BackgroundIncreasing 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 methodsIn 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 IC 50 values of 37.93, 57.83, 67.39, 54.83, and 107.48 μg/ml, respectively, and Alstonia boonei inhibited CYP2D6 (IC 50 = 77.19 μg/ml). Picralima nitida inhibited CYP3A4 (IC 50 = 45.58 μg/ml) and CYP2C19 (IC 50 = 73.06 μg/ml) moderately but strongly inhibited CYP2D6 (IC 50 = 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.ConclusionPotential 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.

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 5cmHO. Peak inspiratory pressure (PIP) was set at 25cmHO. The sheep received either 150μg/kg vatinoxan HCl (VAT+DEX) or saline intravenously (IV) 10min before IV dexmedetomidine HCl (3μg/kg, DEX). Cardiopulmonary variables were measured before treatments (baseline), 3min after vatinoxan or saline, and 5, 15 and 25min after dexmedetomidine. Computed tomography (CT) of lung parenchyma was performed at baseline, 2min before dexmedetomidine, and 10, 20 and 30min 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.

The effect of MK‐467, a peripheral α2‐adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2‐week washout periods. Medetomidine (MED) 30 μg/kg alone or combined in the same syringe with MK‐467 300 μg/kg (MMK) was injected intramuscular, followed by ATI 150 μg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK‐467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine‐related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK‐467 was included. In this study, MK‐467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.

OBJECTIVE To evaluate effects of the peripherally acting α-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine. ANIMALS 9 healthy adult female sheep. PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 μg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 μg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 μg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25. RESULTS Heart rate, cardiac output, and Pao decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments. CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.

BackgroundHibiscus sabdariffabeverage (HSB) is widely consumed as a medicinal herb and sometimes used concomitantly with drugs. This study evaluated thein vitroinhibitory potential of the aqueous extract ofH. sabdariffacalyces (AEHS) on selected cytochrome P450 (CYP) isozymes and the effect of HSB on the pharmacokinetics of caffeinein vivo.MethodsIn vitroinhibitions of eight major CYP isozymes by AEHS were estimated by monitoring CYP-specific model reactions of 10 CYP probe substrates usingN-in-one assay method. Subsequently, an open, randomized, two-period crossover design was used to evaluate the effect of HSB on the pharmacokinetics of single-dose 200 mg caffeine in six healthy human volunteers. Blood samples were obtained at specific times over a 24 h period. Probe drugs and metabolites were analyzed in their respective matrices with ultra-performance liquid chromatography/mass spectrometer/mass spectrometer and reversed-phase high-performance liquid chromatography/ultraviolet detection.ResultsTheH. sabdariffaaqueous extract weakly inhibited the selected CYP isozymesin vitro, with IC50of >100 μgmL-1in the order of CYP1A2 > CYP2C8 > CYP2B6 >> CYP2D6 > CYP2C19 > CYP3A4 > CYP2A6 > CYP2C9. HSB decreased terminal t1/2and Tmaxof caffeine by 13.6% and 13.0%, respectively, and increased Cmaxby 10.3%. Point estimates of primary pharmacokinetic endpoints, Cmax= 1.142 (90% confidence interval (CI) = 0.882, 1.480) and AUC0–∞= 0.992 (90% CI = 0.745, 1.320), were outside the 90% CI of 0.8–1.25 bioequivalence limits.ConclusionThe aqueous extract ofH. sabdariffaweakly inhibited eight CYP isozymesin vitro, but HSB modified the exposure to caffeine in human. Caution should be exercised in administering HSB with caffeine or similar substrates of CYP1A2 until more clinical data are available.