title: Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates.
abstract: BACKGROUND
  Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria.
  
  
  METHODS
  In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay.
  
  
  RESULTS
  Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC₅₀) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected.
  
  
  CONCLUSIONS
  Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria.
authors.forename: Peter
authors.initials: P
authors.lastname: Starzengruber
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fuehrer
authors.forename: Paul
authors.initials: P
authors.lastname: Swoboda
authors.forename: Deepa
authors.initials: D
authors.lastname: Ganesh
authors.forename: Rashidul
authors.initials: R
authors.lastname: Haque
authors.forename: Wasif A
authors.initials: WA
authors.lastname: Khan
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Graninger
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria. harald.noedl@meduniwien.ac.at.
authors.forename: Harald
authors.initials: H
authors.lastname: Noedl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D002648:Child; D002738:Chloroquine / Q000494:pharmacology; D002981:Clindamycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D055815:Young Adult
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D037621:Artemisinins; C055852:tafenoquine; D002981:Clindamycin; C039060:artenimol; D002738:Chloroquine; C000867:mirincamycin