title: Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid.
abstract: Cutaneous leishmaniasis (CL) is a neglected tropical disease that causes prominent skin scaring. No water soluble, non-toxic, short course and low cost treatment exists. We developed a new water soluble amphotericin B-polymethacrylic acid (AmB-PMA) using established and scalable chemistries. AmB-PMA was stable for 9 months during storage. In vitro, it was effective against Leishmania spp. promastigotes and amastigote infected macrophages. It was also less toxic and more effective than deoxycholate-AmB, and similar to liposomal AmB. Its in vivo activity was determined in both early and established CL lesion models of Leishmania major infection in genetically susceptible non-healing BALB/c mice. Intradermal AmB-PMA at a total dose of 18 mg of AmB/kg body weight led to rapid parasite killing and lesion healing. No toxicity was seen. No parasite relapse occurred after 80 days follow-up. Histological studies confirmed rapid parasite clearance from macrophages followed by accelerated fibroblast mediated tissue repair, regeneration and cure of the infection. Quantitative mRNA studies of the CL lesions showed that accelerated healing was associated with increased Tumour Necrosis Factor-α and Interferon-γ, and reduced Interleukin-10. These results suggest that a cost-effective AmB-PMA could be used to pharmacologically treat and immuno-therapeutically accelerate the healing of CL lesions.
authors.affiliation: Department of Medicine, Infectious Diseases & Immunity, Hammersmith Hospital, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Karina
authors.initials: K
authors.lastname: Corware
authors.forename: Debra
authors.initials: D
authors.lastname: Harris
authors.forename: Ian
authors.initials: I
authors.lastname: Teo
authors.forename: Matthew
authors.initials: M
authors.lastname: Rogers
authors.forename: Kikkeri
authors.initials: K
authors.lastname: Naresh
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
mesh_terms: D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000150:complications / Q000188:drug therapy / Q000469:parasitology / Q000473:pathology; D056747:Immunomodulation / Q000187:drug effects; D018320:Leishmania major / Q000187:drug effects; D016773:Leishmaniasis, Cutaneous / Q000150:complications / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D011109:Polymethacrylic Acids / Q000627:therapeutic use* / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D018675:Toxicity Tests; D014867:Water / Q000737:chemistry*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D018925:Chemokines; D011109:Polymethacrylic Acids; D012333:RNA, Messenger; D014867:Water; C030613:polymethacrylic acid; D000666:Amphotericin B