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Title: Cutaneous leishmaniasis : skin barrier properties and drug delivery strategies
Author: Van Bocxlaer, K.
ISNI:       0000 0004 7659 8280
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Cutaneous leishmaniasis (CL) is a parasitic disease caused by several species of the protozoan parasite Leishmania and affects approximately 10 million people worldwide. The drugs currently available such as miltefosine, amphotericin B and pentavalent antimonials, are limited by high cost, considerable side effects and restricted efficacy. CL could potentially be treated by a topical formulation. In its simplest form CL consists of a single nodule or papule, typically on exposed body parts, with the parasites residing in the lower epidermis and dermis. A topical treatment would minimise possible adverse effects by reducing the amount of drug taken up in the systemic circulation and would be easy to apply which is important for patient compliance. The overall aim of the work described in this thesis was to explore the use of different drugs in a topical formulation to cure CL. To be efficacious, a topical treatment requires the permeation of the active ingredient through the stratum corneum and into the deeper layers of the skin where the Leishmania parasites resides. Intact skin is a highly effective barrier against xenobiotics. However many skin diseases are known to affect the skin barrier making it more or less permeable to drugs. An understanding of the permeability of the skin hosting the Leishmania parasites is a prerequisite when trying to optimize drug delivery to the skin. Therefore the barrier function of Leishmania infected skin in early stages of CL was characterised with respect to histology, transepidermal water loss and drug permeation. Suitable anti-leishmanial drugs with the potential to permeate into the skin were identified through literature review, taking into account the information obtained from the skin barrier characterisation. The leishmanicidal activity of the drugs was evaluated in an intracellular amastigote-macrophage model and potent compounds were selected for further work. First, the re-formulation of miltefosine, currently used to treat leishmaniasis via oral administration, into a topical formulation was explored. The effects of different solvents on its permeation through and disposition in the skin was evaluated using in vitro Franz diffusion cell permeation studies. Secondly, a drug discovery approach was used to identify lead benzoxaboroles, a set of interesting anti-leishmanial compounds. In the early stages, in vitro ADME studies were conducted to establish basic pharmacokinetic parameters of a range of benzoxaboroles. This information together with previously unpublished data was used to select compounds for further testing such as stability and binding in skin homogenate and permeation evaluation. The three most promising compounds were tested in vivo in a CL model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available