ANTIPLASMODIAL ACTIVITY OF KETOTIFEN-ARTEMETHER-LUMEFANTRINE ON PLASMODIUM BERGHEI INFECTED MICE

Authors

  • Georgewill Udeme Owunari Department of Pharmacology, Faculty of Clinical Sciences, University of Port Harcourt, Rivers State, Nigeria https://orcid.org/0000-0002-6738-1544
  • Ezerioha Chidi Emmanuel Department of Pharmacology, Faculty of Clinical Sciences, University of Port Harcourt, Rivers State, Nigeria https://orcid.org/0000-0003-3706-4844
  • Elias Adikwu Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria

DOI:

https://doi.org/10.29121/granthaalayah.v8.i11.2020.2439

Keywords:

Ketotifen, Artemether/Lumefantrine, Antiplasmodium, Mice

Abstract [English]

Introduction: The development of new antimalarial drugs is time-consuming and costly, thus repurposing of drugs with initial indications for possible antimalarial indication is imperative. This study assessed the antiplasmodial effect of ketotifen (KT) in combination with artemether/lumefantrine (A/L) in Plasmodium bergei infected mice.


Materials and Methods: Adult mice (25-30g) were parasitized with Plasmodium berghei, grouped and treated per oral (p.o) with KT (0.1mg/kg), A/L (2.3/13.7mg/kg) and KT/A/L daily in curative, suppressive and prophylactic studies. The negative control (NC) and the positive control (PC) were treated daily p.o with normal saline (0.2mL) and chloroquine (CQ) (10mg/kg) for 4 days respectively. After treatment, blood samples were collected and assessed for percentage parasitemia level, hematological and lipid parameters.


Results: The curative, suppressive and prophylactic studies showed significant decreases in percentage parasitemia levels at KT (0.1mg/kg) (p<0.01), A/L (2.3/13.7 mg/kg) (p<0.001) and KT/A/L (p<0.0001) when compared to negative control. Significant increases in mean survival times occurred at KT (0.1 mg/kg) (p<0.01), A/L (2.3/13.7mg/kg) (p<0.001) and A/L/T (p<0.0001) when compared to negative control. Significant increases in packed cell volume, red blood cells, hemoglobin, high density lipoprotein cholesterol levels with significant decreases in total cholesterol, white blood cells, low density lipoprotein cholesterol and triglyceride levels at KT (28.6 mg/kg) (p<0.05), A/L (2.3/13.7mg/kg) (p<0.01) and KT/A/L (p<0.001) when compared to negative control.


Conclusion: KT may be repurposed in combination with A/L for malaria treatment.

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References

Mandal A. News Medical- Life sciences and Medicine. Malaria Epidemiology. Retrieved from http://www.news-medical.net/health/Malaria-Epidemiology.aspx, 2013.

WHO, “World Health Organization, 2019. World Malaria Report,” https://www.who.int/malaria/en/.

Eastman RT, Pattaradilokrat S, Raj DK, Dixit S, Deng B, Miura K et al., A Class of Tricyclic Compounds Blocking Malaria Parasite Oocyst Development and Transmission Antimicrob Agents and Chem, 2013; 57;425–435 DOI: https://doi.org/10.1128/AAC.00920-12

Penna-Coutinho J, Aguiar AC, Krettli AU. Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum Mem Inst Oswaldo Cruz, Rio de Janeiro, 113(12): e180279, 2018 DOI: https://doi.org/10.1590/0074-02760180279

Ashburn T.T., Thor K.B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 2004;3(8):673–683 DOI: https://doi.org/10.1038/nrd1468

Car B.D. In: Polypharmacology in Drug Discovery. Peters J.-U., editor. Wiley; 2012

Kola I., Landis J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 2004;3(8):711–715 DOI: https://doi.org/10.1038/nrd1470

Nowak-Sliwinskaa P, Scapozzaa L, Altaba AR Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer BBA - Rev on Can 2019; 1871 434–454 DOI: https://doi.org/10.1016/j.bbcan.2019.04.005

Montazeri M, Rezaei K, Ebrahimzadeh MA, Sharif1M, Sarvi1 S, Ahmadpour E, Rahimi MT, Moreira de Oliveira EA, Lang KL, Drug Repositioning: Concept, Classification, Methodology, and Importance in Rare/Orphans and Neglected Diseases Journal of Appl Pharm Sci 2018; 8 (08), 157-165 DOI: https://doi.org/10.7324/JAPS.2018.8822

Grahnen A, Lonnebo A, Beck O, Eckernas SA, Dahlstrom B, Lindstrom B. 1992. Pharmacokinetics of ketotifen after oral administration to healthy male subjects. Biopharm. Drug Dispos. 13:255–262 DOI: https://doi.org/10.1002/bdd.2510130404

Milner E, Sousa J, Pybus B, Auschwitz J, Caridha D, Gardner S et al., Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy. Eur. J. Drug Metab. Pharmacokinet. 2012 Mar;37(1):17-22 DOI: https://doi.org/10.1007/s13318-012-0080-2

Basco LK, Ringwald P, Le Bras J. 1991. Chloroquine-potentiating action of antihistaminics in Plasmodium falciparum in vitro. Ann. Trop. Med. Parasitol. 191; 85:223–228. DOI: https://doi.org/10.1080/00034983.1991.11812549

Quan H, Tang LH. 2008. In vitro potentiation of chloroquine activity in Plasmodium falciparum by ketotifen and cyproheptadine. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 26:338 –342. (In Chinese.)

Singh N, Puri SK. Interaction between chloroquine and diverse pharmacological agents in chloroquine resistant Plasmodium yoelii nigeriensis. Acta Trop. 2000; 77:185–193. DOI: https://doi.org/10.1016/S0001-706X(00)00133-9

Ibrahim AM, Elhag ER, Mustafa SE. Ketotifen in treatment of uncomplicated falciparum malaria. Saudi Med J. 2000;21(3):257-65

Sirima SB, Ogutu B, Lusingu JPA, et al. Comparison of artesunate-mefloquine and artemether-lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial. Lancet Infect Dis. 2016;16(10):1123-1133. DOI: https://doi.org/10.1016/S1473-3099(16)30020-2

You L, Ni B, Cao HM. Effects of low dose of ketotifen and chloroquine combination on the infrastructure of chloroquine resistant strain of Plasmodium yoelii. J Shanghai Univ. 2000;4(4):338-42. DOI: https://doi.org/10.1007/s11741-000-0055-4

Somsak V, Damkaew A, and Onrak P Antimalarial Activity of Kaempferol and Its Combination with Chloroquine in Plasmodium berghei Infection in Mice. Jour of Path 2018; 2018;1- 7 DOI: https://doi.org/10.1155/2018/3912090

Ryley, J.F. and Peters, W. The antimalarial activity of some quinolone esters. Ann. Trop. Med. Parasitol. 1970; 84: 209-222.

Knight, D.J. and Peters, W. The antimalarial action of N-Benzyl oxydihydrotriazines and the studies on its mode of action. Ann of Trop Med and Par. 1980; 74: 393-404. DOI: https://doi.org/10.1080/00034983.1980.11687360

Peters, W. Rational methods in the search for antimalarial drugs. Trans. R. Soc. Trop. Med. Hyg. 1967; 61: 400-410.

Moreira de Oliveira EA, Lang KL. Drug Repositioning: Concept, Classification, Methodology, and Importance in Rare/Orphans and Neglected Diseases Jour of Appl Pharm Sci 2016 8(08), 157-165

Thomas AM, Van Der Wel AM, Thomas AW, Janse CJ, Waters AP (1998). Transfection systems for animal models of malaria. Parasitol. Today, 14: 248-249.

David AF, Philip JR, Simon IC, Reto B, Solomon N (2004). Antimalarial drug discovery: Efficacy models for compound screening. Nassture Rev., 3: 509-520

Fidock DA, Rosenthal PJ, Croft SL, Brun R, Nwaka S. Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov. 2004;3(6):509–520. DOI: https://doi.org/10.1038/nrd1416

Tarkang PA, Appiah-Opong R, Ofori MF, Ayong LS, Nyarko AK. Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification. Biomark Res. 2016;4(1):25. DOI: https://doi.org/10.1186/s40364-016-0077-0

Olanlokun JO, Babarinde CO and Olorunsogo O. O. Toxicity of Anchomanes difformis, An Antimalarial Herb in Murine Models Eur Jour of Med Plants 2017; 20(3): 1-13

Saxena R, Bhatia A, Midha K, Debnath M, Kaur P. Malaria: A Cause of Anemia and Its Effect on Pregnancy. World J Anemia. 2017;1(2):51-62. DOI: https://doi.org/10.5005/jp-journals-10065-0030

Chinchilla M, Guerrero O, Abarca G, Barrios M, Castro O. An in vivo model to study the anti-malaria capacity of plant extracts. Rev Biol Trop. 1998;46:1–7

Sirak S, Fola AA, Worku L, Biadgo B. Malaria parasitemia and its association with lipid and hematological parameters among malaria-infected patients attending at Metema Hospital, Northwest Ethiopia. Path and Lab Med Intern. 2016;8:43-50 DOI: https://doi.org/10.2147/PLMI.S118946

Adekunle A.S., Adekunle O.C., Egbewale B.E Serum status of selected biochemical parameters in malaria: An animal model. Biomed Res 2007; 18 (2): 109-113

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Published

2020-12-11

How to Cite

Georgewill, U. O., Ezeriohaa, C. E., & Adikwu, E. (2020). ANTIPLASMODIAL ACTIVITY OF KETOTIFEN-ARTEMETHER-LUMEFANTRINE ON PLASMODIUM BERGHEI INFECTED MICE. International Journal of Research -GRANTHAALAYAH, 8(11), 251–258. https://doi.org/10.29121/granthaalayah.v8.i11.2020.2439