title: Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria.
abstract: Severe malaria due to Plasmodium falciparum causes more than 800,000 deaths every year. Primary therapy with quinine or artesunate is generally effective in controlling P. falciparum parasitemia, but mortality from cerebral malaria and other forms of severe malaria remains unacceptably high. Long-term cognitive impairment is also common in children with cerebral malaria. Of the numerous adjunctive therapies for cerebral malaria and severe malaria studied over the past five decades, only one (albumin) was associated with a reduction in mortality. In this article, we review past and ongoing studies of adjunctive therapy, and examine the evidence of efficacy for newer therapies, including inhibitors of cytoadherence (e.g., levamisole), immune modulators (e.g., rosiglitazone), agents that increase nitric oxide levels (e.g., arginine) and neuroprotective agents (e.g., erythropoietin).
authors.affiliation: Center for Global Pediatrics, 717 Delaware Street SE, Room 363, Minneapolis, MN 55455, USA. ccj@umn.edu
authors.forename: Chandy C
authors.initials: CC
authors.lastname: John
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kutamba
authors.forename: Keith
authors.initials: K
authors.lastname: Mugarura
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D001120:Arginine / Q000627:therapeutic use; D004921:Erythropoietin / Q000627:therapeutic use; D006801:Humans; D007978:Levamisole / Q000627:therapeutic use; D016779:Malaria, Cerebral / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy*; D010963:Plasmodium falciparum; D016032:Randomized Controlled Trials as Topic; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004921:Erythropoietin; D007978:Levamisole; D001120:Arginine
references.citation: Stroke. 2009 Dec;40(12):e647-56
references.pmid: 19834012
references.citation: Trans R Soc Trop Med Hyg. 1997 Jan-Feb;91(1):22-4
references.pmid: 9093619
references.citation: Am J Trop Med Hyg. 1998 Mar;58(3):348-53
references.pmid: 9546417
references.citation: J Pediatr. 1997 Jul;131(1 Pt 1):125-9
references.pmid: 9255203
references.citation: BMC Med. 2009 Dec 09;7:75
references.pmid: 20003178
references.citation: PLoS Pathog. 2006 Sep;2(9):e100
references.pmid: 17009869
references.citation: Trends Parasitol. 2010 Jan;26(1):11-5
references.pmid: 19932638
references.citation: Trends Parasitol. 2009 Jan;25(1):30-6
references.pmid: 19008152
references.citation: Pediatrics. 2008 Jul;122(1):e92-9
references.pmid: 18541616
references.citation: Arch Dis Child. 1997 Mar;76(3):219-26
references.pmid: 9135262
references.citation: Arch Dis Child. 2006 Feb;91(2):142-8
references.pmid: 16326798
references.citation: Lancet. 2000 Feb 26;355(9205):701-6
references.pmid: 10703801
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2634-9
references.pmid: 18263734
references.citation: Nat Med. 2004 Feb;10(2):143-5
references.pmid: 14745442
references.citation: Cytokine. 2008 Mar;41(3):204-8
references.pmid: 18282763
references.citation: Am J Trop Med Hyg. 1991 Nov;45(5):608-12
references.pmid: 1951871
references.citation: J Infect Dis. 2008 Aug 15;198(4):602-8
references.pmid: 18605903
references.citation: N Engl J Med. 2006 Nov 16;355(20):2085-98
references.pmid: 17108343
references.citation: Adv Exp Med Biol. 2002;509:251-72
references.pmid: 12572998
references.citation: Crit Care Med. 2009 Feb;37(2):516-22
references.pmid: 19114891
references.citation: Am J Trop Med Hyg. 2008 Feb;78(2):198-205
references.pmid: 18256412
references.citation: Glia. 1997 Feb;19(2):91-103
references.pmid: 9034826
references.citation: Trop Med Int Health. 2006 Jan;11(1):115-24
references.pmid: 16398762
references.citation: QJM. 1996 Aug;89(8):591-7
references.pmid: 8935480
references.citation: Malar J. 2007 Jul 27;6:96
references.pmid: 17662142
references.citation: Am J Trop Med Hyg. 2001 Jan-Feb;64(1-2 Suppl):57-67
references.pmid: 11425178
references.citation: Malar J. 2008 May 19;7:83
references.pmid: 18489763
references.citation: N Engl J Med. 1982 Feb 11;306(6):313-9
references.pmid: 7033788
references.citation: J Infect Dis. 1995 May;171(5):1317-22
references.pmid: 7751709
references.citation: J Infect Dis. 2006 Sep 15;194(6):837-45
references.pmid: 16941352
references.citation: Trans R Soc Trop Med Hyg. 2005 May;99(5):333-40
references.pmid: 15780339
references.citation: N Engl J Med. 1996 Sep 12;335(11):800-6
references.pmid: 8703186
references.citation: Trop Med Int Health. 2003 Aug;8(8):680-4
references.pmid: 12869088
references.citation: Br J Haematol. 2001 May;113(2):486-91
references.pmid: 11380421
references.citation: Lancet. 2008 Nov 1;372(9649):1545-54
references.pmid: 18984187
references.citation: Malar J. 2008 Oct 17;7:210
references.pmid: 18928535
references.citation: Infect Immun. 1998 Dec;66(12):5972-9
references.pmid: 9826380
references.citation: Clin Infect Dis. 2002 May 1;34(9):1192-8
references.pmid: 11941545
references.citation: Lancet. 1988 Jul 9;2(8602):64-6
references.pmid: 2898696
references.citation: J Exp Med. 1996 Aug 1;184(2):557-67
references.pmid: 8760809
references.citation: Trop Med Int Health. 2002 Oct;7(10):823-30
references.pmid: 12358616
references.citation: Lancet. 2008 Nov 1;372(9649):1555-62
references.pmid: 18984188
references.citation: N Engl J Med. 1989 Jun 15;320(24):1586-91
references.pmid: 2657427
references.citation: Malar J. 2008 Jan 07;7:3
references.pmid: 18179698
references.citation: Br J Clin Pharmacol. 1996 Jan;41(1):29-34
references.pmid: 8824690
references.citation: PLoS Clin Trials. 2007 Feb 09;2(2):e1
references.pmid: 17369877
references.citation: Eur Neurol. 2001;46(4):192-7
references.pmid: 11721125
references.citation: Trends Parasitol. 2009 Jul;25(7):314-8
references.pmid: 19541540
references.citation: J Infect Dis. 1988 Aug;158(2):325-31
references.pmid: 3042874
references.citation: Ann Trop Med Parasitol. 1996 Aug;90(4):395-402
references.pmid: 8944083
references.citation: PLoS Clin Trials. 2006 Sep 15;1(5):e21
references.pmid: 16998584
references.citation: Indian J Med Res. 2002 Jan;115:17-21
references.pmid: 12424933
references.citation: Nature. 2005 Mar 10;434(7030):214-7
references.pmid: 15759000
references.citation: J Dev Behav Pediatr. 2002 Oct;23(5):353-64
references.pmid: 12394524
references.citation: Am J Trop Med Hyg. 1994 Aug;51(2):198-203
references.pmid: 7521140
references.citation: J Infect Dis. 2009 May 15;199(10):1536-45
references.pmid: 19392627
references.citation: Malar J. 2007 Oct 24;6:138
references.pmid: 17958887
references.citation: J Infect Dis. 2007 Aug 1;196(3):460-6
references.pmid: 17597461
references.citation: J Infect Dis. 1996 Nov;174(5):1091-7
references.pmid: 8896514
references.citation: Curr Opin Infect Dis. 2008 Oct;21(5):468-75
references.pmid: 18725795
references.citation: Clin Exp Immunol. 1992 Dec;90(3):357-62
references.pmid: 1458672
references.citation: Blood. 2000 Jul 1;96(1):327-33
references.pmid: 10891469
references.citation: Pediatrics. 2007 Feb;119(2):e360-6
references.pmid: 17224457
references.citation: Trans R Soc Trop Med Hyg. 1998 Mar-Apr;92(2):214-8
references.pmid: 9764337
references.citation: Clin Infect Dis. 2009 Sep 15;49(6):841-9
references.pmid: 19673614
references.citation: N Engl J Med. 1992 Nov 19;327(21):1473-7
references.pmid: 1406879
references.citation: Malar J. 2008 Oct 14;7:208
references.pmid: 18854046
references.citation: Adv Parasitol. 2002;52:235-64
references.pmid: 12521262
references.citation: Malar J. 2009 Jul 24;8:169
references.pmid: 19630971
references.citation: Vaccine. 2004 Jul 29;22(21-22):2701-12
references.pmid: 15246600
references.citation: QJM. 2002 May;95(5):285-90
references.pmid: 11978899
references.citation: Am J Trop Med Hyg. 1997 Apr;56(4):397-403
references.pmid: 9158047
references.citation: Clin Perinatol. 2008 Dec;35(4):793-807, viii
references.pmid: 19026341
references.citation: JAMA. 2004 Jun 2;291(21):2542-4
references.pmid: 15173142
references.citation: Clin Infect Dis. 2005 Feb 15;40(4):538-45
references.pmid: 15712076
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1990;14(6):835-62
references.pmid: 2277850
references.citation: JAMA. 2005 Mar 23;293(12):1461-70
references.pmid: 15784869
references.citation: Transfus Clin Biol. 2008 Feb-Mar;15(1-2):56-7
references.pmid: 18501654
references.citation: Blood. 2003 Mar 15;101(6):2405-11
references.pmid: 12433689
references.citation: JAMA. 2008 Feb 27;299(8):914-24
references.pmid: 18314434
references.citation: BMJ. 2005 Aug 6;331(7512):337-43
references.pmid: 16081449
references.citation: Lancet. 2005 Aug 27-Sep 2;366(9487):717-25
references.pmid: 16125588
references.citation: Parasitol Res. 2009 Nov;105(6):1557-66
references.pmid: 19693540
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1321-6
references.pmid: 18195363