International Journal for Parasitology-Drugs and Drug Resistance 

About: International Journal for Parasitology-Drugs and Drug Resistance is an academic journal published by Elsevier BV. The journal publishes majorly in the area(s): Plasmodium falciparum & Medicine. It has an ISSN identifier of 2211-3207. It is also open access. Over the lifetime, 476 publications have been published receiving 11709 citations.

Drug repurposing and human parasitic protozoan diseases

Abstract: Parasitic diseases have an enormous health, social and economic impact and are a particular problem in tropical regions of the world. Diseases caused by protozoa and helminths, such as malaria and schistosomiasis, are the cause of most parasite related morbidity and mortality, with an estimated 1.1 million combined deaths annually. The global burden of these diseases is exacerbated by the lack of licensed vaccines, making safe and effective drugs vital to their prevention and treatment. Unfortunately, where drugs are available, their usefulness is being increasingly threatened by parasite drug resistance. The need for new drugs drives antiparasitic drug discovery research globally and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. In this review we discuss one of these approaches, drug repurposing or repositioning, with a focus on major human parasitic protozoan diseases such as malaria, trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis.

Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it?

Abstract: Leishmaniasis is one of the most neglected tropical disease in terms of drug discovery and development. Most antileishmanial drugs are highly toxic, present resistance issues or require hospitalization, being therefore not adequate to the field. Recently improvements have been achieved by combination therapy, reducing the time and cost of treatment. Nonetheless, new drugs are still urgently needed. In this review, we describe the current visceral leishmaniasis (VL) treatments and their limitations. We also discuss the new strategies in the drug discovery field including the development and implementation of high-throughput screening (HTS) assays and the joint efforts of international teams to deliver clinical candidates.

Moxidectin and the avermectins: Consanguinity but not identity.

Abstract: The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination.

Is anthelmintic resistance a concern for the control of human soil-transmitted helminths?

Abstract: The major human soil-transmitted helminths (STH), Ascaris lumbricoides, hookworms (Necator americanus and Ancylostoma duodenale) and Trichuris trichiura have a marked impact on human health in many parts of the world. Current efforts to control these parasites rely predominantly on periodic mass administration of anthelmintic drugs to school age children and other at-risk groups. After many years of use of these same drugs for controlling roundworms in livestock, high levels of resistance have developed, threatening the sustainability of these livestock industries in some locations. Hence, the question arises as to whether this is likely to also occur in the human STH, thereby threatening our ability to control these parasites. This is particularly important because of the recent increase in mass control programmes, relying almost exclusively on benzimidazole anthelmintics. It will be important to ensure that resistance is detected as it emerges in order to allow the implementation of mitigation strategies, such as use of drug combinations, to ensure that the effectiveness of the few existing anthelmintic drugs is preserved. In this review we address these issues by firstly examining the efficacy of anthelmintics against the human STH, and assessing whether there are any indications to date that resistance has emerged. We then consider the factors that influence the effect of current drug-use patterns in selecting for resistant parasite populations. We describe the tools currently available for resistance monitoring (field-based coprological methods), and those under development (in vitro bioassays and molecular tests), and highlight confounding factors that need to be taken into account when interpreting such resistance-monitoring data. We then highlight means to ensure that the currently available tools are used correctly, particularly with regard to study design, and we set appropriate drug-efficacy thresholds. Finally, we make recommendations for monitoring drug efficacy in the field, as components of control programmes, in order to maximise the ability to detect drug resistance, and if it arises to change control strategy and prevent the spread of resistance.

P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance

Abstract: Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread.