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.

Pharmacokinetic profile and oral bioavailability of Kaurenoic acid from Copaifera spp. in rats.

Kaurenoic acid (KA) is a kaurane diterpene found in several medicinal plants that displays biological activities, such as anti-inflammatory, smooth muscle relaxant and hypotensive response. However, there are no pharmacokinetic data available about this molecule. The purpose of the study was to determine the pharmacokinetic profile and the oral bioavailability of KA in rats. Wistar rats submitted to jugular vein cannulation received 50 mg/kg of KA by intravenous or oral route. The implanted cannula allowed intravenous administration and serial blood collection along 10 h. Analytical quantification was performed by reversed phase HPLC-UV and mobile phase composed by acetonitrile:acidified water (70:30 v/v). The validated analytical method showed precision, accuracy, robustness, reliability and linearity between 0.75 and 100 µg/mL. KA administered intravenously showed a linear and two-compartment kinetic behavior at the tested dose. The following pharmacokinetic parameters were determined: Cmax = 22.17 ±â€¯1.65 mg/L; V = 14.53 ±â€¯1.47 L/kg; CL = 17.67 ±â€¯1.50 mL/min/kg; AUC0-∞ = 2859.65 ±â€¯278.42 mg·min/L, K = 0.073 ±â€¯0.005 h-1 and t1/2ß = 9.52 ±â€¯0.61 h. Oral treatment did not provide detectable plasma levels of KA, avoiding the determination of its bioavailability.