生物活性

• 描述Akt/PKB is a crucial protein within the phosphatidylinositol3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) intracellular signalling pathway, which is involved in cell survival. Miltefosine is considered an inhibitor of Akt and is the only oral drug to treat infections caused by L. donovani^[7]. Miltefosine belongs to the class of alkylphosphocholine drugs (ALPs), which are phosphocholine esters of aliphatic long-chain alcohols. These alkylphosphocholine compounds are structurally related to the group of alkyl-lysophospholipids, which are synthetic analogues of lysophosphatidylcholines or lysolecithins. From a functional point of view, miltefosine is considered an inhibitor of Akt. The most prominent molecular targets for miltefosine's anticancer activity are related to the antileishmanial targets, and include the inhibition of phosphatidylcholine biosynthesis and the induction of apoptosis by inhibition of the PI3K/Akt/PKB pathway^[8]. The ED50 values of Miltefosine towards inhibiting PI3K/Akt activity are 17.2 μM and 8.1 μM in carcinoma cell lines A431 and HeLa^[9]. Miltefosine is approvaled for application in cutaneous metastasis of breast cancer and visceral and cutaneous leishmaniasis. ALPs have also shown in vitro and in vivo activity against Trypanosoma spp., amoebae, Tricomonas vaginalis, Schistosoma mansoni, HIV, and some fungi and bacteria species^[10].
• 作用机制The mechanism of action of ALPs is not fully understood, they interfere with lipid homeostasis which increased degradation of lipid-droplets via lipophagy and prevent plasma membrane recruitment of the PH domain of AKT by disrupting plasma membrane microdomains thus leading to cell apoptosis^[10].

• 动物研究
  剂量	Rat: 0.1 mg/kg - 10 mg/kg[3] (p.o.) Mice: 50 mg/kg[4] (i.p.) Dog: 2 mg/kg[5] (p.o.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Rats[6] Dose 10 mg/kg Administration i.v. or p.o. T1/2 82.5 h (i.v.) 84.3 h (p.o.) Vz 1.07 L/kg (i.v.) Tmax 24.0 h (p.o.) CL 0.15 ml/min/kg (i.v.) Vss 0.96 L/kg (i.v.) AUC 1104180 ng·h ml (i.v.) 904533 ng·h ml (p.o.)