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.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00696969	Visceral Leishmaniasis	Phase 3	Completed	-	India ... more >> Kala-azar medical centre Muzaffarpur, Bihar, India Rajendra Memorial research Institute Patna, Bihar, India Collapse <<
  NCT02366884	Neoplasms	Phase 2	Enrolling by invitation	December 31, 2020	United States, Maryland ... more >> Atavistic Chemotherapy Clinical Trial Bethesda, Maryland, United States, 20814 Mexico Dr. Frank Arguello Cancer Clinic San Jose del Cabo, Baja California Sur, Mexico Instituto de Ciencia y Medicina Genomica Torreon, Coahuila, Mexico Collapse <<
  NCT00351520	Cutaneous Leishmaniasis	Phase 3	Completed	-	Iran, Islamic Republic of ... more >> Ali Khamesipour Bam city, Kerman province, Iran, Islamic Republic of Collapse <<

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• 参考文献

• [1] Eissa MM, El-Moslemany RM, et al. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study. PLoS One. 2015 Nov 17;10(11):e0141788.

  [2] Chugh P, Bradel-Tretheway B, et al. Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology. 2008 Jan 31;5:11.

  [3] Botschuijver S, van Diest SA, et al. Miltefosine treatment reduces visceral hypersensitivity in a rat model for irritable bowel syndrome via multiple mechanisms. Sci Rep. 2019 Aug 29;9(1):12530.

  [4] Bhatt AP, Bhende PM, et al. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010 Jun 3;115(22):4455-63.

  [5] Manna L, Corso R, et al. Long-term follow-up of dogs with leishmaniosis treated with meglumine antimoniate plus allopurinol versus miltefosine plus allopurinol. Parasit Vectors. 2015 May 28;8:289.

  [6] Miltefosine

  [7] Pinto-Martinez AK, Rodriguez-Durán J, Serrano-Martin X, Hernandez-Rodriguez V, Benaim G. Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca2+ Channel. Antimicrob Agents Chemother. 2017 Dec 21;62(1):e01614-17.

  [8] Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012 Nov;67(11):2576-97.

  [9] Uberall F, Oberhuber H, Maly K, Zaknun J, Demuth L, Grunicke HH. Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity. Cancer Res. 1991 Feb 1;51(3):807-12.

  [10] Pachioni Jde A, Magalhães JG, Lima EJ, Bueno Lde M, Barbosa JF, de Sá MM, Rangel-Yagui CO. Alkylphospholipids - a promising class of chemotherapeutic agents with a broad pharmacological spectrum. J Pharm Pharm Sci. 2013;16(5):742-59.

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