Antihistamines H1 as Potential Anthelmintic Agents against the Zoonotic Parasite Angiostrongylus cantonensis.

Infections caused by parasitic helminths pose significant health concerns for both humans and animals. The limited efficacy of existing drugs underscores the urgent need for novel anthelmintic agents. Given the reported potential of antihistamines against various parasites, including worms, this study conducted a screening of clinically available antihistamines against Angiostrongylus cantonensis-a nematode with widespread implications for vertebrate hosts, including humans. Twenty-one anti-H1 antihistamines were screened against first-stage larvae (L1) of A. cantonensis obtained from the feces of infected rats. Standard anthelmintic drugs ivermectin and albendazole were employed for comparative analysis. The findings revealed four active compounds (promethazine, cinnarizine, desloratadine, and rupatadine), with promethazine demonstrating the highest potency (EC50 = 31.6 µM). Additionally, morphological analysis showed that antihistamines induced significant changes in larvae. To understand the mechanism of action, antimuscarinic activities were reported based on average pK i values for human muscarinic receptor (mAChR) subtypes of the evaluated compounds. Furthermore, an analysis of the physicochemical and pharmacodynamic properties of antihistamines revealed that their anthelmintic activity does not correlate with their activity at H1 receptors. This study marks the first documentation of antihistamines' activity against A. cantonensis, offering a valuable contribution to the quest for novel agents effective against zoonotic helminths.

Antiparasitic properties of 4-nerolidylcatechol from Pothomorphe umbellata (L.) Miq. (Piperaceae) in vitro and in mice models with either prepatent or patent Schistosoma mansoni infections.

ETHNOPHARMACOLOGICAL RELEVANCE: Roots of Pothomorphe umbellata (L.) Miq. are used in traditional medicine of Africa and South America for the treatment of malaria and helminthiasis. However, neither P. umbellata nor its isolated compounds have been evaluated against Schistosoma species. AIMS OF THIS STUDY: To investigate the antischistosomal effects of P. umbellata root extracts and the isolated compound 4-nerolidylcatechol (4-NC) against Schistosoma mansoni ex vivo and in murine models of schistosomiasis. MATERIALS AND METHODS: The crude hydroalcoholic (PuE) and hexane (PuH) extracts of P. umbellata roots were prepared and initially submitted to an ex vivo phenotypic screening against adult S. mansoni. PuH was analyzed by HPLC-DAD, characterized by UHPLC-HRMS/MS, and submitted to chromatographic fractionation, leading to the isolation of 4-NC. The anthelmintic properties of 4-NC were assayed ex vivo against adult schistosomes and in murine models of schistosomiasis for both patent and prepatent S. mansoni infections. Praziquantel (PZQ) was used as a reference compound. RESULTS: PuE (EC50: 18.7 µg/mL) and PuH (EC50: 9.2 µg/mL) kill adult schistosomes ex vivo. The UHPLC-HRMS/MS analysis of PuH, the most active extract, revealed the presence of 4-NC, peltatol A, and peltatol B or C. After isolation from PuH, 4-NC presented remarkable in vitro schistosomicidal activity with EC50 of 2.9 µM (0.91 µg/mL) and a selectivity index higher than 68 against Vero mammalian cells, without affecting viability of nematode Caenorhabditis elegans. In patent S. mansoni infection, the oral treatment with 4-NC decreased worm burden and egg production in 52.1% and 52.3%, respectively, also reducing splenomegaly and hepatomegaly. 4-NC, unlike PZQ, showed in vivo efficacy against juvenile S. mansoni, decreasing worm burden in 52.4%. CONCLUSIONS: This study demonstrates that P. umbellata roots possess antischistosomal activity, giving support for the medicinal use of this plant against parasites. 4-NC was identified from P. umbellata roots as one of the effective in vitro and in vivo antischistosomal compound and as a potential lead for the development of novel anthelmintics.

N-(4-Methoxyphenyl)Pentanamide, a Simplified Derivative of Albendazole, Displays Anthelmintic Properties against the Nematode Toxocara canis.

Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. In this study, a simplified compound, N-(4-methoxyphenyl)pentanamide (N4MP), based on the structure of the most widely used anthelmintic (albendazole), was chemically prepared using 4-anisidine and pentanoic acid. N-(4-Methoxyphenyl)pentanamide was evaluated in vitro against the nematode Toxocara canis, an ascarid roundworm of animals that can infect humans. Similar to albendazole, bioassays showed that N-(4-methoxyphenyl)pentanamide affected the viability of parasites in a time- and concentration-dependent manner. Interestingly, N-(4-methoxyphenyl)pentanamide showed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Pharmacokinetic, drug-likeness, and medicinal chemistry friendliness studies demonstrated an excellent drug-likeness profile for N-(4-methoxyphenyl)pentanamide as well as an adherence to major pharmaceutical companies' filters. Collectively, the results of this study demonstrate that the molecular simplification of albendazole to give N-(4-methoxyphenyl)pentanamide may be an important pipeline in the discovery of novel anthelmintic agents. IMPORTANCE Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. Considering this scenario, the present study reports the preparation of N-(4-methoxyphenyl)pentanamide (N4MP), a simplified molecule based on the structure of the most widely used anthelmintic (albendazole). N4MP was evaluated in vitro against the nematode Toxocara canis, a common ascarid roundworm of domestic animals that can infect humans. Similar to albendazole, bioassays showed that N4MP affected the viability of parasites in a time- and concentration-dependent manner but displayed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Therefore, this study demonstrates that the molecular simplification of albendazole to give N4MP may be an important pipeline in the discovery of novel anthelmintic agents.

Therapeutic Efficacy of Carvacrol-Loaded Nanoemulsion in a Mouse Model of Schistosomiasis.

Since praziquantel is the only drug available to treat schistosomiasis, a neglected parasitic disease that affects more than 240 million people worldwide, there is an urgent demand for new antischistosomal agents. Natural compound-loaded nanoparticles have recently emerged as a promising alternative for the treatment of schistosomiasis. Carvacrol is an antimicrobial monoterpene present in the essential oil extracted from several plants, especially oregano (Origanum vulgare). In this study, a carvacrol nanoemulsion (CVNE) was prepared, characterized, and administered orally (200 mg/kg) in a mouse infected with either immature (prepatent infection) or adult (patent infection) Schistosoma mansoni. For comparison, data obtained with an unloaded nanoemulsion (blank formulation), free carvacrol, and the drug of reference praziquantel are also presented. CVNE was more effective than free carvacrol in reducing the worm burden and egg production in both patent and prepatent infections. Favorably, CVNE had a high effect in terms of reducing the number of worms and eggs (85%-90%) compared with praziquantel (∼30%) in prepatent infection. In tandem, carvacrol-loaded nanoemulsion markedly improved antischistosomal activity, showing efficiency in reducing worm and egg burden, and thus it may be a promising delivery system for the treatment of schistosomiasis.