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Efficacy of methylene blue and artesunate as combination antimalarial therapy in a rhesus monkey model of uncomplicated blood‐stage malaria *
Author(s) -
Barker T. L.,
Gettayacamin M.,
Hansukjariya P.,
Van Gessel Y.,
Melendez V.,
TejaIsavadharm P.,
Vennerstrom J.,
Miller R. S.,
Ohrt C. K.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.117
Subject(s) - parasitemia , malaria , artesunate , medicine , pharmacology , combination therapy , artemisinin , adverse effect , immunology , plasmodium falciparum
Background/Aims Methylene blue (MB), an FDA approved drug for methemoglobinemia, also demonstrates in vitro and in vivo antimalarial activity. Artesunate (AS) is widely used to treat malaria in malaria‐endemic countries. The purpose of this study was to evaluate the anti‐malarial efficacy and safety of intravenous MB when given alone and in combination with intravenous AS in rhesus monkeys. Methods A Rhesus/ P. cynomolgi model of uncomplicated blood stage malaria was used to evaluate different combinations of MB and AS. The study was conducted under an approved protocol in an AAALAC accredited animal facility. The study design used a 3 by 3‐factorial design to compare 3 doses of MB (0, 2 and 8 mg/kg) in combination with 3 doses of AS (0, 1 and 8 mg/kg). Thirty‐four healthy rhesus monkeys were randomly assigned to one of 8 different treatment groups or to an infection control group. Study drugs were administered as three once‐daily intravenous injections after threshold parasitemia levels were attained. Results Parasitemia clearance and cure rates demonstrated dose‐dependency. Combinations were much more likely to result in cure. Four monkeys died with clinical and necropsy findings consistent with severe malaria that were not considered to be related to study drugs. All remaining study animals recovered with no adverse sequelae. Conclusions Intravenous methylene blue was well tolerated and demonstrated dose‐dependent anti‐malarial efficacy, as well as apparent synergy with intravenous artesunate. Clinical Pharmacology & Therapeutics (2005) 77 , P59–P59; doi: 10.1016/j.clpt.2004.12.117