Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2000;1998(2):CD000527.
doi: 10.1002/14651858.CD000527.

Artemisinin derivatives for treating severe malaria

H M McIntosh  1 , P Olliaro
Affiliations

Artemisinin derivatives for treating severe malaria

H M McIntosh et al. Cochrane Database Syst Rev. 2000.

Abstract

Background: Artemisinin derivatives may have advantages over quinoline drugs for treating severe malaria since they are fast acting and effective against quinine resistant malaria parasites.

Objectives: The objective of this review was to assess the effects of artemisinin drugs for severe and complicated falciparum malaria in adults and children.

Search strategy: We searched the Cochrane Infectious Diseases Group trials register, Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, Lilacs, African Index Medicus, conference abstracts and reference lists of articles. We contacted organisations, researchers in the field and drug companies.

Selection criteria: Randomised and pseudo-randomised trials comparing artemisinin drugs (rectal, intramuscular or intravenous) with standard treatment, or comparisons between artemisinin derivatives in adults or children with severe or complicated falciparum malaria.

Data collection and analysis: Eligibility, trial quality assessment and data extraction were done independently by two reviewers. Study authors were contacted for additional information.

Main results: Twenty three trials are included, allocation concealment was adequate in nine. Sixteen trials compared artemisinin drugs with quinine in 2653 patients. Artemisinin drugs were associated with better survival (mortality odds ratio 0.61, 95% confidence interval 0.46 to 0.82, random effects model). In trials where concealment of allocation was adequate (2261 patients), this was barely statistically significant (odds ratio 0.72, 95% CI 0.54 to 0.96, random effects model). In 1939 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (odds ratio 0.63, 95% CI 0.44 to 0.88, random effects model). The difference was not significant however when only trials reporting adequate concealment of allocation were analysed (odds ratio 0.78, 95% CI 0.55 to 1.10, random effects model) based on 1607 patients. No difference in neurological sequelae was shown. Compared with quinine, artemisinin drugs showed faster parasite clearance from the blood and similar adverse effects.

Reviewer's conclusions: The evidence suggests that artemisinin drugs are no worse than quinine in preventing death in severe or complicated malaria. No artemisinin derivative appears to be better than the others.

PubMed Disclaimer

Conflict of interest statement

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

Figures

1.1
1.1. Analysis
Comparison 1 Artemisinin drug vs quinine, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Artemisinin drug vs quinine, Outcome 2 Mortality subgrouped as cerebral or non‐cerebral malaria.
1.3
1.3. Analysis
Comparison 1 Artemisinin drug vs quinine, Outcome 3 Neurological sequelae (cerebral malaria).
1.4
1.4. Analysis
Comparison 1 Artemisinin drug vs quinine, Outcome 4 Parasite clearance at day 7.
1.5
1.5. Analysis
Comparison 1 Artemisinin drug vs quinine, Outcome 5 Parasite clearance at day 28.
1.6
1.6. Analysis
Comparison 1 Artemisinin drug vs quinine, Outcome 6 Coma recovery time.
2.1
2.1. Analysis
Comparison 2 Artemisinin drug vs chloroquine, Outcome 1 Mortality.
3.1
3.1. Analysis
Comparison 3 Artemisinin derivative comparison, Outcome 1 Mortality.
4.1
4.1. Analysis
Comparison 4 Artemisinin derivative dose, Outcome 1 Parasite clearance at day 28.
5.1
5.1. Analysis
Comparison 5 Route of administration, Outcome 1 Mortality.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

References to studies included in this review

Anh VNM 89 {unpublished data only}
    1. Anh TK. Qinghaosu in plasmodium falciparum malaria. WHO M20/181/38 17.
    1. Anh TK, Kim NV, Bich NN, Huong N ng, Phuong NV, et al. Randomised comparative study of artesunate intravenously and quinine in loading dose iv on severe and complicated malaria. Manuscript reference and publication status unknown.
Anh VNM 92‐95 {unpublished data only}
    1. Anh TK. Standard does quinine & IV artesunate in treatment of severe and complicated falciparum malaria. Malaria symposium & workshop, Vungtau , WHO/Geneva/TDCRC/CRH December 1992.
    1. Anh TK, Binh TQ, Kim NV. Comparative study of intravenous artesunate followed by oral mefloquine versus intravenous quinine in the treatment of severe and complicated malaria in Vietnam. Symposium on Tropical Medicine Sanya China. 1995.
    1. Anh TK, Binh TQ, Kim NV, et al. Comparative study of intravenous artesunate followed by oral mefloquine versus intravenous quinine in the treatment of severe and complicated malaria in Viet Nam. Unpublished manuscript 1995.
Birku ETH 96‐7 {published data only}
    1. Birku Y, Makonnen E, Bjorkman A. Comparison of rectal artemisinin with intravenous quinine in the treatment of severe malaria in Ethiopia. East African Medical Journal 1999;76(3):154‐9. - PubMed
Bunnag THI 89‐90 {published data only}
    1. Bunnag D, Karbwang J, Harinasuta T. Artemether in the treatment of multiple drug resistant falciparum malaria. Southeast Asian J Trop Med Public Health 1992;23(4):762‐7. - PubMed
Danis WAF 93‐4 {published and unpublished data}
    1. Danis M, Chandenier J, Doumbo O, et al. Results obtained with i.m. artemether versus i.v. quinine in the treatment of severe malaria in a multi‐centre study in Africa. Jpn J Trop Med Hyg 1996;24(suppl 1):93‐6.
    1. Rhone‐Poulenc Rorer Doma. Study Report PAL 393101, Final version. 18 February 1995.
Hien VNM 89‐90 {published data only}
    1. Hien TT, Arnold K, Vinh H, et al. Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Trans R Soc Trop Med Hyg 1992;86(6):582‐3. - PubMed
Hien VNM 91 {published data only}
    1. Hien TT, Phu NH, Mai NT, et al. An open randomized comparison of intravenous and intramuscular artesunate in severe falciparum malaria. Trans R Soc Trop Med Hyg 1992;86(6):584‐5. - PubMed
Hien VNM 91‐6 {published data only}
    1. Hien TT, Day NP, Nguyen HP, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335(2):76‐83. - PubMed
Karbwang THI 91 {published data only}
    1. Karbwang J, Sukontason K, Rimchala W, et al. Preliminary report: a comparative clinical trial of artemether and quinine in severe falciparum malaria. Southeast Asian J Trop Med Public Health 1992;23(4):768‐72. - PubMed
Karbwang THI 92 {published data only}
    1. Karbwang J, Na‐Bangchang K, Wattanakoon Y, Thanavibul A, Harinasuta T. Artemether 5 versus 7 day regimen for severe falciparum malaria. Southeast Asian J Trop Med Public Health 1994;25(4):702‐6. - PubMed
KarbwangTHI92‐4 {published and unpublished data}
    1. Karbwang J, Na‐Bangchang K, Bunnag D, Harinasuta T. A comparative clinical trial of artemether and quinine in the treatment of severe falciparum malaria. WHO/TDR Registry file M20/181/124.
    1. Karbwang J, Tin T, Rimchala W, et al. Comparison of artemether and quinine in the treatment of severe falciparum malaria in south‐east Thailand. Trans R Soc Trop Med Hyg 1995;89(6):668‐71. - PubMed
LooareesuwanTHI95 {published data only}
    1. Looareesuwan S, Wilairatana P, Molunto W, et al. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand. Am J Trop Med Hyg 1997;57(3):348‐53. - PubMed
Murphy KEN 92‐4 {published and unpublished data}
    1. Murphy S, English M, Waruriu C, Mwangi I, Amoukoye E, Crawley J, Newton C, Winstanley P, Peshu N, Marsh K. An open randomised trial of artemether versus quinine in the treatment of cerebral malaria in African children. Trans R Soc Trop Med Hyg 1996;90:298‐301. - PubMed
    1. Murphy S, Marsh K, Winstanley P, Crawley J. An open randomised comparison of artemether with quinine in severe malaria. WHO/TDR Registry file M20/181/98 April 1995.
    1. Rhone‐Puolenc Rorer Doma. Expert report on clinical documentation IC3. August 1996.
Ojuawo NIG (98) {published data only}
    1. Ojuawo A, Adegboye AR, Oyewalw O. Clinical response and parasite clearance in childhood cerebral malaria: A comparison between intramuscular artemether and intravenous quinine. East African Medical Journal 1998;75(8):450‐2.
Olumese NIG 94‐6 {published and unpublished data}
    1. Olumese PE, Bjorkman A, Gbadegesin RA, Adeyemo AA, Walker O. Comparative efficacy of intramuscular artemether and intravenous quinine in NIgerian children with cerebral malaria. Acta Tropica 1999;73:231‐6. - PubMed
PhuongVNM 92‐5 {published data only}
    1. Phuong CXT, Bethell DB, Phuong PT, et al. Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Trans R Soc Trop Med Hyg 1997;91:335‐42. - PubMed
Seaton PNG 92‐5 {published data only}
    1. Seaton RA, Trevett AJ, Wembri JP, Nwokolo N, Naraqi S, Black J, Laurenson IF, Kevau I, Saweri A, Lalloo D, Warrell DA. Randomised comparison of intramuscular artemether and intravenous quinine in adult Melanesian patients with severe or complicated falciparum malaria in Papua New Guinea. Ann Trop Med Parasitol 1998;92(2):133‐9. - PubMed
Taylor MAL 92‐4 {published and unpublished data}
    1. Rhone Poulenc Rorer Doma. Expert report on clinical documentation IC3 Part IV. August 1996:24/39.
    1. Taylor TE, Molyneux ME, Wills BA, Kazembe P. An open randomised trial comparing artemether versus quinine in the treatment of cerebral malaria in Malawian children. WHO/TDR Registry file M20/181/98 1995.
    1. Taylor TE, Wills BA, Courval JM, Molyneux ME. Intramuscular artemether vs intravenous quinine: An open, randomized trial in Malawian children with cerebral malaria. Trop Med Int Health 1998;3(1):3‐8. - PubMed
Thwe MYA 96 {published data only}
    1. Thwe Y, Than M, Phay S, Oo AZ, Soe AY. Artesunate suppository‐mefloquine tablets (Plasmotrim, Rectocaps, Mefloquine, Lactab) in the treatment of severe falciparum malaria. Jpn J Trop Med Hyg 1996;24(suppl 1):25‐32.
vanHensbroekGAM92‐4 {published and unpublished data}
    1. Hensbroek MB, Onyiorah E, Jaffar S, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335(2):69‐75. - PubMed
    1. Hensbroek MB, et al. Treatment of cerebral malaria with artemether. WHO/TDR Registry file P22/181/11.
Vinh VNM 92‐4 {published data only}
    1. Vinh H, Huong NN, Ha TTB, Cuong BM, Phu NH, Chau TTH, Quoi PT, Arnold K, Hien TT. Severe and complicated malaria treated with artemisinin, artesunate or artemether in Viet Nam. Trans R Soc Trop Med Hyg 1997;91:465‐7. - PubMed
White GAM 89 {published data only}
    1. White NJ, Waller D, Crawley J, et al. Comparison of artemether and chloroquine for severe malaria in Gambian children. Lancet 1992;339(8789):317‐21. - PubMed
Win MYA 89‐91 {published data only}
    1. Win Kyaw, Marlar Than, Ye Thwe. Comparison of combinations of parenteral artemisinin derivatives plus oral mefloquine with intravenous quinine plus oral tetracycline for treating cerebral malaria. Bull World Health Organization 1992;70(6):777‐82. - PMC - PubMed

References to studies excluded from this review

Karbwang THI 92‐4i {unpublished data only}
    1. Karbwang J, Tin T, Rimchala W, Sukontason K, Bunnag D, Harinasuta T. Comparative clinical trial of artemether and quinine in severe falciparum malaria. 6th International Congress for Infectious Diseases Prague. April 16‐30 1994:Abstract 1001.
LuxemburgerTHI‐MYA93 {published data only}
    1. Luxemburger C, Nosten F, Shortar D, Raimond D, Chongsuphajaisiddhi T, White NJ. Oral artesunate in the treatment of uncomplicated hyperparasitaemic falciparum malaria. Am J Trop Med Hyg 1995;53(5):522‐5. - PubMed
Molyneux MAL {published data only}
    1. Molyneux ME, Mhango E, Kazembe P, Wirima JJ, Wills BA, Taylor TE. Artemether in the treatment of cerebral malaria in Malawian children. 6th International Conference for Infectious Diseases Prague. April 27 1994.
Salako NIG 92 {published data only}
    1. Salako LA, Walker O, Sowunmi A. Parenteral therapy of moderately severe malaria: comparison of intramuscular artemether and intramuscular sulfadoxine‐pyrimethamine. Trans R Soc Trop Med Hyg 1994;88(1):89‐91. - PubMed
    1. Salako LA, Walker O, Sowunmi SJ, Omokhodion SJ, Risquat Adio, Oduola AMJ. Artemether in moderately severe and cerebral malaria in Nigerian children. Trans R Soc Trop Med Hyg 1994;88(suppl 1):13‐15. - PubMed
Salako NIG 94 {published data only}
    1. Salako LA, Walker O, Sowunmi SJ, Omokhodion SJ, Risquat Adio, Oduola AMJ. Artemether in moderately severe and cerebral malaria in Nigerian children. Trans R Soc Trop Med Hyg 1994;88(suppl 1):13‐15. - PubMed
Sowumni NIG 93‐4 {published data only}
    1. Sowunmi A, Oduola AMJ. Efficacy of artemether in severe falciparum malaria in African children. Acta Tropica 1996;61:57‐63. - PubMed
Taylor MAL 92i {published data only}
    1. Taylor TE, Wills BA, Kazembe P, et al. Rapid coma resolution with artemether in Malawian children with cerebral malaria. Lancet 1993;341(8846):661‐2. - PubMed
Walker NIG 91‐4i {unpublished data only}
    1. Walker O. Artemether in cerebral malaria in Nigeria. WHO/TDR registry file M20/181/135 August 18 1995.
Walker NIG 91‐4ii {published data only}
    1. Walker O, Salako LA, Omokhodion SI, Sowumni A. An open randomised comparative study of intramuscular artemether and intravenous quinine in cerebral malaria in children. Trans R Soc Trop Med Hyg 1993;87:564‐6. - PubMed

References to studies awaiting assessment

Myint MYA 85 {published data only}
    1. Pe Than Myint, Tin Shwe. A controlled clinical trial of artemether (qinghaosu derivative) versus quinine in complicated and severe falciparum malaria. Trans R Soc Trop Med Hyg 1987;81:559‐561. - PubMed
Shwe MYA 87‐91 {published data only}
    1. Shwe T, Hla KK. The effect of artemether plus mefloquine on Myanmar patients with complicated falciparum malaria. SE Asian J Trop Med Pub Health 1992;23(4):117‐121. - PubMed
    1. Tin Shwe, Pe Than Myint, Ye Htut, Myint W, Lin Soe. The effect of mefloquine‐artemether compared with quinine on patients with complicated falciparum malaria. Trans R Soc Trop Med Hyg 1988;82:665‐6. - PubMed
Vinh VNM 92 {unpublished data only}
    1. Vinh H, Arnold K, Cuong BM, Phu NH, Chau TTH, Hao NTM. Treatment of cerebral malaria comparing artemisinin suppositories with intravenous artesunate and intravenous quinine. XIIIth International Congress for Tropical Medicine and Malaria (Abstracts). 1992:9. - PubMed

Additional references

Altman 1996
    1. Altman DG, Bland JM. Detecting skewness from summary information. BMJ 1996;313:1200. - PMC - PubMed
de Vries 1996
    1. Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 1996;52(6):818‐36. - PubMed
Egger 1997
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315:629‐34. - PMC - PubMed
Gardner 1986
    1. Gardner MJ, Altman DG. Confidence intervals rather than P values: estimation rather than hypothesis testing. BMJ 1986;292:746‐50. - PMC - PubMed
Hien 1993
    1. Hien TT, White NJ. Qinghaosu. Lancet 1993;341:603‐608. - PubMed
Hoffman 1996
    1. Hoffman SL. Artemether in severe malaria ‐ still too many deaths. N Eng J Med 1996;335(2):124‐6. - PubMed
IPD 99
    1. The Artemether‐Quinine Meta‐analysis Study Group. A meta‐analysis of trials comparing artemether with quinine in the treatment of severe falciparum malaria using individual patient data. Final report July 1999. - PubMed
Meshnick 1996
    1. Meshnick SR, Taylor TE, Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxidases: from herbal remedy to targeted chemotherapy. Microbiol Rev 1996;60(2):301‐315. - PMC - PubMed
PRISM 1996
    1. Unit for Policy Research in Science and Medicine. Malaria Research: an audit of international activity. PRISM 1996 Report No 7.
Ribeiro 1998
    1. Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Médecine Tropicale 1998;58(suppl 3):50‐53. - PubMed
Sackett 1996
    1. Sackett DL. On some clinically useful measures of the effects of treatment. Evidence Based Medicine 1996;1:37‐8.
White 1989
    1. White NJ, Krishna S. Treatment of malaria: some considerations and limitations of the current methods of assessment. Trans R Soc Trop Med Hyg 1989;83:767‐7. - PubMed
WHO 1973
    1. World Health Organization. Chemotherapy of malaria and resistance to antimalarials. Technical Report Series 1973, (529). - PubMed
WHO 1986
    1. World Health Organization. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986;80(suppl). - PubMed
WHO 1990a
    1. World Health Organization. Practical chemotherapy of malaria. Technical Report Series 1990, (805). - PubMed
WHO 1990b
    1. World Health Organization (Warrell DA, Molyneux ME, Beales PF. eds). Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(suppl 2):1‐65. - PubMed
WHO 1995
    1. World Health Organization. The world health report 1995: bridging the gaps. WHO, Geneva 1995.
Woerdenbag 1990
    1. Woerdenbag HJ, Lugt CB, Pras N. Artemisia annua L.:a source of novel antimalarial drugs. Pharm Weekbl [Sci] 1990;12(5):169‐81. - PubMed

References to other published versions of this review

IHM 1998
    1. Artemisinin drugs for treating malaria. International Health Matters. Department for International Development. Suitable health Benefits from Applied Research: Malaria 1998, (3):10.
McIntosh 1998
    1. McIntosh HM, Olliaro P. Treatment of severe malaria with Artemisinin derivatives. A systematic review of randomised controlled trials. Médecine Tropicale 1998;58(3 suppl):61‐2. - PubMed

Publication types

LinkOut - more resources