National Center for Natural Product Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
Molecules. 2018 Jul 10;23(7):1674. doi: 10.3390/molecules23071674.
In this study, 2,3-dihydro-1-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from , was evaluated against in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live . Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day () orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu.
在这项研究中，从 中分离得到的 2,3-二氢-1-吲哚啉生物碱-普罗索皮利定（PPD）在隐球菌病的小鼠模型中被评估对抗 的活性。还评估了吲哚里定的体外和体内毒性。通过尾静脉将小鼠感染活 。感染后 24 小时，每天一次（ip）或两次（）口服给予 PPD，或用两性霉素 B（Amp B）腹腔内（IP），或用氟康唑（Flu）口服 5 天进行治疗。无菌取出所有动物的大脑，并回收活 的数量。在 HepG2 细胞中测定吲哚里定生物碱的体外毒性。与用 Amp B（1.5 mg/kg）治疗相比，PPD 在 0.0625 mg/kg 剂量下显示出针对 的强大体内活性，可消除约 76%的生物体。此外，与 Amp B（1.5 mg/kg）相比，当以 0.125 或 0.0625 mg/kg 的剂量通过 IP 途径（每天两次）给予时，PPD 被发现同样有效，但毒性更小。当通过口服途径测试时，PPD（10 mg/kg）在该隐球菌病小鼠模型中表现出强大的活性，约 82%的生物体从脑组织中消除，而 Flu（15 mg/kg）则降低了约 90%的感染。体外结果表明，与叔碱相比，季铵吲哚里定毒性较小。PPD（20 mg/kg）未引起血浆化学特征的任何改变。这些结果表明，与 Amp B 或 Flu 相比，PPD 以较低剂量通过口服和 IP 途径消除隐球菌感染是有效的。
