School of Medicine, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
Research Center in Pathobiology and Tropical Medicine, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
BMC Complement Med Ther. 2024 Mar 23;24(1):129. doi: 10.1186/s12906-024-04427-z.
The potent antiplasmodial activity of 1-hydroxy-5,6,7-trimethoxyxanthone (HTX), isolated from Mammea siamensis T. Anders. flowers, has previously been demonstrated in vitro. However, its in vivo activity has not been reported. Therefore, this study aimed to investigate the antimalarial activity and acute toxicity of HTX in a mouse model and to evaluate the pharmacokinetic profile of HTX following a single intraperitoneal administration.
The in vivo antimalarial activity of HTX was evaluated using a 4-day suppressive test. Mice were intraperitoneally injected with Plasmodium berghei ANKA strain and given HTX daily for 4 days. To detect acute toxicity, mice received a single dose of HTX and were observed for 14 days. Additionally, the biochemical parameters of the liver and kidney functions as well as the histopathology of liver and kidney tissues were examined. HTX pharmacokinetics after intraperitoneal administration was also investigated in a mouse model. Liquid chromatography triple quadrupole mass spectrometry was used to quantify plasma HTX and calculate pharmacokinetic parameters with the PKSolver software.
HTX at 10 mg/kg body weight significantly suppressed parasitemia in malaria-infected mice by 74.26%. Mice treated with 3 mg/kg HTX showed 46.88% suppression, whereas mice treated with 1 mg/kg displayed 34.56% suppression. Additionally, no symptoms of acute toxicity were observed in the HTX-treated groups. There were no significant alterations in the biochemical parameters of the liver and kidney functions and no histological changes in liver or kidney tissues. Following intraperitoneal HTX administration, the pharmacokinetic profile exhibited a maximum concentration (C) of 94.02 ng/mL, time to attain C (T) of 0.5 h, mean resident time of 14.80 h, and elimination half-life of 13.88 h.
HTX has in vivo antimalarial properties against P. berghei infection. Acute toxicity studies of HTX did not show behavioral changes or mortality. The median lethal dose was greater than 50 mg/kg body weight. Pharmacokinetic studies showed that HTX has a long elimination half-life; hence, shortening the duration of malaria treatment may be required to minimize toxicity.
从暹罗梅树的花朵中分离得到的 1-羟基-5,6,7-三甲氧基呫吨酮（HTX）具有很强的抗疟原虫活性，这已在体外得到证实。然而，其体内活性尚未报道。因此，本研究旨在通过小鼠模型研究 HTX 的抗疟活性和急性毒性，并评估其单次腹腔内给药后的药代动力学特征。
采用 4 天抑制试验评价 HTX 的体内抗疟活性。用伯氏疟原虫 ANKA 株感染小鼠，腹腔内注射，每天给予 HTX，连续 4 天。为了检测急性毒性，小鼠单次给予 HTX 并观察 14 天。此外，还检测了肝肾功能的生化参数以及肝肾功能组织的组织病理学变化。还在小鼠模型中研究了腹腔内给药后 HTX 的药代动力学。采用液相色谱三重四极杆质谱法定量血浆 HTX，并使用 PKSolver 软件计算药代动力学参数。
10mg/kg 体重的 HTX 可显著抑制疟疾感染小鼠的寄生虫血症，抑制率为 74.26%。3mg/kg HTX 治疗组的抑制率为 46.88%，1mg/kg HTX 治疗组的抑制率为 34.56%。此外，HTX 治疗组未观察到急性毒性症状。肝肾功能的生化参数无显著变化，肝肾功能组织无组织学变化。腹腔内给予 HTX 后，药代动力学特征显示最大浓度（C）为 94.02ng/mL，达到 C 的时间（T）为 0.5h，平均驻留时间（T）为 14.80h，消除半衰期（t）为 13.88h。
HTX 具有体内抗疟活性，可抗伯氏疟原虫感染。HTX 的急性毒性研究未显示行为改变或死亡。半数致死剂量大于 50mg/kg 体重。药代动力学研究表明，HTX 的消除半衰期较长；因此，为了尽量减少毒性，可能需要缩短疟疾治疗的持续时间。
