Chagas disease, a chronic systemic parasitosis caused by the Kinetoplastid protozoon Trypanosoma cruzi, is the first cause of cardiac morbidity and mortality in poor rural and suburban areas of Latin ...America and the largest parasitic disease burden in the continent, now spreading worldwide due to international migrations. A recent change in the scientific paradigm on the pathogenesis of chronic Chagas disease has led to a consensus that all T. cruzi‐seropositive patients should receive etiological treatment. This important scientific advance has spurred the rigorous evaluation of the safety and efficacy of currently available drugs (benznidazole and nifurtimox) as well as novel anti‐T. cruzi drug candidates in chronic patients, who were previously excluded from such treatment. The first results indicate that benznidazole is effective in inducing a marked and sustained reduction in the circulating parasites’ level in the majority of these patients, but adverse effects can lead to treatment discontinuation in 10–20% of cases. Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, are better tolerated but their efficacy at the doses and treatment duration used in the initial studies was significantly lower; such results are probably related to suboptimal exposure and/or treatment duration. Combination therapies are a promising perspective but the lack of validated biomarkers of response to etiological treatment and eventual parasitological cures in chronic patients remains a serious challenge.
Over recent years, importance has been attributed to the application of criminal sanctions in the fight against IUU fishing due to the seriousness of the threat it represents for the conservation of ...marine living resources. This trend towards the criminalisation of certain activities related with IUU fishing has given rise to the appearance of the notion of fisheries crime, which is increasingly employed in certain international forums. However, from a legal point of view, this term does not define a new type of crime applicable to fisheries activity. Rather, it seeks to demonstrate that certain fishing-related offences are criminal in nature. Thus, it is important to define the scope of this notion of fisheries crime in order to determine what criminal offences are included within this category. Depending on its degree of connection with fisheries activity, fisheries crime covers three separate categories of crimes: the crime of illegal fishing, illicit fisheries-related crimes and crimes committed in the context of the fisheries sector.
•Illegal fisheries activities have been criminalised in the legislation of some States.•Notion of fisheries crime is not a new crime applicable to the fisheries context.•Fisheries crime encompasses all crimes committed along the fisheries value chain.•The notion of fisheries crime is still unclear and require more accurate definition.•Although both notions are related, fishing crime cannot be equated to IUU fishing.
The recent development of a delayed-release tablet formulation of the drug, with a 4-fold higher oral bioavailability than the liquid suspension formula, and no toxic side effects up to at least 400 ...mg/day (4), provides a way to assess the true efficacy of posaconazole for the anti−T. cruzi indication.
This article presents an overview of the currently available drugs
nifurtimox (NFX) and benznidazole (BZN) used against Trypanosoma cruzi
, the aetiological agent of Chagas disease; herein we discuss ...their
limitations along with potential alternatives with a focus on
ergosterol biosynthesis inhibitors (EBI). These compounds are currently
the most advanced candidates for new anti-T. cruzi agents given that
they block de novo production of 24-alkyl-sterols, which are essential
for parasite survival and cannot be replaced by a host's own
cholesterol. Among these compounds, new triazole derivatives that
inhibit the parasite's C14α sterol demethylase are the most
promising, as they have been shown to have curative activity in murine
models of acute and chronic Chagas disease and are active against NFX
and BZN-resistant T. cruzi strains; among this class of compounds,
posaconazole (Schering-Plough Research Institute) and ravuconazole
(Eisai Company) are poised for clinical trials in Chagas disease
patients in the short term. Other T. cruzi-specific EBI, with in vitro
and in vivo potency, include squalene synthase, lanosterol synthase and
squalene epoxidase-inhibitors as well as compounds with dual mechanisms
of action (ergosterol biosynthesis inhibition and free radical
generation), but they are less advanced in their development process.
The main putative advantages of EBI over currently available therapies
include their higher potency and selectivity in both acute and chronic
infections, activity against NFX and BZN-resistant T. cruzi strains,
and much better tolerability and safety profiles. Limitations may
include complexity and cost of manufacture of the new compounds. As for
any new drug, such compounds will require extensive clinical testing
before being introduced for clinical use, and the complexity of such
studies, particularly in chronic patients, will be compounded by the
current limitations in the verification of true parasitological cures
for T. cruzi infections.
Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and ...mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents.
Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America, where it constitutes one of the largest parasitic disease burdens. Specific treatment of this condition ...has been controversial, but there is a growing consensus that elimination of T. cruzi could be a prerequisite to arrest the evolution of the disease. Currently available chemotherapy, based on a nitrofuran (nifurtimox) and a nitroimidazole (benznidazole), is unsatisfactory because of their limited efficacy in the prevalent chronic stage of the disease and their toxic side effects. New approaches to specific chemotherapy are being advanced. Biochemical routes such as the de novo sterol biosynthesis pathway, cruzipain-mediated proteolysis and pyrophosphate metabolism have been chemically validated, and the selective in vitro and in vivo anti-T. cruzi activities of inhibitors of these pathways have been demonstrated. Several of these compounds have now completed pre-clinical studies and are poised for clinical trials in the near future. Other promising approaches include interference with trypanothione synthesis and redox metabolism, in addition to inhibition of purine salvage, dihydrofolate reductase, phospholipid biosynthesis, and protein prenylation and acylation.
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