Understanding the host response of farmed fish to blood flukes (Trematoda: Aporocotylidae) for developing new treatment strategies.

Aporocotylids (Trematoda: Digenea), also known as fish blood flukes infect the circulatory system of fish leading to serious health problems and mortality. Aporocotylids are a particular concern for farmed fish as infection intensity can increase within the farming environment and lead to mortalities. In the context of managing these infections, one of the most crucial aspects to consider is the host response of the infected fish against these blood flukes. Understanding the response is essential to improving current treatment strategies that are largely based on the use of anthelmintic praziquantel to manage infections in aquaculture. This review focuses on the current knowledge of farmed fish host responses against the different life stages of aporocotylids. New treatment strategies that are able to provide protection against reinfections should be a long-term goal and is not possible without understanding the fish response to infection and the interactions between host and parasite.

Targeted drug delivery using beeswax-derived albendazole-loaded solid lipid nanoparticles in Haemonchus contortus, an albendazole-tolerant nematode.

Targeted delivery has not been achieved for anthelmintic treatment, resulting in the requirement of excess drug dose leading to side effects and therapeutic resistance. Gastrointestinal helminths take up lipid droplets from digestive fluid for energy production, egg development, and defense which inspired us to develop biocompatible and orally administrable albendazole-loaded solid lipid nanoparticles (SLN-A) that were derived from beeswax and showed drug loading efficiency of 83.3 ± 6.5 mg/g and sustained-release properties with 84.8 ± 2.5% of drug released at pH 6.4 within 24 h at 37 °C. Rhodamine B-loaded SLN showed time-dependent release and distribution of dye in-vitro in Haemonchus contortus. The sustained-release property was shown by the particles that caused enhancement of albendazole potency up to 50 folds. Therefore, this formulation has immense potential as an anthelminthic drug delivery vehicle that will be able to reduce the dose and drug-induced side effects by enhancing the bioavailability of the drug.

Cysticidal effect of a pure naphthoquinone on Taenia crassiceps cysticerci.

Cysticercosis is a disease caused by the metacestode of the parasite Taenia solium (T. solium). In humans, the most severe complication of the disease is neurocysticercosis. The drug of choice to treat this disease is albendazole; however, the bioavailability and efficacy of the drug are variable. Therefore, new molecules with therapeutic effects against this and other parasitic infections caused by helminths must be developed. Naphthoquinones are naphthalene-derived compounds that possess antibacterial, antifungal, antitumoral, and antiparasitic properties. The aim of this work was to evaluate the in vitro anti-helminthic effect of 2-[(3-chlorophenylamino)phenylmethyl]-3-hydroxy-1,4-naphthoquinone, isolated from a natural source and then synthesized (naphthoquinone 4a), using an experimental model of murine cysticercosis caused by Taenia crassiceps (T. crassiceps). This compound causes paralysis in the cysticerci membrane from day 3 of the in vitro treatment. Additionally, it induces changes in the shape, size, and appearance of the cysticerci and a decrease in the reproduction rate. In conclusion, naphthoquinone 4a has in vitro cysticidal activity on T. crassiceps cysticerci depending on the duration of the treatment and the concentration of the compound. Therefore, it is a promising drug candidate to be used in T. crassiceps and possibly T. solium infections.

Methods for extraction, isolation and sequencing of cyclotides and others cyclic peptides with anti-helminthic activities: An overview.

The mortality rate caused by parasitic worms on their hosts is of great concern and studies have been carried out to find molecules to reduce the prevalence, host-parasite interaction, and resistance of parasites to treatments. Existing drugs on the market are very often toxic and have many side effects, hence the need to find new, more active molecules. It has been demonstrated in several works that medicinal plants constitute a wide range of new molecules that can solve this problem. Several works have already been able to demonstrate that cyclic peptides of plant origin have shown good activity in the fight against different types of helminths. Therefore, this review aims to provide a general overview of the methods and techniques of extraction, isolation, activities and mechanisms of action of cyclotides and other cyclic peptides for application in the treatment of helminthic infections.

Prenylated Isoflavanones with Antimicrobial Potential from the Root Bark of Dalbergia melanoxylon.

Dalbergia melanoxylon Guill. & Perr (Fabaceae) is widely utilized in the traditional medicine of East Africa, showing effects against a variety of ailments including microbial infections. Phytochemical investigation of the root bark led to the isolation of six previously undescribed prenylated isoflavanones together with eight known secondary metabolites comprising isoflavanoids, neoflavones and an alkyl hydroxylcinnamate. Structures were elucidated based on HR-ESI-MS, 1- and 2-D NMR and ECD spectra. The crude extract and the isolated compounds of D. melanoxylon were tested for their antibacterial, antifungal, anthelmintic and cytotoxic properties, applying established model organisms non-pathogenic to humans. The crude extract exhibited significant antibacterial activity against Gram-positive Bacillus subtilis (97% inhibition at 50 µg/mL) and antifungal activity against the phytopathogens Phytophthora infestans, Botrytis cinerea and Septoria tritici (96, 89 and 73% at 125 µg/mL, respectively). Among the pure compounds tested, kenusanone H and (3R)-tomentosanol B exhibited, in a panel of partially human pathogenic bacteria and fungi, promising antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium showing MIC values between 0.8 and 6.2 µg/mL. The observed biological effects support the traditional use of D. melanoxylon and warrant detailed investigations of its prenylated isoflavanones as antibacterial lead compounds.

Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway.

The incidence of melanoma is increasing rapidly worldwide. Additionally, new and effective candidates for treating melanoma are needed because of the increase in drug resistance and the high metastatic potential of this cancer. The STAT3 signaling pathway plays a pivotal role in pathogenesis of melanoma, making STAT3 a promising anticancer target for melanoma therapy. Niclosamide, an FDA-approved anti-helminthic drug, has been identified as a potent STAT3 inhibitor that suppresses STAT3 phosphorylation at Tyr705 and its transcript activity. In this study, we evaluated the biological activities of niclosamide in melanoma in vitro and in vivo. Niclosamide potently inhibited the growth of four melanoma cell lines and induced the apoptosis of melanoma cells via the mitochondrial apoptotic pathway. Further, western blot analysis indicated that cell apoptosis was correlated with activation of Bax and cleaved caspase-3 and decreased expression of Bcl-2. Moreover, niclosamide markedly impaired melanoma cell migration and invasion, reduced phosphorylated STAT3Tyr705 levels, and inhibited matrix metalloproteinase-2 and -9 expression. Additionally, in a xenograft model of A375, intraperitoneal administration of niclosamide inhibited tumor growth and tumor weight in a dose-dependent manner without obvious side effects. Histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells and p-STAT3Try705-positive cells and increase in cleaved caspase-3-positive cells. Notably, niclosamide significantly inhibited pulmonary metastasis in a B16-F10 melanoma lung metastasis model, including the number of lung metastatic nodules and lung/body coefficient. Importantly, a marked reduction in myeloid-derived suppressor cells (Gr1+CD11b+) infiltration in the pulmonary metastasis tissue was observed. Taken together, these results demonstrate that niclosamide is a promising candidate for treating melanoma.

Brassica Nigra: Ethopharmacological Review of a Routinely Used Condiment.

BACKGROUND: Brassica nigra belonging to the family Brassicaceae (syn - black mustard) comprises of dried seeds and is widely cultivated in Mediterranean region and various other countries like India and Europe. The Plant is neither reported in any official book nor reported systematically for pharmacological effects. METHODS: We undertook a structured search of all the official books including pharmacopoeias and ayurvedic textbooks. The data was collected, sorted and compiled to bring the chemical constituents and uses of B. nigra. RESULTS: B. nigra contains glycosinolates which undergoes hydrolysis in the presence of myrosinase enzyme yields allyl isothiocyante. The bitter taste and pungent odor is due to the isothiocyanates. B. Nigra shows various activities that are medically important such as anticancer, anti-bacterial, antifungal, anti-helminthic, protection against renal and hepatic toxicity and can also be used in diabetes treatment. Black mustards are also used in cardiovascular and neurological disorders. CONCLUSION: The present review explores the historical background including the macroscopic and microscopic characteristics, chemical constituents, pharmacological action, various evaluation parameters, formulations and uses of black mustard.

Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer.

Albendazole is an anti-helminthic drug that has been shown to exhibit anti-cancer properties, however its activity in head and neck squamous cell cancer (HNSCC) was unknown. Using a series of in vitro assays, we assessed the ability of albendazole to inhibit proliferation in 20 HNSCC cell lines across a range of albendazole doses (1 nM-10 µM). Cell lines that responded to treatment were further examined for cell death, inhibition of migration and cell cycle arrest. Thirteen of fourteen human papillomavirus-negative HNSCC cell lines responded to albendazole, with an average IC50 of 152 nM. In contrast, only 3 of 6 human papillomavirus-positive HNSCC cell lines responded. Albendazole treatment resulted in apoptosis, inhibition of cell migration, cell cycle arrest in the G2/M phase and altered tubulin distribution. Normal control cells were not measurably affected by any dose tested. This study indicates that albendazole acts to inhibit the proliferation of human papillomavirus-negative HNSCC cell lines and thus warrants further study as a potential chemotherapeutic agent for patients suffering from head and neck cancer.

Anti-helminthic drugs in recurrent apthous stomatitis: A short review.

Recurrent aphthous stomatitis (RAS) is a common mucosal condition producing painful ulcerations in the oral cavity and considerable clinical morbidity. The etiology remains obscure, though local trauma, psychologic stress, hematinic deficiencies and immune dysregulation have been implicated. Though the primary goals of therapy are symptomatic relief of pain, the clinicians are aiming toward reducing the frequency, duration, number of ulcerations and increasing ulcer free periods with systemic drug therapy if topical medications appear ineffective. Levamisole, an antihelminthic drug has been tried with promising results in patients with severe RAS providing long-term benefits.

Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent.

Mebendazole, a well-known anti-helminthic drug in wide clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types. Significantly, there are also two case reports of anti-cancer activity in humans. The data are summarised and discussed in relation to suggested mechanisms of action. Based on the evidence presented, it is proposed that mebendazole would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of mebendazole as an anti-cancer therapeutic is warranted. A number of possible combinations with other drugs are discussed in the Appendix.

Sistemas produtivos de caprinocultura leiteira no semiárido nordestino: controle integrado das parasitoses gastrointestinais visando contornar a resistência anti-helmíntica / Dairy goat production in the Brazilian semiarid region: integrated gastrointestinal nematodes control to overcome anti-helminthic resistance

Goats are very important for the economy of the semiarid region of northeastern Brazil; however, the high frequency of parasitism by gastrintestinal nematodes (GIN) and the increase of anthelmintic resistance are threatening goat industry in the region. In this paper we review the control strategies for GIN in goats including: 1) the differences between goats and sheep to GIN infections; 2) important epidemiological aspects to consider in the control; and 3) technologies to be used for integrated control of GIN and anti-helmintic resistance.

A caprinocultura é muito importante para a economia do semiárido nordestino; no entanto a alta frequência das parasitoses gastrintestinais e o aumento da resistência parasitária ameaçam gravemente essa atividade. Nesta revisão são discutidos vários aspectos importantes para o controle das parasitoses gastrintestinais de caprinos, incluindo: 1) as diferenças entre caprinos e ovinos; 2) aspectos epidemiológicos importantes a serem levados em consideração para o controle; e 3) tecnologias a serem utilizadas para realizar o controle das parasitoses gastrintestinais em forma integrada e diminuir a frequência de resistência anti-helmíntica.

Controle das parasitoses gastrintestinais em ovinos e caprinos na região semiárida do nordeste do Brasil / Gastro-intestinal nematodes control in goats and sheep in the semiarid region northeastern Brazil

Neste artigo são revisados alguns conceitos importantes a serem considerados para o controle de parasitas gastrintestinais em caprinos e ovinos. Descrevem-se as características epidemiológicas desta parasitose no semiárido e o aparecimento de resistência aos anti-helmínticos na região.São propostas alternativas para o controle da doença levando em consideração, principalmente, a adoção de técnicas de controle integrado de parasitas com uma mudança nos sistemas de tratamento preventivo para sistemas que permitam a sobrevivência de parasitas susceptíveis na refugia. São discutidas as diferenças entre caprinos e ovinos, considerando que os caprinos são mais susceptíveis e que para maioria das drogas devem ser tratados com doses maiores.

This paper reviews some important concepts to be considered for the control of gastrointestinal nematode parasites of sheep and goats, including the epidemiology of this parasitic disease in the Brazilian semiarid, and the occurrence of anti-helminthic resistance in the region. Considering the widespread use of preventive treatments during the dry season, new alternatives for the control of gastrointestinal parasites are recommended, taking into account the parasite integrated control system and the use of methods to allow the presence of susceptible parasites in the refugia. Differences between sheep and goats are discussed, taking into account the higher susceptibility of goats and the necessity to use larger doses in goats than in sheep for most anti-helminthics.

Estrongiloidíase disseminada: diagnóstico e tratamento: [revisão] / Disseminated strongyloidiasis: diagnosis and treatment: [review]

JUSTIFICATIVA E OBJETIVOS: A estrongiloidíase disseminada é uma entidade clínica relacionada a estados de imunossupressão como os que ocorrem na síndrome da imunodeficiência aguda (SIDA), nas neoplasias hematológicas e nos tratamentos imunossupressores. Sua ocorrência e gravidade são mais freqüentes em pacientes usando elevadas doses de corticosteróides. A estrongiloidíase disseminada se apresenta habitualmente sob a forma de sepse grave. Essa apresentação clínica inespecífica representa grandes desafios relacionados ao diagnóstico e tratamento, resultando em elevada taxa de mortalidade. O diagnóstico depende de elevada suspeição clínica e da identificação da larva em amostras de fluidos ou tecidos. O envolvimento cutâneo é raro, entretanto por ser característico pode incrementar a possibilidade da hipótese diagnóstica. O objetivo deste estudo foi rever na literatura os aspectos clínicos da estrongiloidíase disseminada, destacando os métodos de diagnóstico e tratamento e ressaltar a importância da suspeição clínica para a profilaxia e tratamento adequados. CONTEÚDO: Foi realizada uma busca sistemática nos últimos 30 anos através da PubMed utilizando os termos disseminated strongyloidiasis, strongyloides and hyperinfection e ivermectin. CONCLUSÕES: Recentes avanços ocorreram na área terapêutica e dentre eles destaca-se o uso da ivermectina. O seu surgimento mudou significativamente o tratamento para estrongiloidíase, no entanto a administração por via oral ou enteral desse fármaco representou importante limitação para sua utilização em pacientes com íleo ou estado de hipoperfusão tecidual. Relatos de resultados positivos com o uso de ivermectina parenteral levantaram a possibilidade de essa modalidade terapêutica ser mais eficaz nas formas graves. No entanto questões relativas à posologia e segurança ainda precisam ser elucidadas.

BACKGROUND AND OBJECTIVES: Disseminated strongyloidiasis is a clinical form of presentation associated with states of severe immunosuppression, as in AIDS, hematological malignancies and in treatment for immunosuppression (especially with high doses of corticosteroids). It usually mimics severe sepsis and still brings a significant challenge related to the diagnosis and treatment. Therefore exceedingly high mortality rates remain unchanged in the past decades. Initially, the diagnosis depends on the clinical suspicion and on the identification of the larva in an organic fluids or tissues. The cutaneous involvement, albeit rare, is typical and can provide an important clue for the diagnostic hypothesis. The emergence of ivermectin for oral use changed significantly the treatment for strongyloidiasis; however, there are still shortcomings for the utilization in critically ill patients. Shock, ileus and hypoperfusion states are associated with difficulties in the absorption that result in erratic systemic levels. Reports of good results with parenteral administration of ivermectin raised the prospect that this therapeutic modality be more effective. However, questions about dosage and safety remain unanswered. The aim of the present article is to review the medical literature on the clinical aspects of disseminated strongyloidiasis. CONTENTS: A systematic review of the literature was performed by searching the PubMed database within the last 30 years. Search terms were: disseminated strongyloidiasis, strongyloides and hyperinfection e ivermectin. CONCLUSIONS: The article highlights the diagnostic and therapeutic aspects emphasizing the importance of the clinical suspicion for the institution of appropriated therapy.

Eficácia do fembendazole no controle de nematódeos de pacu Piaractus mesopotamicus (Holmberg, 1987) / The efficiency of fembendazole in the control of nematodes in pacu Piaractus mesopotamicus (Holmberg, 1987)

O presente trabalho foi realizado no Centro de Pesquisa e Treinamento em Aquicultura (CEPTA/1BAMA), município de Pirassununga, SP. Foram utilizados 60 pacus, dos viveiros da Estação de Piscicultura do CEPTA, com peso médio de 600g. Foi realizado um teste visando avaliar o efeito do Femben-dazote (adicionado no alimento em diferentes dosagens), sobre os nematódeos presentes no tubo intestinal do pacu, utilizando três tratamentos: Tl - grupo testemunha (ração sem Fembendazole), T2 - 20mg de Fembendazole/kg de ração e T3 - 40mg de Fembendazo-le/kg de ração. O delineamento foi inteiramente casualizado. A unidade experimental foi o peixe. Não houve diferença significativa (P 0,05) entre os tratamentos com anti-helmintico Fembendazole nas dosagens de 20mg/kg e 40/ng/kg de ração e o grupo testemunha.

This study was done at lhe Agricultural Centre for Training and Research (CEPTA/IBAMA) m the municipality of Pirassununga, São Paulo. Sixty pacus, wilh an average weight of 600g were obtained from the nurseries of the fish statíon at CEPTA. An experiment to determine the ejfect of fenbendazole (added to the ration in varíous doses) on nematodes in the alimentary canal ofthe pacu was realized using three treatments. Tl - contrai group (ration without fenbendazole, T2 - 20mg fenbendazole/kg ration, and T3 - 40mgfenbendazole/kg ration. The experimental ouüine was totally random. The fish was the experimental unit. There was no significam dijference (P 0.05) befween the treatments wilh the anti-helminthic fenbendazole added to the ration in doses of 20 and 40 mg/kg and the contrai group.