title: Effect of mild medical hypothermia on in vitro growth of Plasmodium falciparum and the activity of anti-malarial drugs.
abstract: BACKGROUND
  Cerebral malaria remains a medical emergency with high mortality. Hypo-perfusion due to obstructed blood vessels in the brain is thought to play a key role in the pathophysiology of cerebral malaria leading to neurological impairment, long-term neuro-cognitive sequelae and, potentially, death. Due to the rapid reversibility of vascular obstruction caused by sequestered Plasmodium falciparum, it is hypothesized that mild medical hypothermia--a standard intervention for other medical emergencies--may improve clinical outcome. This preclinical in vitro study was performed to assess the impact of mild hypothermia on parasite growth and the intrinsic activity of anti-malarials drugs.
  
  
  METHODS
  Three laboratory-adapted clones and two clinical isolates were used for growth assays and standardized drug sensitivity assessments using the standard HRP2 assay. All assays were performed in parallel under normothermic (37 °C), mild hypothermic (32 °C), and hyperthermic (41 °C) conditions.
  
  
  RESULTS
  Parasite growth was higher under standard temperature condition than under hypo- or hyperthermia (growth ratio 0.85; IQR 0.25-1.06 and 0.09; IQR 0.05-0.32, respectively). Chloroquine and mefloquine had comparable in vitro activity under mild hypothermic conditions (ratios for IC50 at 37 °C/32 °C: 0.88; 95% CI 0.25-1.50 and 0.86; 95% CI 0.36-1.36, respectively) whereas dihydroartemisinin was more active under mild hypothermic conditions (ratio for IC50 at 37 °C/32 °C: 0.27; 95% CI 0.19-0.27). Hyperthermia led by itself to almost complete growth inhibition and precluded further testing of the activity of anti-malarial drugs.
  
  
  CONCLUSIONS
  This preclinical evaluation demonstrates that mild medical hypothermia inhibits in vitro growth of P. falciparum and enhances the pharmacodynamic activity of artemisinin derivatives. Based on these preclinical pharmacodynamic data, the further clinical development of mild medical hypothermia as adjunctive treatment to parenteral artesunate for cerebral malaria is warranted.
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Khalid
authors.initials: K
authors.lastname: Rehman
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sauerzopf
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Luzia
authors.initials: L
authors.lastname: Veletzky
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Lötsch
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Groger
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. michael.ramharter@medizin.uni-tuebingen.de.|Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon. michael.ramharter@medizin.uni-tuebingen.de.|Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany. michael.ramharter@medizin.uni-tuebingen.de.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-9259-1885
authors.initials: M
authors.lastname: Ramharter
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D003080:Cold Temperature; D015767:Mefloquine / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000528:radiation effects*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C039060:artenimol; D002738:Chloroquine; D015767:Mefloquine
keywords: Drug activity; HRP2; Hypothermia; In vitro; Malaria; P. falciparum