Antimalaria; Plasmodium falciparum malaria

In vitro tests were conducted to evaluate the antimalarial efficacy of Artemotil against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum parasites. Artemotil's 50% inhibitory concentration (IC50) ranges from 1.57 to 1.92 nM on average. Compared to artemisinin, artemotil is about 2.5 times as efficacious [1].

In addition to causing significant reductions in food consumption and body weight after day 2, the administration of 25 mg/kg of artemotil intravenously (i.v.) for seven days to male Sprague-Dawley rats demonstrated anorexigenic toxicity. The AUC on day 7 was five times higher than the AUC on day 1, and the elimination t1/2 of artemotil was also extended from 13.7 hours (day 1) to 31.2 hours (day 7) [2].

The antimalarial activity of beta-artemether and beta-arteether was compared in three test systems: in vitro against chloroquine-resistant and chloroquine-sensitive Plasmodium falciparum parasites, in mice infected with P. berghei, and in Aotus monkeys infected with chloroquine-resistant P. falciparum. In vitro, the mean 50% inhibitory concentration (IC50) for beta-artemether was 1.74 nM (range 1.34-1.81 nM), and this value for beta-arteether was 1.61 nM (range 1.57-1.92 nM). They were approximately 2.5-fold more potent than artemisinin, which had a mean IC50 of 4.11 nM (range 3.36-4.60 nM)[1].

Animal/Disease Models: SD (SD (Sprague-Dawley)) male rats (220-280g) [2]
Doses: 25 mg/kg; 1 mL/kg body weight
Route of Administration: intravenous (iv) (iv)injection; daily; continued for 7 days
Experimental Results: Anorexigenic toxicity was observed, leading to the first Food consumption and body weight were Dramatically diminished after 2 days.

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In the mouse model, the 50% curative doses (CD50) of beta-artemether and beta-arteether had a mean value of 55 mg/kg (32-78 mg/kg). The 50% effective curative doses (ED50) in the Aotus monkey were 7.1 mg/kg (95% confidence interval [CI] = 3.7-13.5) for beta-artemether and 11.8 mg/kg (95% CI = 6.5-21.3) for beta-arteether. Overall, the activities of the two drugs were comparable.[1]

Multiple administrations of Artemotil (ARTE) at a dose of 25 mg/kg to rats caused central nervous system toxicity and anorexia. This study investigated the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) after a single dose of the same dose of ARTE. ARTE was dissolved in sesame oil and administered continuously for 7 days. Blood samples were collected within 192 hours after administration using a destructive sampling method and analyzed using high-performance liquid chromatography-electron capture detector (HPLC-ECD). Two other groups of rats received a single intravenous or intramuscular injection of 25 mg/kg ARTE, respectively. Drug residues at the intramuscular injection site were also measured. Anorexia toxicity of ARTE was observed during the 7-day treatment period, resulting in a significant decrease in food intake and body weight from day 2 onwards. Pharmacokinetic (TK) data from days 2 to 7 showed significant changes compared to the estimated pharmacokinetic (PK) parameters from day 1. The AUC on day 7 (4367 ng·h/ml) was 5 times that on day 1 (905 ng·h/ml). The steady-state volume of distribution (V(SS)) on day 7 (41.8 L) was 40% of the V(SS) value on day 1 (104.3 L). The clearance (CL) increased by 89% compared to day 1, from 0.98 L/h to 1.85 L/h on day 7. The elimination half-life of ARTE (t(1/2)) also increased from 13.7 hours (day 1) to 31.2 hours (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats due to systemic toxicity. Injection site analysis showed that 38% and 91% of the total ARTE remained in muscle 24 hours after the first injection and 24 hours after 7 consecutive days of multiple daily administration, respectively. Muscle absorption occurred in two phases: rapid absorption and slow absorption, with half-lives of 0.97 hours and 26.3 hours, respectively. Due to the prolonged absorption phase in the muscle, the apparent elimination half-life of ARTE administered intramuscularly (13.7 hours) is much longer than that of intravenous injection (0.67 hours). Acute toxicity data of artemisinin-based drugs showed that animals receiving a single high dose of sesame oil-infused ARTE died within 5–11 days, similar to Artemotil. When animals were given dihydroartemisinin prepared with 50% DMAC/oil, or artesunate and Artemotil prepared with 0.9% saline, they died within 1 to 2 days. This suggests that the delayed toxicity and death of ARTE rats may also be due to slow drug absorption and prolonged drug exposure. Therefore, repeated intramuscular injections may lead to anorexia and drug accumulation, which may affect the toxicokinetics and efficacy of the drug. [2]

[1]. Comparison of beta-artemether and beta-arteether against malaria parasites in vitro and in vivo. Am J Trop Med Hyg. 1993 Mar;48(3):377-84.

[2]. Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):213-23.

Artemotil is an artemisinin derivative. Also known as β-artemisinin, Artemotil is a semi-synthetic derivative of artemisinin and a fast-acting hemolytic schizonticide specifically used to treat cases of Plasmodium falciparum malaria and cerebral malaria resistant to chloroquine.

312.193

C, 65.36; H, 9.03; O, 25.61

75887-54-6

75887-54-6; 109716-83-8;

3000469

White to off-white solid powder

1.2±0.1 g/cm3

372.4±42.0 °C at 760 mmHg

80-820ºC

146.0±27.8 °C

0.0±0.8 mmHg at 25°C

1.516

3.6

0

5

2

22

443

8

O1[C@@]23[C@]4([H])O[C@@]([H])([C@]([H])(C([H])([H])[H])[C@]2([H])C([H])([H])C([H])([H])[C@@]([H])(C([H])([H])[H])[C@]3([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(O1)O4)OC([H])([H])C([H])([H])[H]

NLYNIRQVMRLPIQ-XQLAAWPRSA-N

InChI=1S/C17H28O5/c1-5-18-14-11(3)13-7-6-10(2)12-8-9-16(4)20-15(19-14)17(12,13)22-21-16/h10-15H,5-9H2,1-4H3/t10-,11-,12+,13+,14+,15-,16-,17-/m1/s1

(1R,4S,5R,8S,9R,10S,12R,13R)-10-ethoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecane

Arteether; Arteether; Artemotil; 75887-54-6; Beta-Arteether; SM-227; Artemotilum; .beta.-arteether; Artemotil [INN]; Artemotil Dihydroartemisinin ethyl ether beta-Arteether NSC 665971 SM 227beta-Dihydroartemisinin ethyl ether

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~160.05 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (6.66 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)