Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

Abstract

BackgroundIn vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man.MethodsThe Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions.Results and DiscussionParasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments.ConclusionsThis combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling.Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct.

Nonhuman Primates

“…Owl monkeys have been used extensively in the study of malaria, including maintenance of various malarial strains, antigen production, studies of host-vector relationships, parasite life-cycles, and potential therapeutics (Aikawa et al, 1988;Herrera et al, 2002;Ye et al, 2013). Owl monkeys are susceptible to human and nonhuman LABORATORY ANIMAL MEDICINE primate malarias and can transmit these infections to mosquitoes.…”

Antimalarial Activity of Various Bisbenzylisoquinoline and AporphineBenzylisoquinoline Alkaloids and their Structure-Activity Relationships against Chloroquine – Sensitive and Resistant Plasmodium falciparum Malaria in vitro

“…Recently, we have demonstrated that tetrandrine (a bisbenzyl isoquinoline) in combination with chloroquine can cure chloroquineresistant-falciparum malaria in Aotus monkeys if given over a several week period [24]. Since we know that tetrandrine can boost the antimalarial activity of chloroquine over 40 fold in a chloroquineresistant falciparum malarial strain [2], and since tetrandrine has a long biological half-life (weeks) in man and monkeys, our studies in Aotus should not be particularly surprising.…”

Cheminformatics Based Machine Learning Models for AMA1‐RON2 Abrogators for Inhibiting Plasmodium falciparum Erythrocyte Invasion

“…Since the model has been developed upon the inhibitors of AMA1‐RON2 interaction, we feel an important achievement of this work is to produce a testable hypothesis for experimental biologists to find out whether, in addition to other possible mechanisms, these compounds work as anti‐malarials by inhibiting interaction of AMA1 and RON2. We feel this is relevant as Tetrandrine has been recently shown to work even on Chloroquine resistant strains of P. Falciparum in Aotus monkeys 37a. As Quinines target intra‐erythrocytic stage therefore a strong possibility exists that Tetrandrine works by a different mechanism.…”