Effect of Artemether Treatment on Plasma Lipid Profile in Malaria

Nkereuwem Edikpo, Paul Obiekwe Okonkwo, Elias Adikwu

Department of Pharmacology, Faculty of Basic Medical Sciences, University of Port Harcourt, Choba, Nigeria.

DOI: 10.4236/pp.2014.57074                

Abstract

This study was undertaken to assess the effect of artemether treatment on plasma lipid profile in malaria infection. While the importance of lipid to plasmodial infective processes and metabolism is being increasingly appreciated, little is known about the attendant effect of chemotherapy on plasma lipid profile. Thirty patients with uncomplicated malaria were chosen from two secondary health-care facilities in Yobe State, Nigeria with informed consents and ethical clearance. Based on predetermined inclusion criteria patients were given 3.2 mg/kg of artemether with 1.6 mg/kg on subsequent days for a total of five days. This was done after the collection of urine and blood samples for urinalysis, malaria parasite density count and serum lipid analysis. A follow-up was planned seven (7) days from first dose during when clinical assessment and repeat malaria parasite density count and serum lipid analysis were done. Data were analyzed with statistical package for social scientist and Microsoft Excel spread sheet while level of significance at p ≤ 0.05 was calculated using paired t-test. Serum HDL cholesterol concentration recorded a significant decline of 0.13 mmol/L from a pre-treatment mean concentration of 1.17 mmol/L (p < 0.04). Triglyceride, total cholesterol, LDL-cholesterol, VLDL-cholesterol showed increment or reductions that were not significant. The clinical cure rate was 50% and mean percentage reduction in parasitaemia was 52%. A possible explanation for this low cure rate could be resistance, unfavorable pharmacokinetic disposition or lack of full adherence. A trial with complete parasite clearance, possibly using artemisinin-based combinational therapy would provide a more compelling result.

Keywords

Artemether, Plasma Lipid Profile, Malaria, Humans

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Bruce-Chwatt, L.J. (1988) History of Malaria from Prehistory to Eradication. In: Wernsdorfer, W.H. and McGregor, I., Eds., Malaria: Principles and Practice of Malariology, Churchill Livingstone, Edinburgh, 1-59.
[2]	Ross, R. (1897) On Some Peculiar Pigmented Cells Found in Two Mosquitoes Fed on Malarial Blood. British Medical Journal, 2, 1786-1788.
[3]	Cox, F.E.G. (2010) History of the Discovery of the Malaria Parasites and Their Vectors. Parasites and Vectors, 3, 5. http://dx.doi.org/10.1186/1756-3305-3-5
[4]	Jongwutiwes, S., Putaporntip, C., Iwasaki, T., Sata, T. and Kanbara, H. (2004) Naturally Acquired Plasmodium Knowlesi Malaria in Human in Thailand. Emerging Infectious Disease, 10, 2211-2213. http://dx.doi.org/10.3201/eid1012.040293
[5]	Sherman, I.W. (1979) Biochemistry of Plasmodium. Microbiological Review, 43, 453-459.
[6]	Hsiao, L.L., Howard, R.J., Aikawa, M. and Taraschi, T.F. (1991) Modification of Host Cell Membrane Lipid Composition by the Intraerythrocytic Human Malaria Parasite Plasmodium falciparum. Biochemistry Journal, 274, 121-132.
[7]	Onongbu, I.C. and Onyeneke, E.C. (1983) Plasma Lipid Changes in Human Malaria. Tropical Medicine and Parasitology, 34, 193-196.
[8]	Nilsson-Ehle, I. and Nilsson-Ehle, P. (1990) Changes in Plasma Lipoproteins in Acute Malaria. Journal of Internal Medicine, 227, 151-155. http://dx.doi.org/10.1111/j.1365-2796.1990.tb00136.x
[9]	Mohanty, S., Mishra, S.K., Das, B.S., Sathpathy, S.K., Mohanty, D. and Patnaik, J. (1992) Altered Plasma Lipid Pattern in falciparum Malaria. Annals of Tropical Medical Parasitology, 86, 601-606.
[10]	Clark, I.A., Alleva, L.M., Mills, A.C. and Cowden, W.B. (2004) Pathogenesis of Malaria and Clinically Similar Conditions. Clinical Microbiology Reviews, 17, 509-539. http://dx.doi.org/10.1128/CMR.17.3.509-539.2004
[11]	Haldar, K., Mohandas, N., Samuel, B.U., Harrison, T., Hiller, N.L. and Akompong, T. (2002) Protein and Lipid Trafficking Induced in Erythrocytes Infected by Malaria Parasites. Cellular Microbiology, 4, 383. http://dx.doi.org/10.1046/j.1462-5822.2002.00204.x
[12]	Grellier, P., Rigomier, D., Clavey, V., Fruchart, J.C. and Schrevel, J. (1991) Lipid Trafficking between High-Density Lipoproteins and Plasmodium falciparum-Infected Red Blood Cells. Journal of Cell Biology, 112, 267-277. http://dx.doi.org/10.1083/jcb.112.2.267
[13]	Mitamura, T., Hanada, K., Ko-mitamura, E.P., Nishijima, M. and Horii, T. (2000) Serum Factors Governing Intraerythrocytic Development and Cell Cycle Progression of Plasmodium falciparum. Parasitology International, 49, 219-229. http://dx.doi.org/10.1016/S1383-5769(00)00048-9
[14]	Samuel, B.U., Mohandas, N., Harrison, T., McManus, H., Rosse, W. and Reid, M. (2001) The Role of Cholesterol and Glycosylphatidylinositol-Anchored Proteins of Erythrocyte Raft in Regulating Raft Protein Content and Malarial Infection. Journal of Biological Chemistry, 276, 29319-29329. http://dx.doi.org/10.1074/jbc.M101268200
[15]	Lauer, S., Van Wye, J., Harrison, T., McManus, H., Samuel, B.U. and Hiller, N.L. (2000) Vacuolar Uptake of Host Components and a Role for Cholesterol and Sphigomyelin in Malarial Infection. The EMBO Journal, 19, 3556-3564. http://dx.doi.org/10.1093/emboj/19.14.3556
[16]	Mitamura, T. and Palacpac, N.M.Q. (2003) Lipid Metabolism in Plasmodium falciparum-Infected Erythrocytes: Possible New Targets for Malaria Chemotherapy. Microbes and Infection, 5, 545-552. http://dx.doi.org/10.1016/S1286-4579(03)00070-4
[17]	Mamoun, C.B., Prigge, S.T. and Vial, H. (2010) Targeting the Lipid Metabolic Pathways for the Treatment of Malaria. Drug Development Research, 71, 44-45.
[18]	Grellier, P., Depoix, D., Schrével, J. and Florent, I. (2008) Discovery of New Targets for Antimalarial Chemotherapy. Parasite, 15, 219-225. http://dx.doi.org/10.1051/parasite/2008153219
[19]	Kirkwood, B. (1994) Essentials of Medical Statistics. 4th Edition, Blackwell Science, Cambridge.
[20]	Johnson, R., McNutt, P., MacMahon, S. and Robson, R. (1997) Use of the Friedewald Formula to Estimate LDL-Cholesterol in Patients with Chronic Renal Failure on Dialysis. Clinical Chemistry, 43, 2183-2184.
[21]	Cheesbrough, M. (2005) District Laboratory in Tropical Countries, Part 1. 2nd Edition, Cambridge University Press, Cambridge. http://dx.doi.org/10.1017/CBO9780511581304
[22]	American Association for Clinical Chemistry. (2009) Urinalysis. http://labtestsonline.org/understanding/analytes/urinalysis/sample.html
[23]	Cowling, T. and Lloyd, E. (2011) The Correct Way to Perform a Medical Urinalysis. http://www.brighthub.com/science/medical/articles/71520.aspx
[24]	Breman, J.G., Alilioand, M.S. and Mills, A. (2004) Conqueringthe Intolerable Burden of Malaria: What’s New, What’s Needed: A Summary. http://www.ncbi.nlm.nih.gov/ books/NBK3750/
[25]	UNICEF (2013) Malaria. http://www.unicef.org/health /index_ malaria.html
[26]	Barnadas, C., Ratsimbasoa, A., Tichit, M., Bouchier, C., Jahevitra, M., Picot, S. and Ménard, D. (2008) Plasmodium vivax Resistance to Chloroquine in Madagascar: Clinical Efficacy and Polymorphisms in pvmdr1 and pvcrt-o genes. Antimicrobial Agents Chemotherapy, 52, 4233-4240. http://dx.doi.org/10.1128/AAC.00578-08
[27]	Rieckmann, K.H., Davis, D.R. and Hutton, D.C. (1989) Plasmodium vivax Resistance Tochloroquine? The Lancet, 334, 1183-1184. http://dx.doi.org/10.1016/S0140-6736(89)91792-3
[28]	Kurcer, M.A., Simsek, Z. and Kurcer, Z. (2006) The Decreasing Efficacy of Chloroquine in the Treatment of Plasmodium vivax Malaria, in Sanliurfa, South-Eastern Turkey. Annals of Tropical Medicine and Parasitology, 100, 109-113. http://dx.doi.org/10.1179/136485906X86284
[29]	Guthmann, J.P., Pittet, A., Lesage, A., Imwong, M., Lindegardh, N., et al. (2008) Plasmodium vivax Resistance to Chloroquine in Dawei, Southern Myanmar. Tropical Medicine and International Health, 13, 91-98. http://dx.doi.org/10.1111/j.1365-3156.2007.01978.x
[30]	Tu, Y. (2011) The Discovery of Artemisinin (Qinghaosu) and Gifts from Chinese Medicine. Nature Medicine, 17, 1217-1220.
[31]	Maude, C.J., Woodrow, C.J. and White, L.J. (2010) Artemisinin Antimalarials: Preserving the “Magic Bullet”. Drug Development Research, 71, 12-19.
[32]	Awofeso, N. (2011) Project 523: Transformation of Artemisinin from Traditional Chinese Medicine to Mainstream Anti-Malaria Chemotherapy. Spatula DD, 1, 113-118.
[33]	Li, J. and Zhou, B. (2010) Biological Actions of Artemisinin: Insights from Medicinal Chemistry Studies. Molecules, 15, 1378-1397. http://dx.doi.org/10.3390/molecules15031378
[34]	Batty, K.T., Thu, L.T.A., Davis, T.M.E., Llet, K.F., Mai, T.X., Hung, N.C., et al. (1998) A Pharmacokineticand Pharmacodynamic Study of Intravenous vs Oralartesunate in Uncomplicated Falciparum Malaria. British Journal of Clinical Pharmacology, 45, 123-129.
[35]	De Vries, V.J. and Dien, T.K. (1996) Clinical Pharmacology and Therapeutic Potential of Artemisinin and Its Derivatives in the Treatment of Malaria. Drugs, 52, 818-836. http://dx.doi.org/10.2165/00003495-199652060-00004
[36]	Xiaonan, Z. (2010) Protein Binding Determination of Dihydroartemisinin (DHA) in Human Plasma by HPL CusingPost-Columnon-Line Alkali Derivatization and UV Detection. http://publications.lib.chalmers.se/records/fulltext/126728
[37]	Li, Q.G., Peggins, J.O., Fleckenstein, L.L., Masonic, K., Heiffer, M.H. and Brewer, T.G. (1998) The Pharmacokinetics and Bioavailability of Dihydroartemisinin, Arteether, Artemether, Artesunicacid and Artelinic Acid in Rats. Journal of Pharmacy and Pharmacolology, 50, 173-182
[38]	Krishna, S., Uhlemann, A. and Haynes, R.K. (2004) Artemisinins: Mechanisms of Action and Potential for Resistance. Drug Resistance Updates, 7, 233-244. http://dx.doi.org/10.1016/j.drup.2004.07.001
[39]	Woodrow, C.J., Haynes, R.K. and Krishna, S. (2005) Artemisinins. Postgraduate Medicine Journal, 81, 71-78. http://dx.doi.org/10.1136/pgmj.2004.028399
[40]	Krishna, A.P., Chandrik, A., Kumar, S., Acharya, M. and Patil, S.L. (2009) Variation in Common Lipid Parameters in Malaria Infected Patients. Indian Journal of Physiology and Pharmacology, 53, 271-274.
[41]	Nwobodo, N., Okonkwo, P.O., Nwobodo, E. and Igwe, S.A. (2008) Evaluation of Effects of Malaria Infection on Serum Lipid Profile of Patients Attending Two District Hospitals in Enugu, Nigeria. Oriental Journal of Chemistry, 24, 415-418.
[42]	Faucher, J., Ngou-Milama, E., Missinou, M.A., Ngomo, R., Kombila, M. and Kremsner, P.G. (2002) The Impact of Malaria on Common Lipid Parameters. Parasitology Research, 88, 1040-1043. http://dx.doi.org/10.1007/s00436-002-0712-6
[43]	Chimanuka, B., Francois, G., Timperman, G., Heyden, Y.V., Holenz, J. and Plaizier-Vercammen, J. (2001) A Comparison of the Stage-Specific Efficacy of Chloroquine, Artemether and Dioncophylline B against the Rodent Malaria Parasite Plasmodium chabaudi chabaudi in Vivo. Parasitology Research, 87, 795-803. http://dx.doi.org/10.1007/s004360000358
[44]	Woodrow, C.J., Haynes, R.K. and Krishna, S. (2005) Artemisinins. Postgraduate Medical Journal, 81, 71-78. http://dx.doi.org/10.1136/pgmj.2004.028399
[45]	Karbwang, J., Bangchang, K.N., Thanavibul, A., Bunnang, D., Chongsuphajaisiddhi, T. and Harinasuta, T. (1992) Comparison of Oral Artemether and Mefloquine in Acute Uncomplicated Falciparum Malaria. The Lancet, 340, 1245-1248. http://dx.doi.org/10.1016/0140-6736(92)92947-E
[46]	Silamut, K., Newton, P.N., Teja-Isavadharm, P., Suputtamongkol, Y., Siriyanonda, D., Rasameesoraj, M., et al. (2003) Artemether Bioavailability after Oral or Intramuscular Administration in Uncomplicated Falciparum Malaria. Antimicrobial Agents and Chemotherapy, 47, 3795-3798. http://dx.doi.org/10.1128/AAC.47.12.3795-3798.2003
[47]	Alin, M.H., Ashton, M., Kihamia, C.M., Mtey, G.J.B. and Björkman, A. (1996) Multiple Dose Pharmacokinetics of Oral Artemisinin and Comparison of Its Efficacy with That of Oral Artesunate in Falciparum Malaria Patients. Transaction of Royal Society of Tropical Medicine and Hygiene, 90, 61-65. http://dx.doi.org/10.1016/S0035-9203(96)90480-0
[48]	Ittarat, W., Pickard, A.L., Rattanasinganchan, P., Wilairatana, P., Looareesuwan, S. and Emery, K. (2003) Recrudescence in Artesunate-Treated Patients with Falciparum Malaria Is Dependent on Parasite Burden Not on Parasite Factors. American Journal of Tropical Medicine and Hygiene, 68, 147-152.
[49]	Codd, A., Teuscher, F., Kyle, D.E., Cheng, Q. and Gatton, M.L. (2011) Artemisinin-Induced Parasite Dormancy: A Plausible Mechanism for Treatment Failure. Malaria Journal, 10, 56. http://dx.doi.org/10.1186/1475-2875-10-56
[50]	Miller, L.H., Ackerman, H.C., Su, X. and Wellems, T.E. (2013) Is Recrudescence after Artemisinin Treatment Linked to a Dormancy Phenomenon? Nature Medicine, 19, 156-167. http://dx.doi.org/10.1038/nm.3073
[51]	Teja-Isavadharm, P., Nosten, F., Kyle, D.E., Luxemburger, C., TerKulie, F. and Peggins, J.O. (1996) Comparative Bioavailability of Oral, Rectal, and Intramuscular Artemether in Healthy Subjects: Use of Simultaneous Measurement by High Performance Liquid Chromatography and Bioassay. British Journal of Clinical Pharmacology, 42, 599-604. http://dx.doi.org/10.1111/j.1365-2125.1996.tb00115.x
[52]	Karbwang, J., Na-Bancgchang, K., Congpuong, K. and Thanayibul, A. (1997) Pharmacokinetics and Bioavailability of Oral and Intramuscular Artemether. European Journal of Clinical Pharmacology, 52, 307-310. http://dx.doi.org/10.1007/s002280050295
[53]	Gordi, T. and Lepist, E.I. (2004) Artemisinin Derivatives: Toxic for Laboratory Animals, Safe for Humans? Toxicological Letters, 147, 99-107. http://dx.doi.org/10.1016/j.toxlet.2003.12.009
[54]	Hien, T.T., Turner, G.D., Mai, N.T., Phu, N.H., Blakemore, W.F., et al. (2003) Neuropathological Assessment of Artemether-Treated Severe Malaria. The Lancet, 362, 295-296. http://dx.doi.org/10.1016/S0140-6736(03)13974-8
[55]	Kissinger, E., Hien, T.T., Hung, N.T., Nam, N.D., Tuyen, N.L. and Dinh, B.V. (2000) Clinical and Neurophysiological Study of the Effects of Multiple Doses of Artemisinin on Brain-Stem Function in Vietnamese Patients. American Journal of Tropical Medicine and Hygiene, 63, 48-55.
[56]	Van Vugt, M., Angus, B.J., Price, R.N., Mann, C., Simpson, J.A. and Poletto, C. (2000) A Case-Control Auditory Evaluation of Patients Treated with Artemisinin Derivatives for Multidrug-Resistant Plasmodium Falciparum Malaria. American Journal of Tropical Medicine and Hygiene, 62, 65-69.
[57]	Maude, R.J., Woodrow, C.J. and White, L.J. (2010) Artemisinin Antimalarials: Preserving the “Magic Bullet”. Drug Development Research, 71, 12-19.
[58]	Brewer, T.G., Grate, S.J., Peggins, J.O., Weina, P.J., Petras, J.M. and Levine, B.S. (1994) Fatal Neurotoxicity of Arteether and Artemether. American Journal of Tropical Medicine and Hygiene, 51, 251-259.
[59]	Izunya, A.M., Nwaopara, A.O., Aigbiremolen, A., Odike, M.A.C., Oaikhena, G.A. and Bankole, J.K. (2010) Histological Effects of Oral Administration of Artesunate on the Liver in Wistar Rats. Research Journal of Applied Sciences, Engineering and Technology, 2, 314-318.
[60]	Huda, S.N., Shahab, T., Al, S.M., Afzal, K. and Khan, H.M. (2003) A Comparative Clinical Trial of Artemether and Quinine in Children with Severe Malaria. Indian Paediatrics, 40, 939.