36 research outputs found
Modifying amphotericin B for the treatment of cutaneous leishmaniasis
Cutaneous leishmaniasis (CL) is a neglected tropical disease. It presents as
disfiguring and deforming skin lesions. There is an urgent need for a simple, low-cost
and non-toxic treatment for use in resource poor countries. As amphotericin B (AmB)
has transformed visceral leishmaniasis treatment, I have developed and optimised a
poly (methacrylic acid)-AmB drug (AmB-PMA). This involved the use of a
commercially available, non-toxic, well-defined narrow molecular weight distribution
polymer, poly (methacrylic acid sodium salt) (PMA) associated with AmB to create
AmB-PMA. After chemical synthesis optimisation, AmB-PMA was shown to be less
toxic than clinical grade AmB, and it was effective against Leishmania spp.
promastigotes and amastigotes in vitro. To determine in vivo efficacy, studies were
performed using BALB/c mice. They develop progressive non-healing skin lesions
and are unable to control parasite growth. Mice were infected subcutaneously with L.
major (LV39) promastigotes and treated locally with AmB-PMA. Studies were then
conducted to evaluate the optimum route of administration, treatment frequency and
dosing schedules. The results showed a reduction in both parasite burden and lesion
size of the infected treated footpad with no adverse toxicity. Cytokine production was
determined by quantitative real-time PCR for mRNA at the lesion site and the
draining lymph node. I found that the AmB-PMA could effectively heal an established
lesion and cure a CL infection. This was associated with: - (i) increased IFN-Y and
TNF-α production, (ii) reduced IL-10 and MIP-1β production, when compared to
infected, untreated lesions. The success of this treatment approach was also
evaluated by histological studies. In addition, treated mice with resolved primary
cutaneous lesions mounted a delayed type hypersensitivity response 24 h after
challenge of the contra-lateral footpad with L. major. My thesis demonstrates the new
opportunity for a cost-effective AmB based polymer drug that can be used locally to
cure CL
Local Increase of Arginase Activity in Lesions of Patients with Cutaneous Leishmaniasis in Ethiopia
The leishmaniases are a complex of diseases caused by Leishmania parasites. Currently, the diseases affect an estimated 12 million people in 88 countries, and approximately 350 million more people are at risk. The leishmaniases belong to the most neglected tropical diseases, affecting the poorest populations, for whom access to diagnosis and effective treatment are often not available. Leishmania parasites infect cells of the immune system called macrophages, which have the capacity to eliminate the intracellular parasites when they receive the appropriate signals from other cells of the immune system. In nonhealing persistent leishmaniasis, lymphocytes are unable to transmit the signals to macrophages required to kill the intracellular parasites. The local upregulation of the enzyme arginase has been shown to impair lymphocyte effector functions at the site of pathology. In this study, we tested the activity of this enzyme in skin lesions of patients presenting with localized cutaneous leishmaniasis. Our results show that arginase is highly upregulated in these lesions. This increase in arginase activity coincides with lower expression of a signalling molecule in lymphocytes, which is essential for efficient activation of these cells. These results suggest that increased arginase expression in the localized cutaneous lesions might contribute to persistent disease in patients presenting with cutaneous leishmaniasis
Modifying amphotericin B for the treatment of cutaneous leishmaniasis
Cutaneous leishmaniasis (CL) is a neglected tropical disease. It presents as disfiguring and deforming skin lesions. There is an urgent need for a simple, low-cost and non-toxic treatment for use in resource poor countries. As amphotericin B (AmB) has transformed visceral leishmaniasis treatment, I have developed and optimised a poly (methacrylic acid)-AmB drug (AmB-PMA). This involved the use of a commercially available, non-toxic, well-defined narrow molecular weight distribution polymer, poly (methacrylic acid sodium salt) (PMA) associated with AmB to create AmB-PMA. After chemical synthesis optimisation, AmB-PMA was shown to be less toxic than clinical grade AmB, and it was effective against Leishmania spp. promastigotes and amastigotes in vitro. To determine in vivo efficacy, studies were performed using BALB/c mice. They develop progressive non-healing skin lesions and are unable to control parasite growth. Mice were infected subcutaneously with L. major (LV39) promastigotes and treated locally with AmB-PMA. Studies were then conducted to evaluate the optimum route of administration, treatment frequency and dosing schedules. The results showed a reduction in both parasite burden and lesion size of the infected treated footpad with no adverse toxicity. Cytokine production was determined by quantitative real-time PCR for mRNA at the lesion site and the draining lymph node. I found that the AmB-PMA could effectively heal an established lesion and cure a CL infection. This was associated with: - (i) increased IFN-Y and TNF-α production, (ii) reduced IL-10 and MIP-1β production, when compared to infected, untreated lesions. The success of this treatment approach was also evaluated by histological studies. In addition, treated mice with resolved primary cutaneous lesions mounted a delayed type hypersensitivity response 24 h after challenge of the contra-lateral footpad with L. major. My thesis demonstrates the new opportunity for a cost-effective AmB based polymer drug that can be used locally to cure CL.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Leishmania infantum proteophosphoglycans regurgitated by the bite of its natural sand fly vector, Lutzomyia longipalpis, promote parasite establishment in mouse skin and skin-distant tissues
We demonstrate that a proteophosphoglycan-rich gel secreted by Leishmania infantum inside the midgut of Lutzomyia longipalpis sand flies (promastigote secretory gel) is regurgitated along with an average dose of 500 L. infantum metacyclic promastigotes per infected bite. Using both low (10³) and high (10⁵) doses of parasites in the ears of BALB/c mice we show that the infections benefit from the presence of vector saliva and parasite gel in the skin. However, chronic infection of the spleen was only enhanced in high dose co-infections with gel. These results provide the framework for a more natural experimental model of visceral leishmaniasis
Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid.
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
Herstellung und Untersuchungen der Struktur und Eigenschaften von nanokristallinen Materialien Schlussbericht
SIGLEAvailable from TIB Hannover: F97B23+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman
Cinnamic acids derived compounds with antileishmanial activity target Leishmania amazonensis
Arginase activity - a marker of disease status in patients with visceral leishmaniasis in ethiopia.
The underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood. Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells