Drug Information

Drug (ID: DG00223) and It's Reported Resistant Information

• Name: Dihydroartemisinin
• Synonyms: Artenimol; Cotecxin; Dihydroartemisinine; Dihydroqinghaosu; Dihydroquinghaosu; Dihydroquinghoasu; VM3352; Artenimol (INN); JAV-110; GNF-PF-5634; (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j][1,2]benzodioxepin-10-ol; [3R-(3.alpha.,5a.beta.,6.beta.,8a.beta.,9.alpha.,10.alpha.,12.beta.,12aR*)]-Decahydro-10-hydroxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4.3-j]-1,2-benzodioxepin; 1,5,9-trimethyl-(1R,4S,5R,8S,9R,10S,12R,13R)-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-ol(Dihydroartemisinin)
• Indication:
  In total 1 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [2]
• Target: Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A); NOUNIPROTAC; [1]
• Formula: C15H24O5
• IsoSMILES: C[C@@H]1CC[C@H]2[C@H]([C@H](O[C@H]3[C@@]24[C@H]1CC[C@](O3)(OO4)C)O)C
• InChI: 1S/C15H24O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-13,16H,4-7H2,1-3H3/t8-,9-,10+,11+,12+,13-,14-,15-/m1/s1
• InChIKey: BJDCWCLMFKKGEE-ISOSDAIHSA-N
• PubChem CID: 3000518
• ChEBI ID: CHEBI:135921
• TTD Drug ID: D0N6FH
• DrugBank ID: DB11638

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Molecule Alteration: Missense mutation; p.M908L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Drug Resistance: In vitro drug assay
• Mechanism Description: Studies of genetic polymorphisms in two candidate genes of drug resistance (pvmdr1 and pvcrt-o) of the P. vivax isolates from this area and found association between the M908L substitution in pvmdr1 with reduced sensitivities to and chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartem.

Key Molecule: Chloroquine resistance transporter (CRT) [2]

• Molecule Alteration: Missense mutation; p.F145I
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Mechanism Description: The PfCRT 145I mutation was only observed in parasites with amplified plasmepsin II/III copy number, suggesting that perhaps in nature this mutation has only occurred or only attains high frequency on a background of amplified plasmepsin II/III. Moreover, the mean piperaquine IC90 was greater in parasites with both amplified plasmepsin II/III and PfCRT 145I compared with parasites with just amplified plasmepsin II/III, suggesting that 145I results in an additional resistance effect beyond that caused by amplified plasmepsin.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [3]

• Molecule Alteration: Missense mutation; p.K76T
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Nested PCR
• Mechanism Description: Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Molecule Alteration: Missense mutation; p.N86Y
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Nested PCR
• Mechanism Description: Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Molecule Alteration: Missense mutation; p.N86Y
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: DNA assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: The most striking phenotype observed with the replacement of N86Y with the wild-type N86 residue was a significant increase in the IC50 and IC90 values for LMF, MFQ and DHA. In the case of DHA, the change to N86 resulted in -1.5-fold increased IC50 values in both backgrounds.

References

• Ref 1: Ex vivo susceptibilities of Plasmodium vivax isolates from the China-Myanmar border to antimalarial drugs and association with polymorphisms in Pvmdr1 and Pvcrt-o genes. PLoS Negl Trop Dis. 2020 Jun 12;14(6):e0008255. doi: 10.1371/journal.pntd.0008255. eCollection 2020 Jun.
• Ref 2: Association of a Novel Mutation in the Plasmodium falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity. J Infect Dis. 2017 Aug 15;216(4):468-476. doi: 10.1093/infdis/jix334.
• Ref 3: Prevalence of chloroquine and antifolate drug resistance alleles in Plasmodium falciparum clinical isolates from three areas in Ghana. AAS Open Res. 2018 Dec 3;1:1. doi: 10.12688/aasopenres.12825.2. eCollection 2018.
• Ref 4: Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nat Commun. 2016 May 18;7:11553. doi: 10.1038/ncomms11553.