Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
권호 표지
DOI QR코드

DOI QR Code

Evaluating the activity of N-89 as an oral antimalarial drug

  • Nagwa S. M. Aly (Department of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Hiroaki Matsumori (Department of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Thi Quyen Dinh (Department of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Akira Sato (Department of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Shin-ichi Miyoshi (Department of Sanitary Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Kyung-Soo Chang (Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan) ;
  • Hak Sun Yu (Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University) ;
  • Takaaki Kubota (Department of Natural Products Chemistry, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University) ;
  • Yuji Kurosaki (Department of Pharmaceutical Formulation Design, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Duc Tuan Cao (Department of Pharmaceutical Chemistry and Quality Control, Faculty of Pharmacy, Hai Phong University of Medicine and Pharmacy) ;
  • Gehan A. Rashed (Department of Parasitology, Benha Faculty of Medicine, Benha University) ;
  • Hye-Sook Kim (Department of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University)
  • Received : 2023.04.08
  • Accepted : 2023.07.20
  • Published : 2023.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t1/2 was 0.97 h, Tmax was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED50) and ED90 values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89-treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

Keywords

Acknowledgement

We thank Tomoko Tanaka and Kazuaki Okada (Okayama University) for performing experiments and discussing the results. This study was supported in part by a grant from the Program of the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID, JP22wm0125004) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (MEXT) and the Japan Agency for Medical Research and Development (AMED).

References

  1. World Health Organization. World Malaria Report 2022. World Health Organization. Geneva, Switzerland. 2022. https://www.who.int/publications/i/item/9789240064898
  2. World Health Organization. Guidelines for the Treatment of Malaria. World Health Organization. Geneva, Switzerland. 2022. https://www.who.int/publications/i/item/guidelines-formalaria
  3. van der Pluijm RW, Imwong M, Chau NH, Hoa NT, ThuyNhien NT, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis 2019;19(9):952-961. https://doi.org/10.1016/S1473-3099(19)30391-3
  4. Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis 2017;17(5):491-497. https://doi.org/10.1016/S1473-3099(17)30048-8
  5. Dormoi J, Amalvict R, Gendrot M, Pradines B. Methylene blue-based combination therapy with amodiaquine prevents severe malaria in an experimental rodent model. Pharma-ceutics 2022;14(10):2031. https://doi.org/10.3390/pharmaceutics14102031
  6. Khairani S, Fauziah N, Wiraswati HL, Panigoro R, Setyowati EY, et al. Oral administration of piperine as curative and prophylaxis reduces parasitaemia in Plasmodium berghei ANKAinfected mice. J Trop Med 2022;2022:5721449. https://doi.org/10.1155/2022/5721449
  7. Gebremariam GK, Desta HK, Teklehaimanot TT, Girmay TG. In Vivo antimalarial activity of leaf latex of Aloe melanacantha against Plasmodium berghei infected mice. J Trop Med 2021; 2021:6690725. https://doi.org/10.1155/2021/6690725
  8. Kim HS, Nagai Y, Ono K, Begum K, Wataya Y, et al. Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes. J Med Chem 2001;44:2357-2361. https://doi.org/10.1021/jm010026g
  9. Aly NS, Hiramoto A, Sanai H, Hiraoka O, Hiramoto K, et al. Proteome analysis of new antimalarial endoperoxide against Plasmodium falciparum. Parasitol Res 2007;100(5):1119-1124. https://doi.org/10.1007/s00436-007-0460-8
  10. Morita M, Koyama T, Sanai H, Sato A, Hiramoto A, et al. Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum. Parasitol Int 2015;64(1):113-117. https://doi.org/10.1016/j.parint.2014.10.007
  11. Sato A, Hiramoto A, Morita M, Matsumoto M, Komichi Y, et al. Antimalarial activity of endoperoxide compound 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol. Parasitol Int 2011;60(3):270-273. https://doi.org/10.1016/j.parint.2011.04.001
  12. Aly NSM, Matsumori H, Dinh TQ, Sato A, Miyoshi SI, et al. Formulation and evaluation of the antimalarial N-89 as a transdermal drug candidate. Parasitol Int 2023;93:102720. https://doi.org/10.1016/j.parint.2022.102720
  13. Aly NSM, Matsumori H, Dinh TQ, Sato A, Miyoshi SI, et al. Pioneer use of antimalarial transdermal combination therapy in rodent malaria model. Pathogens 2023;12(3):398. https://doi.org/10.3390/pathogens12030398
  14. Aly NSM, Matsumori H, Dinh TQ, Sato K, Miyoshi SI, et al. Antimalarial effect of synthetic endoperoxide on Plasmodium chabaudi infected mice. Parasites Hosts Dis 2023;61(1):33-41. https://doi.org/10.3347/PHD.22119
  15. Imada C, Takahashi T, Kuramoto M, Masuda K, Ogawara K, et al. Improvement of oral bioavailability of N-251, a novel antimalarial drug, by increasing lymphatic transport with long-chain fatty acid-based self-nanoemulsifying drug delivery system. Pharm Res 2015;32(8):2595-2608. https://doi.org/10.1007/s11095-015-1646-x
  16. Okada K, Sato A, Hiramoto A, Isogawa R, Kurosaki Y, et al. Pharmacokinetic analysis of new synthetic antimalarial N-251. Trop Med Health 2019;47:40. https://doi.org/10.1186/s41182-019-0167-4
  17. Sato A, Kawai S, Hiramoto A, Morita M, Tanigawa N, et al. Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec4-yl)hexan-1-ol (N-251) and its carboxylic acid de-rivatives. Parasitol Int 2011;60(4):488-492. https://doi.org/10.1016/j.parint.2011.08.017
  18. Morita M, Sanai H, Hiramoto A, Sato A, Hiraoka O, et al. Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antima-larial endoperoxides, N 89 and N 251. J Proteome Res 2012;11(12):5704-5711. https://doi.org/10.1021/pr 3005315
  19. La Greeca N, Hibbs AR, Riffkin C, Foley M, Tilley L. Identification of an endoplasmic reticulum-resident calcium-binding protein with multiple EF-hand motifs in asexual stage of Plasmodium falciparum. Mol Biochem Parasitol 1997;89(2):283-293. https://doi.org/10.1016/s0166-6851(97)00134-5
  20. Fierro MA, Asady B, Brooks CF, Cobb DW, Villegas A, et al. An endoplasmic reticulum CREC family protein regulates the egress proteolytic cascade in malaria parasites. mBio 2020;11(1):e03078-03019. https://doi.org/10.1128/mBio.03078-19
  21. Gabriela M, Matthews KM, Boshoven C, Kouskousis B, Jonsdottir TK, et al. A revised mechanism for how Plasmodium falciparum recruits and exports proteins into its erythrocytic host cell. PLoS Pathog 2022;18(2):e1009977. https://doi.org/10.1371/journal.Ppat.1009977
  22. Tabata K, Yamaoka K, Kaibara A, Suzuki S, Terakawa M, et al. Moment analysis pro-gram available on Microsoft Excel. Xenobio Metabol Dispos 1999;14:286-293. https://www.pharm.kyoto-u.ac.jp/byoyaku/Kinetics/download.html#moment https://doi.org/10.2133/dmpk.14.286
  23. Hashimoto M, Taguchi K, Imoto S, Yamasaki K, Mitsuya H, et al. Pharmacokinetic properties of orally Administered 4'-cyano-2'-deoxyguanosine, a novel nucleoside analog in-hibitor of the Hepatitis B, in viral liver injury model rats. Biol Pharm Bull 2020;43(9):1426-1429. https://doi.org/10.1248/bpb.b20-00372
  24. Peters W. The chemotherapy of rodent malaria, XXII. The value of drug-resistant strains of P. berghei in screening for blood schizontocidal activity. Ann Trop Med Parasitol 1975;69(2):155-171. https://doi.org/10.1080/00034983.1975.11686997
  25. Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in oral drug delivery. Front Pharmacol 2021;12:618411. https://doi.org/10.3389/fphar.2021.618411
  26. Fu C, Shi H, Chen H, Zhang K, Wang M, et al. Oral bioavailability comparison of artemisinin, deoxyartemisinin, and 10-deoxoartemisinin based on computer simulations and pharmacokinetics in rats. ACS Omega 2021;6(1):889-899. https://doi.org/10.1021/acsomega.0c05465
  27. Klayman DL, Ager AL, Fleckenstein L, Lin AJ. Transdermal artelinic acid: an effective treatment for Plasmodium bergheiinfected mice. Am J Trop Med Hyg 1991;45(5):602-607. https://doi.org/10.4269/ajtmh.1991.45.602
  28. Lin AJ, Ager AL Jr, Klayman DL. Antimalarial activity of dihydroartemisinin derivatives by transdermal application. Am J Trop Med Hyg 1994;50(6):777-783. https://doi.org/10.4269/AJTMH.1994. 50.777