Schwartz Juana, Moreno Esther, Fernández Celia, Navarro-Blasco Iñigo, Nguewa Paul A, Palop Juan A, Irache Juan M, Sanmartín Carmen, Espuelas Socorro
Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain; Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain.
Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain.
Eur J Pharm Sci. 2014 Oct 1;62:309-16. doi: 10.1016/j.ejps.2014.06.010. Epub 2014 Jun 22.
Topical therapy is the ideal outpatient treatment of cutaneous leishmaniasis (CL) because of the ease of administration and lower cost. It could be suitable as monotherapy for localized cutaneous leishmaniasis (LCL) or in combination with systemic therapies for more severe forms of the disease. Although paromomycin (PM) ointment can be recommended for the treatment of LCL caused by Leishmaniamajor, a more effective topical treatment should be achieved regarding the physicochemical properties of this aminoglucoside and its rather poor intrinsic antileishmanial activity, that hampers the accumulation of enough amount of drug in the dermis (where the infected macrophages home) to exert its activity. In this work, we determined a 50% effective dose of 5.6 μM for a novel compound, bis-4-aminophenyldiselenide, against L. major intracellular amastigotes. This compound and PM were formulated in chitosan hydrogels and ex vivo permeation and retention studies in the different skin layers were performed with pig ear skin in Franz diffusion cells. The results showed that less than 2-4% of the diselenide drug penetrated and permeated through the skin. In contrast, the percentage of PM penetration was about 25-60% without important retention in the skin. When topically applied to lesions of L. major infected BALB/c mice, the novel diselenide chitosan formulation was unable to slow lesion progression and reduce parasite burden. Considerations during the process of novel drug development and formulation discovery algorithm for CL are discussed.
局部治疗因其给药方便且成本较低，是皮肤利什曼病（CL）理想的门诊治疗方法。它可作为局限性皮肤利什曼病（LCL）的单一疗法，或与全身疗法联合用于治疗更严重的疾病形式。尽管巴龙霉素（PM）软膏可推荐用于治疗由硕大利什曼原虫引起的LCL，但鉴于这种氨基糖苷的物理化学性质及其相当差的内在抗利什曼活性，应实现更有效的局部治疗，其内在抗利什曼活性阻碍了足够量的药物在真皮（受感染巨噬细胞归巢的部位）中积累以发挥其活性。在这项工作中，我们确定了一种新型化合物双-4-氨基苯二硒醚对硕大利什曼原虫细胞内无鞭毛体的50%有效剂量为5.6 μM。将该化合物和PM制成壳聚糖水凝胶，并在Franz扩散池中用猪耳皮肤进行不同皮肤层的离体渗透和滞留研究。结果表明，不到2-4%的二硒醚药物穿透并渗透过皮肤。相比之下，PM的穿透百分比约为25-60%，在皮肤中无明显滞留。当局部应用于感染硕大利什曼原虫的BALB/c小鼠的病变部位时，新型二硒醚壳聚糖制剂无法减缓病变进展和减轻寄生虫负担。讨论了CL新药开发过程中的注意事项以及CL制剂发现算法。
