In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains.
BACKGROUND
Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca²⁺-ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane) was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy.


METHODS
Drug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay.


RESULTS
The sum 50% and 90% fractional inhibitory concentration (∑FIC₅₀, ₉₀) of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4.


CONCLUSIONS
The interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets.
Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria.
Oyindamola O
OO
Abiodun
Reto
R
Brun
Sergio
S
Wittlin
D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D004347:Drug Interactions; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D019271:Hypoxanthine / Q000378:metabolism; D007553:Isotope Labeling; D010545:Peroxides / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology*; D014316:Tritium / Q000378:metabolism
D000962:Antimalarials; D037621:Artemisinins; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D013141:Spiro Compounds; D014316:Tritium; D019271:Hypoxanthine; C489136:arterolane; D019284:Thapsigargin; C031327:artemisinin