Division of Parasitology, Central Drug Research Institute (CSIR), Chattar Manzil Palace, M.G. Road, Lucknow, 226001 Uttar Pradesh, India.
Parasitol Res. 2012 Aug;111(2):563-70. doi: 10.1007/s00436-012-2868-z. Epub 2012 Mar 6.
Current drugs for the treatment of visceral leishmaniasis are inadequate, and their efficacies are also compromised due to suppression of immune function during the course of infection. Miltefosine is the only promising orally active antileishmanial drug, but due to its long half-life, there is risk of development of resistance. To overcome these problems, efforts are needed to develop combination therapy of miltefosine with effective immunostimulating agents where a decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In the present study, we have explored the antileishmanial efficacy of a subcurative dose of miltefosine in combination with free as well as liposomal palmitoyl tuftsin (p-tuftsin) using a Leishmania donovani/BALB/c mouse model. When miltefosine (2.5 mg/kg for 5 days) was given with free p-tuftsin, the inhibitory effect was significantly increased from 49.6% to 66% (P < 0.01), which was further enhanced up to 81% (P < 0.001) when given after liposomal encapsulation of p-tuftsin. Significant enhancement in parasitic inhibition (93%, P < 0.01) was witnessed when animals were co-administered with liposomal p-tuftsin + 5 mg/kg × 5 days dose of miltefosine (72.1%). Enhancement in the production of Th1 cytokines (IL-12, TNF-α, and IFN-γ), reactive oxygen, and nitrogen metabolites was witnessed in the combination group. A remarkable increase in phagocytosis index was also observed indicating overall immunological enhancement to antileishmanial activity of miltefosine by p-tuftsin.
目前治疗内脏利什曼病的药物不够有效，而且由于感染过程中免疫功能受到抑制，其疗效也受到影响。米替福新是唯一有前途的口服抗利什曼原虫药物，但由于其半衰期长，存在产生耐药性的风险。为了克服这些问题，需要努力开发米替福新与有效免疫刺激剂的联合治疗，从而可以降低寄生虫负担并同时增强适应性免疫。在本研究中，我们使用利什曼原虫/ BALB/c 小鼠模型探索了亚治疗剂量米替福新联合游离和脂质体棕榈酰化 tuftsin（p-tuftsin）的抗利什曼原虫疗效。当给予米替福新（2.5mg/kg，连用 5 天）联合游离 p-tuftsin 时，抑制作用从 49.6%显著增加到 66%（P<0.01），当 p-tuftsin 脂质体包封后给予时，进一步增加到 81%（P<0.001）。当给予脂质体 p-tuftsin+5mg/kg×5 天剂量的米替福新（72.1%）时，寄生虫抑制作用显著增强（93%，P<0.01）。联合组观察到 Th1 细胞因子（IL-12、TNF-α和 IFN-γ）、活性氧和氮代谢物的产生增加。吞噬指数也显著增加，表明 p-tuftsin 整体增强了米替福新的抗利什曼原虫活性的免疫作用。
