Dataset Information

H1-antihistamines as antischistosomal drugs: in vitro and in vivo studies.

ABSTRACT:

Background

Schistosomiasis is a socioeconomically devastating parasitic infection afflicting hundreds of millions of people and animals worldwide. It is the most important helminth infection, and its treatment relies solely on the drug praziquantel. Oral H1-antihistamines are available worldwide, and these agents are among the most widely used of all medications in children and adults. Given the importance of the drug repositioning strategy, we evaluated the antischistosomal properties of the H1-antihistamine drugs commonly used in clinical practices.

Methods

Twenty-one antihistamine drugs were initially screened against adult schistosomes ex vivo. Subsequently, we investigated the anthelmintic properties of these antihistamines in a murine model of schistosomiasis for both early and chronic S. mansoni infections at oral dosages of 400 mg/kg single dose or 100 mg/kg daily for five consecutive days. We also demonstrated and described the ability of three antihistamines to induce tegumental damage in schistosomes through the use of scanning electron microscopy.

Results

From phenotypic screening, we found that desloratadine, rupatadine, promethazine, and cinnarizine kill adult S. mansoni in vitro at low concentrations (5-15 µM). These results were further supported by scanning electron microscopy analysis. In an animal model, rupatadine and cinnarizine revealed moderate worm burden reductions in mice harboring either early or chronic S. mansoni infection. Egg production, a key mechanism for both transmission and pathogenesis, was also markedly inhibited by rupatadine and cinnarizine, and a significant reduction in hepatomegaly and splenomegaly was recorded. Although less effective, desloratadine also revealed significant activity against the adult and juvenile parasites.

Conclusions

Although the worm burden reductions achieved are all only moderate, comparatively, treatment with any of the three antihistamines is more effective in early infection than praziquantel. On the other hand, the clinical use of H1-antihistamines for the treatment of schistosomiasis is highly unlikely.

SUBMITTER: Xavier RP

PROVIDER: S-EPMC7268501 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

H1-antihistamines as antischistosomal drugs: in vitro and in vivo studies.

Xavier Rogério P RP Mengarda Ana C AC Silva Marcos P MP Roquini Daniel B DB Salvadori Maria C MC Teixeira Fernanda S FS Pinto Pedro L PL Morais Thiago R TR Ferreira Leonardo L G LLG Andricopulo Adriano D AD de Moraes Josué J

Parasites & vectors 20200601 1

<h4>Background</h4>Schistosomiasis is a socioeconomically devastating parasitic infection afflicting hundreds of millions of people and animals worldwide. It is the most important helminth infection, and its treatment relies solely on the drug praziquantel. Oral H1-antihistamines are available worldwide, and these agents are among the most widely used of all medications in children and adults. Given the importance of the drug repositioning strategy, we evaluated the antischistosomal properties o ...[more]

PMID: 32487175

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Project description:Allergic rhinitis is characterized by a chronic inflammation of nasal mucosa and represents a risk factor for asthma occurrence. H1 antihistamines reduce the symptoms of rhinitis, but some compounds may have anti-inflammatory properties.We evaluated the plasma level of some cytokines in patients with persistent allergic rhinitis (PAR) and their evolution after a 4-week treatment with H1 anti-histamines, as well as the risk of asthma after 1.5 years.Randomized clinical trial.Eighty-five patients with PAR and 30 healthy volunteers were included in the study. The patients with PAR were randomly divided into 2 groups: 41 patients treated with 5 mg/day desloratadine and 44 patients under 5 mg/day levocetirizine for 4 weeks. The clinical and biological evaluations were performed before and after treatment and included rhinitis symptoms and total symptoms score, type of sensitization, and plasmatic levels of total IgE, IL-1?, IL-6, IL-8 and TNF-?.IL-8 and TNF-? were significantly increased in patients with PAR compared to healthy volunteers (5.85 vs 3.12, p<0.001 and 2.32 vs 1.06, p<0.001, respectively). Both H1 antihistamines reduce all symptoms of allergic rhinitis, including nasal congestion and the plasmatic level of IL-1?, IL-6, IL-8 and TNF-?, after 4 weeks of treatment. The reduction of cytokine levels was not influenced by patients' age, sex, duration or severity of rhinitis, or type of sensitization. Levocetirizine has a superior effect compared to desloratadine in reducing the rhinitis symptoms and cytokines' level. Twenty eight (32.9%) of the patients presented asthma symptoms after 1.5 years. The occurrence of asthma was influenced by house dust sensitization (OR-14.6; CI 95% 1.8-116.3; p=0.01), but baseline values of cytokines were not predictive factors for its appearance.Levocetirizine and desloratadine as a prolonged therapy reduce plasmatic levels of some pro-inflammatory cytokines in patients with PAR. Levocetirizine has a better effect on decreasing the symptoms and plasmatic levels of IL-1? and IL-8. (ClinicalTrials. gov Identifier: NCT02507635).POSDRU and University of Medicine and Pharmacy, Iuliu Ha?ieganu, Cluj Napoca.

Project description:Schistosomiasis is a parasitic disease that afflicts approximately 250 million people worldwide. There is an urgent demand for new antiparasitic agents because praziquantel, the only drug available for the treatment of schistosomiasis, is not universally effective and may derail current progress toward the WHO goal of eliminating this disease as a public health problem by 2030. Nifuroxazide (NFZ), an oral nitrofuran antibiotic, has recently been explored to be repurposed for parasitic diseases. Here, in vitro, in vivo, and in silico studies were conducted to evaluate the activity of NFZ on Schistosoma mansoni. The in vitro study showed significant antiparasitic activity, with 50% effective concentration (EC50) and 90% effective concentration (EC90) values of 8.2 to 10.8 and 13.7 to 19.3 μM, respectively. NFZ also affected worm pairing and egg production and induced severe damage to the tegument of schistosomes. In vivo, a single oral dose of NFZ (400 mg/kg of body weight) to mice harboring either prepatent or patent S. mansoni infection significantly reduced the total worm burden (~40%). In patent infection, NFZ achieved a high reduction in the number of eggs (~80%), but the drug caused a low reduction in the egg burden of animals with prepatent infection. Finally, results from in silico target fishing methods predicted that serine/threonine kinases could be one of the potential targets for NFZ in S. mansoni. Overall, the present study revealed that NFZ possesses antischistosomal properties, mainly in terms of egg burden reduction in animals with patent S. mansoni infection. IMPORTANCE The increasing recognition of the burden imposed by helminthiasis, associated with the limited therapeutic arsenal, has led to initiatives and strategies to research and develop new drugs for the treatment of schistosomiasis. One of these strategies is drug repurposing, which considers low-risk compounds with potentially reduced costs and shorter time for development. In this study, nifuroxazide (NFZ) was evaluated for its anti-Schistosoma mansoni potential through in vitro, in vivo, and in silico studies. In vitro, NFZ affected worm pairing and egg production and induced severe damage to the tegument of schistosomes. In vivo, a single oral dose of NFZ (400 mg/kg) to mice harboring either prepatent or patent S. mansoni infection significantly reduced the total worm burden and egg production. In silico investigations have identified serine/threonine kinases as a molecular target for NFZ. Collectively, these results implied that NFZ might be a potential therapeutic candidate for the treatment of schistosomiasis.

Dataset Information

H1-antihistamines as antischistosomal drugs: in vitro and in vivo studies.

Background

Methods

Results

Conclusions

Publications

H1-antihistamines as antischistosomal drugs: in vitro and in vivo studies.

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