Dermal microdialysis: A method to determine drug levels in the skin of patients with Post kala-azar dermal leishmaniasis (PKDL).

Objectives: Post-kala-azar-dermal leishmaniasis (PKDL) is an infectious skin disease that occurs as sequela of visceral leishmaniasis (VL) and causes cutaneous lesions on the face and other exposed body parts. While the first-line drug miltefosine is typically used for 28 days to treat VL, 12 weeks of therapy is required for PKDL, highlighting the need to evaluate the extent of drug penetration at the dermal site of infection. In this proof-of-concept study, we demonstrate the use of a minimally invasive sampling technique called microdialysis to measure dermal drug exposure in a PKDL patient, providing a tool for the optimization of treatment regimens.

Efficacy of oleylphosphocholine in experimental cutaneous leishmaniasis.

Objectives: Cutaneous leishmaniasis (CL) is a neglected tropical disease causing a range of skin lesions for which safe and efficacious drugs are lacking. Oleylphosphocholine (OLPC) is structurally similar to miltefosine and has previously demonstrated potent activity against visceral leishmaniasis. We here present the in vitro and in vivo efficacy of OLPC against CL-causing Leishmania species.

Challenges of using modelling evidence in the visceral leishmaniasis elimination programme in India.

As India comes closer to the elimination of visceral leishmaniasis (VL) as a public health problem, surveillance efforts and elimination targets must be continuously revised and strengthened. Mathematical modelling is a compelling research discipline for informing policy and programme design in its capacity to project incidence across space and time, the likelihood of achieving benchmarks, and the impact of different interventions. To gauge the extent to which modelling informs policy in India, this qualitative analysis explores how and whether policy makers understand, value, and reference recently produced VL modelling research.

Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria.

Covering: 2000 up to 2021Natural products are an important resource in drug discovery, directly or indirectly delivering numerous small molecules for potential development as human medicines. Among the many classes of natural products, alkaloids have a rich history of therapeutic applications. The extensive chemodiversity of alkaloids found in the marine environment has attracted considerable attention for such uses, while the scarcity of these natural materials has stimulated efforts towards their total synthesis.

Pharmacokinetics and pharmacodynamics in the treatment of cutaneous leishmaniasis - challenges and opportunities.

Pharmacological efficacy is obtained when adequate concentrations of a potent drug reach the target site. In cutaneous leishmaniasis, a heterogeneous disease characterised by a variety of skin manifestations from simple nodules, skin discoloration, plaques to extensive disseminated forms, the parasites are found in the dermal layers of the skin. Treatment thus involves the release of the active compound from the formulation (administered either topically or systemically), it's permeation into the skin, accumulation by the local macrophages and further transport into the phagolysosome of the macrophage.

Film-Forming Systems for the Delivery of DNDI-0690 to Treat Cutaneous Leishmaniasis.

In cutaneous leishmaniasis (CL), parasites reside in the dermis, creating an opportunity for local drug administration potentially reducing adverse effects and improving treatment adherence compared to current therapies. Polymeric film-forming systems (FFSs) are directly applied to the skin and form a thin film as the solvent evaporates. In contrast to conventional topical dosage forms, FFSs strongly adhere to the skin, favouring sustained drug delivery to the affected site, reducing the need for frequent applications, and enhancing patient compliance.

Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug.

Background: Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1.

Pharmacokinetic / pharmacodynamic relationships of liposomal amphotericin B and miltefosine in experimental visceral leishmaniasis.

Background: There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL.

Costs and outcomes of active and passive case detection for visceral leishmaniasis (Kala-Azar) to inform elimination strategies in Bihar, India.

Background: Effective case identification strategies are fundamental to capturing the remaining visceral leishmaniasis (VL) cases in India. To inform government strategies to reach and sustain elimination benchmarks, this study presents costs of active- and passive- case detection (ACD and PCD) strategies used in India's most VL-endemic state, Bihar, with a focus on programme outcomes stratified by district-level incidence.

Methods: Expenditure analysis was complemented by onsite micro-costing to compare the cost of PCD in hospitals alongside index case-based ACD and a combination of blanket (house-to-house) and camp ACD from January to December 2018.

Too many wild boar? Modelling fertility control and culling to reduce wild boar numbers in isolated populations.

Wild boar and feral swine number and range are increasing worldwide in parallel with their impact on biodiversity and human activities. The ecological and economic impact of this species include spread of diseases, vehicle collisions, damage to crops, amenities and infrastructures and reduction in plant and animal abundance and richness. As traditional methods such as culling have not contained the growth and spread of wild boar and feral pigs, alternative methods such as fertility control are now advocated.

Chitosan Contribution to Therapeutic and Vaccinal Approaches for the Control of Leishmaniasis.

The control of leishmaniases, a complex parasitic disease caused by the protozoan parasite , requires continuous innovation at the therapeutic and vaccination levels. Chitosan is a biocompatible polymer administrable via different routes and possessing numerous qualities to be used in the antileishmanial strategies. This review presents recent progress in chitosan research for antileishmanial applications.

Activity of Amphotericin B-Loaded Chitosan Nanoparticles against Experimental Cutaneous Leishmaniasis.

Chitosan nanoparticles have gained attention as drug delivery systems (DDS) in the medical field as they are both biodegradable and biocompatible with reported antimicrobial and anti-leishmanial activities. We investigated the application of chitosan nanoparticles as a DDS for the treatment of cutaneous leishmaniasis (CL) by preparing two types of chitosan nanoparticles: positively charged with tripolyphosphate sodium (TPP) and negatively charged with dextran sulphate. Amphotericin B (AmB) was incorporated into these nanoparticles.

Novel 2D and 3D Assays to Determine the Activity of Anti-Leishmanial Drugs.

The discovery of novel anti-leishmanial compounds remains essential as current treatments have known limitations and there are insufficient novel compounds in development. We have investigated three complex and physiologically relevant in vitro assays, including: (i) a media perfusion based cell culture model, (ii) two 3D cell culture models, and (iii) iPSC derived macrophages in place of primary macrophages or cell lines, to determine whether they offer improved approaches to anti-leishmanial drug discovery and development. Using a Leishmania major amastigote-macrophage assay the activities of standard drugs were investigated to show the effect of changing parameters in these assays.

Modelling Spatial and Temporal Patterns of African Swine Fever in an Isolated Wild Boar Population to Support Decision-Making.

African swine fever (ASF) is a highly contagious disease affecting all suids including wild boar. As the disease can damage commercial pig production and its circulation can threaten international trade, understanding the risks produced by free-living wild boar (as a wildlife reservoir) is important to ensure proportionate policies to exclude the disease, as well as an effective contingency response. The recent spread of the virus into Western Europe has produced concerns in many stakeholders including pig producers and national governments.

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis.

Liposomal amphotericin B (AmBisome®) as a treatment modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic.  As the mode of action of AmBisome® is poorly understood, we compared the tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL.    BALB/c mice infected with ere treated with 8mg/kg AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period.

Activity of Chitosan and Its Derivatives against Leishmania major and Leishmania mexicana .

There is an urgent need for safe, efficacious, affordable, and field-adapted drugs for the treatment of cutaneous leishmaniasis, which newly affects around 1.5 million people worldwide annually. Chitosan, a biodegradable cationic polysaccharide, has previously been reported to have antimicrobial, antileishmanial, and immunostimulatory activities.

Using species distribution models to predict potential hot-spots for Rift Valley Fever establishment in the United Kingdom.

Vector borne diseases are a continuing global threat to both human and animal health. The ability of vectors such as mosquitos to cover large distances and cross country borders undetected provide an ever-present threat of pathogen spread. Many diseases can infect multiple vector species, such that even if the climate is not hospitable for an invasive species, indigenous species may be susceptible and capable of transmission such that one incursion event could lead to disease establishment in these species.

An efficient and novel technology for the extraction of parasite genomic DNA from whole blood or culture.

The aim of this study was to assess pathogen DNA extraction with a new spin column-based method (DNA-XT). DNA from either whole-blood samples spiked with or  amastigote culture was extracted with DNA-XT and compared with that produced by a commercial extraction kit (DNeasy). Eluates from large and small sample volumes were assessed by PCR and spectroscopy.

Linking global drivers of agricultural trade to on-the-ground impacts on biodiversity.

Consumption of globally traded agricultural commodities like soy and palm oil is one of the primary causes of deforestation and biodiversity loss in some of the world's most species-rich ecosystems. However, the complexity of global supply chains has confounded efforts to reduce impacts. Companies and governments with sustainability commitments struggle to understand their own sourcing patterns, while the activities of more unscrupulous actors are conveniently masked by the opacity of global trade.

Modeling current and potential distributions of mammal species using presence-only data: A case study on British deer.

Aim: Decisions on wildlife conservation, management, and epidemiological risk are best based on robust evidence. The continual improvement of species distributions, such that they can be relied upon in decision-making, is important. Here we seek to refine aspects of a generic modelling approach and improve the utility of species distribution maps.

Development of an in vitro media perfusion model of Leishmania major macrophage infection.

Background: In vitro assays are widely used in studies on pathogen infectivity, immune responses, drug and vaccine discovery. However, most in vitro assays display significant differences to the in vivo situation and limited predictive properties. We applied medium perfusion methods to mimic interstitial fluid flow to establish a novel infection model of Leishmania parasites.

Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis.

The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent and activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative pathogen. This study evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of DNDI-0690 in mouse models of CL.