Potential inhibition of major human cytochrome P450 isoenzymes by selected tropical medicinal herbs—Implication for herb–drug interactions

BACKGROUND: Increasing use of medicinal herbs as nutritional supplements and traditional medicines for the treatment of diabetes, hypertension, hyperlipidemia, and malaria fever with conventional drugs poses possibilities of herb–drug interactions (HDIs). The potential of nine selected widely used tropical medicinal herbs in inhibiting human cytochrome P450 (CYP) isoenzymes was investigated. MATERIALS AND METHODS: In vitro inhibition of eight major CYP isoenzymes by aqueous extracts of Allium sativum, Gongronema latifolium, Moringa oleifera, Musa sapientum, Mangifera indica, Tetracarpidium conophorum, Alstonia boonei, Bauhinia monandra, and Picralima nitida was estimated in human liver microsomes by monitoring twelve probe metabolites of nine probe substrates with UPLC/MS‐MS using validated N‐in‐one assay method. RESULTS: Mangifera indica moderately inhibited CYP2C8, CYP2B6, CYP2D6, CYP1A2, and CYP2C9 with IC50 values of 37.93, 57.83, 67.39, 54.83, and 107.48 μg/ml, respectively, and Alstonia boonei inhibited CYP2D6 (IC50 = 77.19 μg/ml). Picralima nitida inhibited CYP3A4 (IC50 = 45.58 μg/ml) and CYP2C19 (IC50 = 73.06 μg/ml) moderately but strongly inhibited CYP2D6 (IC50 = 1.19 μg/ml). Other aqueous extracts of Gongronema latifolium, Bauhinia monandra, and Moringa oleifera showed weak inhibitory activities against CYP1A2. Musa sapientum, Allium sativum, and Tetracarpidium conophorum did not inhibit the CYP isoenzymes investigated. CONCLUSION: Potential for clinically important CYP‐metabolism‐mediated HDIs is possible for Alstonia boonei, Mangifera indica, and Picralima nitida with drugs metabolized by CYP 2C8, 2B6, 2D6, 1A2, 2C9, 2C19, and 3A4. Inhibition of CYP2D6 by Picralima nitida is of particular concern and needs immediate in vivo investigations

Cardiopulmonary effects of vatinoxan in sevoflurane-anaesthetised sheep receiving dexmedetomidine

The effects of pre-treatment with vatinoxan (MK-467) on dexmedetomidine-induced cardiopulmonary alterations were investigated in sheep. In a crossover study design with a 20-day washout, seven sheep were anaesthetised with sevoflurane in oxygen and air. The sheep were ventilated with the pressure limited volume-controlled mode and a positive end-expiratory pressure of 5 cmH(2)O. Peak inspiratory pressure (PIP) was set at 25 cmH(2)O. The sheep received either 150 mu g/kg vatinoxan HCl (VAT + DEX) or saline intravenously (IV) 10 min before IV dexmedetomidine HCl (3 mu g/kg, DEX). Cardiopulmonary variables were measured before treatments (baseline), 3 min after vatinoxan or saline, and 5, 15 and 25 min after dexmedetomidine. Computed tomography (CT) of lung parenchyma was performed at baseline, 2 min before dexmedetomidine, and 10, 20 and 30 min after DEX. Bronchoalveolar lavage (BAL) was performed after the last CT scan and shortly before sheep recovered from anaesthesia. After VAT, cardiac output significantly increased from baseline. DEX alone significantly decreased partial arterial oxygen tension, total dynamic compliance and tidal volume, whereas PIP was significantly increased. With VAT + DEX, these changes were minimal. No significant changes were detected in haemodynamics from baseline after DEX. With VAT + DEX, mean arterial pressure and systemic vascular resistance were significantly decreased from baseline, although hypotension was not detected. On CT lung density was significantly increased with DEX as compared to baseline. No visual abnormalities were detected in bronchoscopy and no differences were detected in the BAL fluid after either treatment. The pre-administration of vatinoxan alleviates dexmedetomidine-induced bronchoconstriction, oedema and hypoxaemia in sevoflurane-anaesthetised sheep. (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Bridged Epipolythiodiketopiperazines from <i>Penicillium raciborskii</i>, an Endophytic Fungus of <i>Rhododendron tomentosum</i> Harmaja

Three new epithiodiketopiperazine natural products [outovirin A (<b>1</b>), outovirin B (<b>2</b>), and outovirin C (<b>3</b>)] resembling the antifungal natural product gliovirin have been identified in extracts of <i>Penicillium raciborskii</i>, an endophytic fungus isolated from <i>Rhododendron tomentosum</i>. The compounds are unusual for their class in that they possess sulfide bridges between α- and β-carbons rather than the typical α–α bridging. To our knowledge, outovirin A represents the first reported naturally produced epimonothio­diketopiperazine, and antifungal outovirin C is the first reported trisulfide gliovirin-like compound. This report describes the identification and structural elucidation of the compounds by LC-MS/MS and NMR