 hr after an injection of CQ. Verapamil and desipramine substantially increased CQ levels in both CQ-resistant and CQ-sensitive parasites. These results suggest that not only Ca2+ antagonists but tricyclic antidepressants reverse CQ resistance in CQ-resistant parasites and enhance the inhibitory effect in sensitive parasites by increasing CQ levels in those parasites. The effects of Ca2+ antagonists, tricyclic antidepressants, and phenothiazines on a pyrimethamine-resistant line of P. chabaudi were also studied. None of the Ca2+ antagonists (verapamil, nicardipine, and diltiazem) affected the growth of the parasite in combination with 20 mg/kg pyrimethamine. Tricyclic antidepressants and phenothiazines suppressed pyrimethamine-resistant parasites to some extent. However, the extent of this suppression was less pronounced as compared with that of suppression of CQ resistance by the same drugs.
Miki
A
A
Department of Medical Zoology, Osaka City University Medical School, Japan.
Tanabe
K
K
Nakayama
T
T
Kiryon
C
C
Ohsawa
K
K
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002738:Chloroquine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D002746:Chlorpromazine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003891:Desipramine / Q000494:pharmacology; D004351:Drug Resistance; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005260:Female; D007099:Imipramine / Q000494:pharmacology; D008288:Malaria / Q000469:parasitology*; D051379:Mice; D008813:Mice, Inbred ICR; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D002121:Calcium Channel Blockers; D014268:Trifluoperazine; D002738:Chloroquine; D007099:Imipramine; D003891:Desipramine; D002746:Chlorpromazine