title: Synergistic anti-malarial action of cryptolepine and artemisinins.
abstract: BACKGROUND
  Cryptolepine (CPE) is the major indoloquinoline isolated from the popular West African anti-malarial plant, Cryptolepis sanguinolenta. CPE possesses various pharmacological activities with potent anti-malarial activity against both chloroquine (CQ)-resistant and -sensitive strains. The search for safe and novel anti-malarial agents and combinations to delay resistance development to Plasmodium falciparum directed this work aimed at evaluating the anti-malarial interaction and safety of CPE in combination with some artemisinin derivatives.
  
  
  METHODS
  The in vitro SYBR Green I, fluorescent-based, drug sensitivity assay using a fixed ratio method was carried out on the CQ-sensitive plasmodial strain 3D7 to develop isobolograms from three CPE-based combinations with some artemisinin derivatives. CPE and artesunate (ART) combinations were also evaluated using the Rane's test in ICR mice infected with Plasmodium berghei NK-65 strains in a fixed ratio combination (1:1) and fractions of their ED50s in order to determine the experimental ED50 (Zexp) of the co-administered compounds. Isobolograms were constructed to compare the Zexp to the Zadd.
  
  
  RESULTS
  CPE exhibited promising synergistic interactions in vitro with ART, artemether and dihydroartemisinin. In vivo, CPE combination with ART again showed synergy as the Zexp was 1.02 ± 0.02, which was significantly less than the Zadd of 8.3 ± 0.31. The haematological, biochemical, organ/body weight ratio and histopathology indices in the rats treated with CPE at all doses (25, 50, 100 mg kg(-1) po) and in combination with ART (4 mg kg(-1)) showed no significant difference compared to the control group.
  
  
  CONCLUSIONS
  The combination of CPE with the artemisinin derivatives were safe in the rodent model and showed a synergistic anti-malarial activity in vivo and in vitro. This study supports the basis for the selection of CPE as a prospective lead compound as the search for new anti-malarial combinations continues.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. forkuoarnold@yahoo.com.
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Forkuo
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. cansah.pharm@knust.edu.gh.
authors.forename: Charles
authors.initials: C
authors.lastname: Ansah
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. qwesimensah@gmail.com.
authors.forename: Kwesi M
authors.initials: KM
authors.lastname: Boadu
authors.affiliation: Department of Biomedical and Forensic Sciences, School of Biological Science, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana. jonboamus@yahoo.com.
authors.forename: Johnson N
authors.initials: JN
authors.lastname: Boampong
authors.affiliation: Department of Biomedical and Forensic Sciences, School of Biological Science, College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana. elvisameyaw@gmail.com.
authors.forename: Elvis O
authors.initials: EO
authors.lastname: Ameyaw
authors.affiliation: Department of Immunology, Noguchi Memorial Institute for Biomedical Research, University of Ghana, Legon, Ghana. bgyan@noguchi.ug.edu.gh.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Gyan
authors.affiliation: Department of Immunology, Noguchi Memorial Institute for Biomedical Research, University of Ghana, Legon, Ghana. atwumwaaarku@noguchi.ug.edu.gh.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Arku
authors.affiliation: Department of Immunology, Noguchi Memorial Institute for Biomedical Research, University of Ghana, Legon, Ghana. mofori@noguchi.ug.edu.gh.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Ofori
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D031106:Cryptolepis / Q000737:chemistry; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D026121:Indole Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D026121:Indole Alkaloids; D011804:Quinolines; C024015:cryptolepine; C031327:artemisinin