Artemether - CAS 71963-77-4

Artemether - CAS 71963-77-4 Catalog number: BADC-00236

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Artemether is an antimalarial for the treatment of multiple drug-resistant strains of Plasmodium falciparum malaria.

Category
ADCs Cytotoxin
Product Name
Artemether
CAS
71963-77-4
Catalog Number
BADC-00236
Molecular Formula
C16H26O5
Molecular Weight
298.37
Artemether

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Description
Artemether is an antimalarial for the treatment of multiple drug-resistant strains of Plasmodium falciparum malaria.
Synonyms
3,12-epoxy-12h-pyrano(4,3-j)-1,2-benzodioxepin,decahydro-10-methoxy-3,6,9-trim; 5a-beta,6-beta,8a-beta,9-alpha,12-beta,12ar)-(3-alph(+)-ethyl; artemisininelactolmethylether; cgp56696; dihydroartemisininmethylether; dihydroquinghaosumethylether; methyl-dihydroartemisinine; [3r-(3r,5as,6s,8as,9r,10r,12s,12ar**)]-decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12h-pyrano[4,3-j]-1,2-benzodioxepin
IUPAC Name
(1R,4S,5R,8S,9R,10S,12R,13R)-10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecane
Canonical SMILES
CC1CCC2C(C(OC3C24C1CCC(O3)(OO4)C)OC)C
InChI
InChI=1S/C16H26O5/c1-9-5-6-12-10(2)13(17-4)18-14-16(12)11(9)7-8-15(3,19-14)20-21-16/h9-14H,5-8H2,1-4H3/t9-,10-,11+,12+,13+,14-,15?,16-/m1/s1
InChIKey
SXYIRMFQILZOAM-GXTLMGRASA-N
Solubility
DMSO: =20 mg/ml
Melting Point
89 ºC
Optical Rotation
Specific optical rotation = 177 deg at 19.5 °C
LogP
3.53
Vapour Pressure
4X10-5 mm Hg at 25 °C (est)
Mechanism Of Action
Involves an interaction with ferriprotoporphyrin IX ("heme"), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from proteolysis of hemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen and carbon-centered radicals.
Pharmacology
In the body, artemether is metabolized into the active metabolite metabolite dihydroartemisinin. The drug works against the erythrocytic stages of P. falciparum by inhibiting nucleic acid and protein synthesis. Artemether is administered in combination with lumefantrine for improved efficacy. Artemether has a rapid onset of action and is rapidly cleared from the body. It is thought that artemether provides rapid symptomatic relief by reducing the number of malarial parasites. Lumefantrine has a much longer half life and is believed to clear residual parasites.
Toxicity (LD50)
Animal studies on acute toxicity show that the LD50 of Artemether in mice is a single i.g. administration of 895mg/kg and a single i.m. injection of 296mg/kg dose; in rats, the LD50 is a single i.m. injection of 597mg/kg dose.
In Vitro
In the in vitro blood distribution studies, the content ratios from blood cells to plasma were compared in the concentrations from 20 ng/mL to 1000 ng/mL. Such ratios were determined to be 1.1-1.6 for artemisinin, 0.9-1.2 for artemether, and around 0.7 for dihydroartemisinin. Referring to the in vitro distribution, the AUC(0-t) ratios from the blood cells measurements to the plasma measurements of these three antimalarial drugs were also in a similar trend as the in vitro distribution measurements. Furthermore, the half-life (t1/2) of artemether in blood cells was even longer than that in plasma, while the clearance of artemisinin, artemether, or dihydroartemisinin in blood cells was slower than that in plasma. Particularly, it was found that the concentrations of artemisinin and artemether were presented in blood cells over longer time period than in plasma above their antimalarial IC50, which might result from both the affinity toward blood cells and the drugs clearance differences between blood cells and plasma.
In Vivo
In the oral administration pharmacokinetic studies in rats, the concentration ratios from blood cells to plasma were from high (2.6-3.6) to medium (1.3-2.5), and low (0.5-1.5) for artemisinin, artemether, and dihydroartemisinin respectively in all measuring time points, displaying the similar affinity order toward blood cells in artemisinin > artemether > dihydroartemisinin as the in vitro measurements. The dosages of 10 mg/kg for intravenous administrations of artemisinin and 200 mg/kg for oral administrations of artemisinin or artemether were used for the pharmacokinetic study in rats. The geometric mean exposures (AUC(0-t)) of artemisinin, artemether and dihydroartemisinin in blood cells were determined to be 2.6 folds, 1.7 folds, or 1.2 folds greater than those in plasma, respectively. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, tumour necrosis factor-alpha (TNFα) and interleukin (IL)-6); Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-κB and p38 MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether.
Clinical Trial Information
NCT NumberCondition Or DiseasePhaseStart DateSponsorStatus
NCT01625871Vivax MalariaPhase 32013-01-17University of KhartoumCompleted
NCT04080895PharmacokineticPhase 12021-09-28University of OxfordNot yet recruiting
NCT02348788Plasmodium Vivax Malaria Without ComplicationPhase 32017-02-01Menzies School of Health ResearchUnknown Verified January 2017 by Menzies School of Health Research. Recruitment status was Recruiting
NCT02089841Plasmodium Falciparum MalariaPhase 42014-03-18Richard MwaisweloCompleted
NCT04829695Falciparum MalariaPhase 42021-04-02University of Yaounde 1Not yet recruiting
Application
ADCs Cytotoxin
Appearance
White to Off-White Solid
Purity
>99%
Quantity
Milligrams-Grams-Kilograms
Quality Standard
Enterprise Standard
Shipping
-20°C (International: -20°C)
Storage
Providing storage is as stated on the product vial and the vial is kept tightly sealed, the product can be stored for up to 24 months(2-8C).
Pictograms
Irritant
Signal Word
Warning
1.Systemic Delivery of Artemether by Dissolving Microneedles.
Qiu Y1, Li C1, Zhang S1, Yang G1, He M1, Gao Y2. Int J Pharm. 2016 May 2. pii: S0378-5173(16)30372-6. doi: 10.1016/j.ijpharm.2016.05.006. [Epub ahead of print]
Dissolving microneedles (DMNs) based transdermal delivery is an attractive drug delivery approach with minimal invasion. However, it is still challenging to load poorly water-soluble drugs in DMNs for systemic delivery. The aim of the study was to develop DMNs loaded with artemether (ARM) as a model drug, to enable efficient drug penetration through skin for systemic absorption and distribution. The micro-conduits created by microneedles were imaged by confocal laser scanning microscopy (CLSM), and the insertion depth was suggested to be about 270μm. The maximum amount of ARM delivered into skin was 72.67±2.69% of the initial dose loaded on DMNs preparation. Pharmacokinetics study in rats indicated a dose-dependent profile of plasma ARM concentrations, after ARM-loaded DMNs treatment. In contrast to intramuscular injection, DMNs application resulted in lower peak plasma levels, but higher plasma ARM concentration at 8hours after administration.
2.Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential.
Tripathi CB1, Beg S1, Kaur R2, Shukla G3, Bandopadhyay S4, Singh B1,2. Drug Deliv. 2016 Mar 29:1-15. [Epub ahead of print]
The current studies entail systematic development of self-nanoemulsifying drug delivery systems (SNEDDS) containing medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) for augmenting the biopharmaceutical performance of artemether. Equilibrium solubility and pseudoternary phase diagram studies facilitated selection of Captex 355 and Ethyl oleate as MCTs and LCTs, and Cremophor RH 40 and Tween 80 as surfactants, while Transcutol HP as cosolvent for formulating the SNEDDS. Systematic optimization was performed employing the Box-Behnken design taking concentrations of lipid, surfactant and cosolvent as the critical material attributes (CMAs), while evaluating for globule size, emulsification time, dissolution efficiency and permeation as the critical quality attributes (CQAs). In situ single pass intestinal perfusion (SPIP) studies in Wistar rats substantiated significant augmentation in the absorption (5- to 6-fold) and permeation (4- to 5-fold) parameters from the optimized MCT and LCT-SNEDDS vis-à-vis the pure drug.
3.Apoptotic activity and anti-Toxoplasma effects of artemether on the tachyzoites and experimental infected Vero and J774 cell lines by Toxoplasma gondii.
Mikaeiloo H1, Ghaffarifar F1, Dalimi A1, Sharifi Z2, Hassan ZM3. Indian J Pharmacol. 2016 Mar-Apr;48(2):179-85. doi: 10.4103/0253-7613.178838.
OBJECTIVES: Drugs used for toxoplasmosis have limited efficacy and also severe side effects. A new drug with good efficacy and limited side effects is need of the hour. We studied the effects of artemether on Toxoplasma gondii in vitro conditions.
4.Artemether-Lumefantrine Concentrations in Tablets and Powders from Ghana Measured by a New High-Performance Liquid Chromatography Method.
Debrah P1, Nettey H2, Miltersen KK2, Ayeh-Kumi P2, Brock B2, Sarkodie J2, Akwo-Kretchy I2, Owusu-Danso P2, Adjei S2, Petersen E2, Hardlei TF2. Am J Trop Med Hyg. 2016 May 2. pii: 15-0868. [Epub ahead of print]
We developed and validated a new analytical method for the simultaneous quantification of artemether and lumefantrine in fixed-dose tablets and powders for reconstitution into pediatric suspensions (PSs). The method showed linearity (r2 > 0.9947), precision (coefficient of variation < 2%), accuracy (deviation of mean from actual concentrations < 4%), and specificity (peak purities > 99%). The validated method was used to analyze 24 batches of fixed-dose tablets and PSs of artemether and lumefantrine. Of the samples, 23 were obtained using convenience sampling of commonly available brands within Accra in Ghana and one was obtained from Aarhus University Hospital. In all, 83.3% (confidence interval: 80-120%) passed for both artemether and lumefantrine contents, 16.7% failed by the U.S. Pharmacopoeia standards, 8.3% failed for one content, and 8.3% failed for both contents. All four products (16.7%) that failed were PSs, and two (8.

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Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2

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