Top

Published in:

Open Access 01-12-2009 | Research

Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali

Authors: Stéphane Picot, Anne-Lise Bienvenu, Salimata Konate, Sibiri Sissoko, Abdoulaye Barry, Elisabeth Diarra, Karidiatou Bamba, Abdoulaye Djimdé, Ogobara K Doumbo

Published in: Malaria Journal | Issue 1/2009

Abstract

Background

Cerebral malaria carries an unacceptable case fatality rate in children despite timely and adequate chemotherapy. To improve the survival rate, adjunctive therapies previously tested mainly focused on the modulation of the inflammatory response, without definitive effect in humans. In this context, a new adjunctive strategy using a neuroprotective drug: erythropoietin (epoietin-beta, Epo) was proposed.

Methods

An open-labelled study including cerebral malaria children (Blantyre coma score below 3) was conducted in Mali. The objective was to assess the short-term safety (seven days) of erythropoietin at high doses (1,500 U/kg/day during three days) combined to quinine.

Results

35 patients with unrousable coma were included in the study. None of expected side effects of erythropoietin were observed during the seven days follow-up. No significant increase in the case fatality rate (7/35 patients) was observed compared to other studies with mortality rates ranging from 16 to 22% in similar endemic areas.

Conclusion

These data provide the first evidence of the short-term safety of erythropoietin at high doses combined to quinine. A multicentre study is needed to assess the potential of Epo as an adjunctive therapy to increase the survival during cerebral malaria.

Clinical registration number

ClinicalTrials.gov ID: NCT00697164

Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group: Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005, 366: 717-725. 10.1016/S0140-6736(05)67176-0.CrossRefPubMed

Golenser J, McQuillan J, Hee L, Mitchell AJ, Hunt MH: Conventional and experimental treatment of cerebral malaria. Int J Parasitol. 2006, 36: 583-593. 10.1016/j.ijpara.2006.02.009.CrossRefPubMed

Di Perri G, Di Perri IG, Monteiro GB, Bonora S, Hennig C, Cassatella M, Micciolo R, Vento S, Dusi S, Bassetti D: Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J Infect Dis. 1995, 171: 1317-1322.CrossRefPubMed

van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S, Kwiatkowski D, Greenwood B: The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis. 1996, 174: 1091-1097.CrossRefPubMed

Thuma PE, Mabeza GF, Biemba G, Bhat GJ, McLaren CE, Moyo VM, Zulu S, Khumalo H, Mabeza P, M'Hango A, Parry D, Poltera AA, Brittenham GM, Gordeuk VR: Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria. Trans R Soc Trop Med Hyg. 1998, 92: 214-218. 10.1016/S0035-9203(98)90753-2.CrossRefPubMed

Day N, Dondorp AM: The management of patients with severe malaria. Am J Trop Med Hyg. 2007, 77: 29-35.PubMed

Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, Harinasuta T: Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med. 1982, 306: 313-319.CrossRefPubMed

Sirén AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P: Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA. 2001, 98: 4044-4049. 10.1073/pnas.051606598.PubMedCentralCrossRefPubMed

Villa P, Bigini P, Mennini T, Agnello D, Laragione T, Cagnotto A, Viviani B, Marinovich M, Cerami A, Coleman TR, Brines M, Ghezzi P: Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med. 2003, 198: 971-975. 10.1084/jem.20021067.PubMedCentralCrossRefPubMed

10.

Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Rüther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Sirén AL: Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002, 8: 495-505.PubMedCentralPubMed

11.

Li F, Chong ZZ, Maiese K: Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Neurosignals. 2004, 13: 265-289. 10.1159/000081963.CrossRefPubMed

12.

Chen J, Chopp M: Neurorestorative treatment of stroke: cell and pharmacological approaches. NeuroRx. 2006, 3: 466-473. 10.1016/j.nurx.2006.07.007.PubMedCentralCrossRefPubMed

13.

Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ: Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. J Neurosurg. 2009, 111 (1): 171-80. 10.3171/2009.3.JNS081332.CrossRefPubMed

14.

Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E, Diaz D, Gomez D, Hand C, Coleman T, Cerami A: Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA. 2004, 101: 14907-14912. 10.1073/pnas.0406491101.PubMedCentralCrossRefPubMed

15.

Digicaylioglu M, Lipton SA: Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature. 2001, 412: 641-647. 10.1038/35088074.CrossRefPubMed

16.

Buemi M, Cavallaro E, Floccari F, Sturiale A, Aloisi C, Trimarchi M, Corica F, Frisina N: The pleiotropic effects of erythropoietin in the central nervous system. J Neuropathol Exp Neurol. 2003, 62: 228-236.CrossRefPubMed

17.

Kaiser K, Texier A, Ferrandiz J, Buguet A, Meiller A, Latour C, Peyron F, Cespuglio R, Picot S: Recombinant Human Erythropoietin Prevents the Death of Mice during Cerebral Malaria. J Infect Dis. 2006, 193: 987-995. 10.1086/500844.CrossRefPubMed

18.

Storring PL, Tiplady RJ, Gaines Das RE, Stenning BE, Lamikanra A, Rafferty B, Lee J: Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol. 1998, 100: 79-89. 10.1046/j.1365-2141.1998.00521.x.CrossRefPubMed

19.

Fukuda MN, Sasaki H, Lopez L, Fukuda M: Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood. 1989, 73: 84-89.PubMed

20.

Ghezzi P, Brines M: Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ. 2004, 11 (Suppl 1): 37-44. 10.1038/sj.cdd.4401450.CrossRef

21.

World Health Organization: Guidelines for the treatment of malaria. Geneva. 2006

22.

Miyashita K, Tojo A, Kimura K, Goto A, Omata M, Nishiyama K, Fujita T: Blood pressure response to erythropoietin injection in hemodialysis and predialysis patients. Hypertens Res. 2004, 27: 79-84. 10.1291/hypres.27.79.CrossRefPubMed

23.

Rosenzweig MQ, Bender CM, Lucke JP, Yasko JM, Brufsky AM: The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. J Pain Symptom Manage. 2004, 27: 185-190. 10.1016/j.jpainsymman.2003.06.010.CrossRefPubMed

24.

Praygod G, de Frey A, Eisenhut M: Artemisinin derivatives versus quinine in treating severe malaria in children: a systematic review. Malar J. 2008, 7: 210-10.1186/1475-2875-7-210.PubMedCentralCrossRefPubMed

25.

Newton CR, Krishna S: Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther. 1998, 79: 1-53. 10.1016/S0163-7258(98)00008-4.CrossRefPubMed

26.

Enwere G: A review of the quality of randomized clinical trials of adjunctive therapy for the treatment of cerebral malaria. Trop Med Int Health. 2005, 10: 1171-1175. 10.1111/j.1365-3156.2005.01505.x.CrossRefPubMed

27.

Namutangula B, Ndeezi G, Byarugaba JS, Tumwine JK: Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: a randomized clinical trial. Malar J. 2007, 6: 138-10.1186/1475-2875-6-138.PubMedCentralCrossRefPubMed

28.

Bienvenu AL, Ferrandiz J, Kaiser K, Latour C, Picot S: Artesunate-erythropoietin combination for murine cerebral malaria treatment. Acta Trop. 2008, 106: 104-108. 10.1016/j.actatropica.2008.02.001.CrossRefPubMed

29.

Brines M, Cerami A: Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 2005, 6: 484-494. 10.1038/nrn1687.CrossRefPubMed

30.

Ehrenreich H, Aust C, Krampe H, Jahn H, Jacob S, Herrmann M, Siren AL: Erythropoietin: novel approaches to neuroprotection in human brain disease. Metab Brain Dis. 2004, 19: 195-206. 10.1023/B:MEBR.0000043969.96895.3c.CrossRefPubMed

31.

Brines M, Cerami A: Discovering erythropoietin's extra-hematopoietic functions, biology and clinical promise. Kidney Int. 2006, 70: 246-250. 10.1038/sj.ki.5001546.CrossRefPubMed

32.

Casals-Pascual C, Idro R, Picot S, Roberts DJ, Newton CR: Can erythropoietin be used to prevent brain damage in cerebral malaria?. Trends Parasitol. 2009, 25: 30-36. 10.1016/j.pt.2008.10.002.CrossRefPubMed

33.

Taylor TE: Caring for children with cerebral malaria: insights gleaned from 20 years on a research ward in Malawi. Trans R Soc Trop Med Hyg. 2009, 103 (Suppl 1): S6-10. 10.1016/j.trstmh.2008.10.049.CrossRefPubMed

34.

Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, Newton C, Winstanley P, Warn P, Peshu N: Indicators of life-threatening malaria in African children. N Engl J Med. 1995, 332: 1399-1404. 10.1056/NEJM199505253322102.CrossRefPubMed

35.

Taylor T, Olola C, Valim C, Agbenyega T, Kremsner P, Krishna S, Kwiatkowski D, Newton C, Missinou M, Pinder M, Wypij D: Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the SMAC network. Trans R Soc Trop Med Hyg. 2006, 100: 615-622. 10.1016/j.trstmh.2005.09.021.PubMedCentralCrossRefPubMed

36.

Idro R, Ndiritu M, Ogutu B, Mithwani S, Maitland K, Berkley J, Crawley J, Fegan G, Bauni E, Peshu N, Marsh K, Neville B, Newton C: Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children. JAMA. 2007, 297: 2232-2240. 10.1001/jama.297.20.2232.PubMedCentralCrossRefPubMed

37.

Ranque S, Poudiougou B, Traoré A, Keita M, Oumar AA, Safeukui I, Marquet S, Cabantous S, Diakité M, Mintha D, Cissé MB, Keita MM, Dessein AJ, Doumbo OK: Life-threatening malaria in African children: a prospective study in a mesoendemic urban setting. Pediatr Infect Dis J. 2008, 27: 130-135.PubMed

Title: Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali
Authors: Stéphane Picot
Anne-Lise Bienvenu
Salimata Konate
Sibiri Sissoko
Abdoulaye Barry
Elisabeth Diarra
Karidiatou Bamba
Abdoulaye Djimdé
Ogobara K Doumbo
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Malaria Journal / Issue 1/2009
Electronic ISSN: 1475-2875
DOI: https://doi.org/10.1186/1475-2875-8-169

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali

Abstract

Background

Methods

Results

Conclusion

Clinical registration number

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Clinical registration number

Please log in to get access to this content

Other articles of this Issue 1/2009

Cellular responses to modified Plasmodium falciparum MSP119 antigens in individuals previously exposed to natural malaria infection

Impact of Plasmodium falciparum infection on the frequency of moderate to severe anaemia in children below 10 years of age in Gabon

Preliminary study of malaria incidence in Nouakchott, Mauritania

Comparison of Plasmodium falciparum allelic frequency distribution in different endemic settings by high-resolution genotyping

Rural Gambian women's reliance on health workers to deliver sulphadoxine – pyrimethamine as recommended intermittent preventive treatment for malaria in pregnancy

Is flow cytometry better in counting malaria pigment-containing leukocytes compared to microscopy?

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page