title: Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys.
abstract: BACKGROUND
  In 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.
  
  
  METHODS
  The 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 5×10(6) 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.
  
  
  CONCLUSIONS
  Parasitaemia 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Pharmacology, Institute of Chinese Materia Medica, Academy of Traditional Chinese Medicine, Beijing 100700, China.
authors.forename: Zuguang
authors.initials: Z
authors.lastname: Ye
authors.forename: Knox
authors.initials: K
authors.lastname: Van Dyke
authors.forename: Richard N
authors.initials: RN
authors.lastname: Rossan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D001029:Aotus trivirgatus; D044182:Benzylisoquinolines / Q000008:administration & dosage*; D002738:Chloroquine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000379:methods; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000302:isolation & purification*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D044182:Benzylisoquinolines; C009438:tetrandrine; D002738:Chloroquine
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