morphinans and sinococuline

Dengue virus (DENV) infection has increased worldwide, with over 400 million infections annually, and has become a serious public health concern. Several drug candidates, new and repurposed, have failed to meet the primary efficacy endpoints. We have recently shown that Aqueous Extract of the stem of Cocculus hirsutus (AQCH) was effective in vitro and in vivo against DENV and was safe in humans. We now report that an active ingredient of AQCH, Sinococuline, protects against the antibody-mediated secondary-DENV infection in the AG129 mouse model. DENV infection markers were assessed, viz. serum viremia and vital organs pathologies-viral load, proinflammatory cytokines and intestinal vascular leakage. The treatment with Sinococuline at 2.0 mg/kg/day; BID (twice a day), was the most effective in protecting the severely DENV-infected AG129 mice. Also, this dose effectively reduced serum viremia and tissue-viral load and inhibited the elevated expression levels of proinflammatory cytokines (TNF-α and IL-6) in several vital organs. Based on these findings, it could be explored further for pre-clinical and clinical developments for the treatment of dengue.

Topics: Animals; Cocculus; Cytokines; Dengue Virus; Disease Models, Animal; Humans; Mice; Morphinans; Viremia

A selective, highly sensitive, precise, and novel bioanalytical method has been developed and validated to quantify sinococuline, an active constituent present in the phytopharmaceutical drug product containing Cocculus hirsutus plant extract, in vivo. Chromatographic separation was achieved on a Luna Omega Polar-C18 bonded analytical column maintained at 45°C. The isocratic mobile phase consisted of methanol and ammonium formate buffer (60:40, v/v) at acidic pH with a low flow rate of 0.250 mL/min. Detection was performed on an API 4000 mass spectrometer using electrospray ionization in positive polarity and multiple reaction monitoring mode to achieve a lower limit of quantification of 1.50 ng/mL. Excellent accuracy and precision were obtained after extracting the analyte from plasma samples using a chemical analogue as an internal standard in the absence of an isotope-labeled compound. The extraction efficacy was evidenced from recovery study, and the analyte was found to be stable in plasma. Validation study demonstrated linearity with coefficient of correlation, r ≥ 0.99, and minimal matrix effect. This bioanalytical method was successfully applied to evaluate pharmacokinetic parameters of sinococuline from a phase I clinical trial of an aqueous extract of C. hirsutus in healthy human volunteers.

Topics: Chromatography, Liquid; Humans; Morphinans; Reproducibility of Results; Tandem Mass Spectrometry

Decoction of Strychnopsis thouarsii is used in the Malagasy traditional medicine to combat malaria. We have shown that this traditional remedy prevents malaria infection by targeting Plasmodium at its early liver stage. Bioassay-guided fractionation of S. thouarsii stem barks extracts, using a rodent Plasmodium yoelii liver stage parasites inhibition assay, led to isolate the new morphinan alkaloid tazopsine (1) together with sinococuline (2) and two other new related morphinan analogs, 10-epi-tazopsine (3) and 10-epi-tazoside (4). Structures were characterized by 2D NMR, MS, and CD spectral analysis. Compounds 1-3 were found to fully inhibit the rodent P. yoelii liver stage parasites in vitro.

Topics: Animals; Antimalarials; Cells, Cultured; Hepatocytes; Liver Diseases, Parasitic; Menispermaceae; Mice; Morphinans; Plant Bark; Plants, Medicinal; Plasmodium yoelii

Two new bisbenzylisoquinoline alkaloids, (+)-coccuorbiculatine A (2) and (+)-10-hydroxyisotrilobine (3), two new amidic aporphines, a mixture of (+)-laurelliptinhexadecan-1-one (6) and (+)-laurelliptinoctadecan-1-one (7), and one new protoberberine (-)-4-methoxy-13,14-dihydrooxypalmatine (8) have been isolated from the stems of Taiwanese Cocculus orbiculatus. The structures were established on the basis of extensive analysis of spectroscopic data and by comparison with known related metabolites. Cytotoxicity of the isolated compounds was examined toward HepG2, Hep3B, MCF-7, and MDA-MB-231 cancer cell lines. Alkaloids 1 and (-)-sinococuline (9) showed significant inhibitory activity against the target cell lines.

Topics: Antineoplastic Agents, Phytogenic; Aporphines; Benzylisoquinolines; Berberine Alkaloids; Fatty Acids; Menispermum; Molecular Structure; Morphinans; Plant Stems; Plants, Medicinal; Taiwan

Three alkaloids, aknadinine, 1-nitroaknadinine and sinococuline, isolated from Stephania sutchuenensis were studied for their effects on a fibroblast cell line, eight tumor cell lines and a rat alveolar macrophage culture. Sinococuline is an effective tumor cell growth inhibitor whereas the toxicity of aknadinine and 1-nitroaknadinine towards all tested cells is low. A dose-dependent decrease in cell viability and in the uptake of tritiated-thymidine, -leucine and -uridine by these cells was observed when they were grown in the presence of sinococuline for 24 h. Exposure to sinococuline in vitro also altered the macrophage function by reducing the production of tumor necrosis factor and reactive nitrogen intermediates. Human leukaemic HL60 cells and mouse fibroblast L929 cells were used to study the underlying mechanism of cytotoxicity and apoptosis seem to be the mode of death induced by sinococuline

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; HL-60 Cells; Humans; Kinetics; L Cells; Leucine; Lipopolysaccharides; Macrophages, Alveolar; Mice; Morphinans; Plants, Medicinal; Rats; Thymidine; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Uridine