A combination of tetrandrine and chloroquine effectively treats chloroquine resistant falciparum malaria (human) in Aotus monkeys

Malar J.2013 Apr;12

Zuguang Ye(1,2), Knox Van Dyke(2) and Richard Rossan(3)

Institute of Chinese Materia Medica –Beijing China(1), Biochemistry-West Virginia University Medical School,Morgantown,WV 26506 (2),and Gorgas Memorial Laboratory-*retired-Las Vegas,NV

Abstract

Resistance to chloroquine by falciparum malaria has spread throughout the tropical world in the last 50 years. This has prompted a vigorous search for new and effective drugs to combat this deadly disease. Regardless which drug has been used to combat malaria eg artemisinins drug resistance has followed closely. We chose a different approach by using the previously effective drug chloroquine  in combination – a second antimalarial drug tetrandrine that could counter a variety of resistance mechanisms. We tested the drug combination in culture with chloroquine sensitive and resistant Plasmodium falciparum resistant parasites infecting human red cells.Using  Berenbaum Plots we found a 44 fold synergism of the two drugs occurred against chloroquine resistant malaria. This prompted us to try experiments in Aotus monkeys infected with Plasmodium falciparum malaria in human erythrocytes and using the combination  tetrandrine and chloroquine. Parasitemia was rapidly cleared with the two drug combination while chloroquine  was ineffective against  the malarial infection. Recrudescence occurred 7-14 days post drug treatment. A second combination drug treatment cured the animals. Certainly this result emanated via drug and host immune reactions. One malaria infected animal without drug treatment died. This combination forms a possible new basis for human treatment that could be effective against chloroquine resistant malaria. Tetrandrine appears to attack both chloroquine resistant mechanisms ie Multiple Drug Resistance (MDR) and PFCRT.

 

Supplement

The rise of chloroquine resistance in both falciparum and vivax malaria has stimulated the search for new and effective antimalarial agents. However, instead of using more drug screening to find drugs which might have unfavorable side effects, a directed attack on Plasmodium falciparum multiple drug resistance(MDR) and the chloroquine resistance transporter (PfCRT) might be more effective. Tetrandrine is known to be an inhibitor of nuclear factor b which is a transcription inhibitor linked to MDR. It also has been shown be an inhibitor of the MDR-ATPase which inhibits the drug pump. Therefore this bisbenzylisoquinoline, tetrandrine has a dual action which inhibits MDR. Verapamil is a calcium channel inhibitor which reverses MDR and PfCRT resistance. The malaria Vietnam Smith strain that we used in our experiments- likely has both MDR and PfCRT –driven resistance. Tetrandrine is a calcium channel inhibitor which we know inhibits the MDR mechanism and likely inhibits PfCRT like verapamil which is also a calcium channel inhibitor. Our previous work demonstrated that calcium channels are not involved with the resistance per se but these inhibitors are very lipid soluble.  It could well be that the mechanisms involving drug resistance reversal are governed at least in part by their lipid solubility. It is well known that the MDR pump is situated on the membrane of drug resistant cells and it excretes lipid soluble substances out of the cell as demonstrated beautifully by Victor Ling and his colleagues for MDR cancer cells.  The PfCRT mechanism apparently normally carries lipid like substances into a cell. Therefore chloroquine sensitive malarial parasites use the transporter to get chloroquine into parasites. But the mechanism can undergo genetic modification that prevents chloroquine entry or causes pump action reversal to excrete chloroquine. Theoretically tetrandrine could cause PfCRT reversal or somehow affect the genetic modification of PfCRT. It is not entirely clear how the drug mechanism operates but it could just be similar to verapamil but without its overt toxicity.

 Knox Van Dyke-1

Knox Van Dyke-2

Figure 1: Aotus nancymaae Photo: Rosie Bolen

 Knox Van Dyke-3

Knox Van Dyke-4

Knox Van Dyke-5

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