Lumefantrine

Last updated

Lumefantrine
Lumefantrine.svg
Clinical data
Other namesbenflumetol
AHFS/Drugs.com International Drug Names
MedlinePlus a609024
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • US:C
  • EU:Rx-only
Pharmacokinetic data
Protein binding 99.7%
Metabolites desbutyl-lumefantrine
Elimination half-life 3-6 days
Identifiers
  • 2-(Dibutylamino)-1-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.133.797 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C30H32Cl3NO
Molar mass 528.94 g·mol−1
3D model (JSmol)
Melting point 130 to 132 °C (266 to 270 °F)
Solubility in water 30.9ng/mL
  • Clc1ccc(cc1)\C=C3\c4c(c2c(cc(Cl)cc23)C(O)CN(CCCC)CCCC)ccc(Cl)c4
  • InChI=1S/C30H32Cl3NO/c1-3-5-13-34(14-6-4-2)19-29(35)28-18-23(33)17-27-25(15-20-7-9-21(31)10-8-20)26-16-22(32)11-12-24(26)30(27)28/h7-12,15-18,29,35H,3-6,13-14,19H2,1-2H3/b25-15- Yes check.svgY
  • Key:DYLGFOYVTXJFJP-MYYYXRDXSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination. [1] Lumefantrine has a much longer half-life compared to artemether (3-6 days vs. 2 hours [2] ), and is therefore thought to clear any residual parasites that remain after combination treatment. [3]

Contents

Mechanism of action

Exact mechanism by which lumefantrine acts on erythrocytic stages of Plasmodium falciparum is unknown. However, it was shown to exert its action through possible two mechanisms: [3] [2] [4]

Moreover, it was shown to interact with human sodium/potassium ATPase subunit α1. [4]

Metabolism

Lumefantrine is metabolised in the liver by cytochrome P450 3A4 isoenzyme (CYP3A4) and 2D6 (CYP2D6), yielding desbutyl-lumefantrine as a major metabolite. [5] [2]

Adverse effects

Lumefantrine, as used in combination with artemether, was shown to induce the following side effects:

People taking efavirenz as a part of HIV therapy should be wary of potential deviations during treatment, due to a decrease of AUC of this antiretroviral. [6] [7]

History

Lumefantrine, along with pyronaridine and naphthoquine, were synthesized during the Chinese Project 523 antimalaria drug research effort initiated in 1967; these compounds are all used in combination antimalaria therapies. [8] [9] [10]

Research

Lumefantrine is being investigated as a part of a regimen with ganaplacide for the treatment of Plasmodium falciparum malaria. [11]

O-choline O-choline.png
O-choline

Along with O-choline (octadecyl 2-(trimethylammonio)ethyl phosphate), lumefantrine inhibits in vivo growth of Theileria equi and Babesia caballi , due to inhibition of membrane phospholipid synthesis, hemoglobin digestion and targeting lactate metabolism. [12] Additionally, it can inhibit Babesia gibsoni growth in vitro (synergistically with artemisinin derivatives). [13]

It may exert negative effects on aquatic ecosystems by adversely acting on Chlorella vulgaris , Raphidocelis subcapitata , Lemna minor and Microcystis aeruginosa . [14] [15] Moreover, it is classified as a potential endocrine disrupting compound by decreasing FSHB and increasing prolactin secretion. [16] [17]

Lumefantrine and calcium phosphate-loaded lipid nanoparticles or cubosomes were investigated as a potential treatment of lung cancer due to probable antiangiogenic and anti-inflammatory properties of this combination. [18] [19]

General structure of selene-containing lumefantrine derivatives Selene lumefantrine derivatives.png
General structure of selene-containing lumefantrine derivatives

Selenium-containing lumefantrine derivatives synthesised through Knoevenagel condensation (which itself is used to synthesise lumefantrine) exhibit potential antibacterial and antifungal activity. Compared with ciprofloxacin, they were shown to more potently bind to E. coli MurB enzyme – an enzyme participating in cell cycle and cell wall synthesis. [20]

See also

References

  1. ↑ Toovey S, Jamieson A, Nettleton G (August 2003). "Successful co-artemether (artemether-lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique". Travel Medicine and Infectious Disease. 1 (3): 177–179. doi:10.1016/j.tmaid.2003.09.002. PMID   17291911.
  2. 1 2 3 "Coartem - Highlights of prescribing information" (PDF). Novartis. August 2019. Retrieved 26 February 2025.
  3. 1 2 White NJ, van Vugt M, Ezzet F (August 1999). "Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine". Clinical Pharmacokinetics. 37 (2): 105–125. doi:10.2165/00003088-199937020-00002. PMID   10496300. S2CID   72714420.
  4. 1 2 "Lumefantrine". go.drugbank.com. Retrieved 2025-02-26.
  5. ↑ "Lumefantrine". go.drugbank.com. Retrieved 2025-02-26.
  6. ↑ Usman SO, Oreagba IA, Akinyede AA, Agbaje EO, Akinleye MO, Onwujuobi AG, et al. (November 2020). "Effect of nevirapine, efavirenz and lopinavir/ritonavir on the therapeutic concentration and toxicity of lumefantrine in people living with HIV at Lagos University Teaching Hospital, Nigeria". Journal of Pharmacological Sciences. 144 (3): 95–101. doi: 10.1016/j.jphs.2020.07.013 . PMID   32921396.
  7. ↑ Zakaria Z, Badhan RK (July 2018). "The impact of CYP2B6 polymorphisms on the interactions of efavirenz with lumefantrine: Implications for paediatric antimalarial therapy" (PDF). European Journal of Pharmaceutical Sciences. 119: 90–101. doi:10.1016/j.ejps.2018.04.012. PMID   29635009.
  8. ↑ Cui L, Su XZ (October 2009). "Discovery, mechanisms of action and combination therapy of artemisinin". Expert Review of Anti-Infective Therapy. 7 (8): 999–1013. doi:10.1586/eri.09.68. PMC   2778258 . PMID   19803708.
  9. ↑ Benjamin J, Moore B, Lee ST, Senn M, Griffin S, Lautu D, et al. (May 2012). "Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a tolerability, safety, and preliminary efficacy study". Antimicrobial Agents and Chemotherapy. 56 (5): 2465–2471. doi:10.1128/AAC.06248-11. PMC   3346652 . PMID   22330921.
  10. ↑ Laman M, Moore BR, Benjamin JM, Yadi G, Bona C, Warrel J, et al. (December 2014). "Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial". PLOS Medicine. 11 (12): e1001773. doi: 10.1371/journal.pmed.1001773 . PMC   4280121 . PMID   25549086.
  11. ↑ Ogutu B, Yeka A, Kusemererwa S, Thompson R, Tinto H, Toure AO, et al. (September 2023). "Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial". The Lancet. Infectious Diseases. 23 (9): 1051–1061. doi:10.1016/S1473-3099(23)00209-8. PMID   37327809.
  12. ↑ Maji C, Goel P, Suthar A, Mandal KD, Gopalakrishnan A, Kumar R, et al. (April 2019). "Lumefantrine and o-choline - Parasite metabolism specific drug molecules inhibited in vitro growth of Theileria equi and Babesia caballi in MASP culture system". Ticks and Tick-Borne Diseases. 10 (3): 568–574. doi:10.1016/j.ttbdis.2019.01.004. PMID   30733146.
  13. ↑ Iguchi A, Matsuu A, Matsuyama K, Hikasa Y (April 2015). "The efficacy of artemisinin, artemether, and lumefantrine against Babesia gibsoni in vitro". Parasitology International. 64 (2): 190–193. doi:10.1016/j.parint.2014.12.006. PMID   25523292.
  14. ↑ Chia MA, Ameh I, Agee JT, Otogo RA, Shaba AF, Bashir H, et al. (July 2021). "Effects of the antimalarial lumefantrine on Lemna minor, Raphidocelis subcapitata and Chlorella vulgaris". Environmental Toxicology and Pharmacology. 85 103635. Bibcode:2021EnvTP..8503635C. doi:10.1016/j.etap.2021.103635. PMID   33716093.
  15. ↑ Dauda S, Uyovbisere EE, Alhassan AB, Sha'aba RI, Gadzama IM, Onaji MO, et al. (2024-05-01). "Allelopathic interactions between Lemna minor and Microcystis aeruginosa are influenced by the antimalarial drug lumefantrine" . Aquatic Botany. 192 103759. Bibcode:2024AqBot.19203759D. doi:10.1016/j.aquabot.2024.103759. ISSN   0304-3770.
  16. ↑ Andres S, Dulio V, Taha HM (2024-04-08), S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2, doi:10.5281/ZENODO.10944198 , retrieved 2025-02-26
  17. ↑ Abolaji AO, Adesanoye OA, Awogbindin I, Farombi EO (November 2016). "Endocrine disruption and oxidative stress implications of artemether-lumefantrine combination therapy in the ovary and uterus of rats". Human & Experimental Toxicology. 35 (11): 1173–1182. Bibcode:2016HETox..35.1173A. doi:10.1177/0960327115626580. PMID   26811345.
  18. ↑ Sethuraman V, Janakiraman K, Krishnaswami V, Natesan S, Kandasamy R (March 2021). "In vivo synergistic anti-tumor effect of lumefantrine combined with pH responsive behavior of nano calcium phosphate based lipid nanoparticles on lung cancer". European Journal of Pharmaceutical Sciences. 158 105657. doi:10.1016/j.ejps.2020.105657. PMID   33271276.
  19. ↑ Sethuraman V, Janakiraman K, Krishnaswami V, Natesan S, Kandasamy R (November 2019). "pH responsive delivery of lumefantrine with calcium phosphate nanoparticles loaded lipidic cubosomes for the site specific treatment of lung cancer". Chemistry and Physics of Lipids. Practical insights into drug delivery systems. 224 104763. doi:10.1016/j.chemphyslip.2019.03.016. PMID   30951710.
  20. 1 2 Puthran D, Poojary B, Nayak SG, Purushotham N, Rasheed MS, Hegde H (2020). "Design, synthesis, molecular docking, and biological evaluation of novel selenium containing lumefantrine analogues" . Journal of Heterocyclic Chemistry. 57 (3): 1319–1329. doi:10.1002/jhet.3868. ISSN   1943-5193.
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