Inhibition of cytochrome P450 activities by extracts of 'Hyptis verticillata' Jacq. : assessment for potential HERB-drug interactions

Understanding the potential for adverse drug reactions (ADRs), from herb-drug interactions, is a key aspect of medicinal plant safety, with particular relevance for public health in countries where medicinal plant use is highly prevalent. We undertook an in-depth assessment of extracts of Hyptis verticillata Jacq., via its impact on activities of key cytochrome P450 (CYP) enzymes (CYPs 1A1, 1A2, 1B1, 3A4 and 2D6), its antioxidant properties (determined by DPPH assays) and chemical characterisation (using LC-MS). The dried plant aqueous extract demonstrated potent inhibition of the activities of CYPs 1A1 (7.6 µg/mL), 1A2 (1.9 µg/mL), 1B1 (9.4 µg/mL) and 3A4 (6.8 µg/mL). Further analysis of other crude extracts demonstrated potent inhibition of CYP1A2 activity for a dried plant ethanol extract (1.5 µg/mL), fresh plant ethanol extract (3.9 µg/mL), and moderate activity for a fresh plant aqueous extract (27.8 µg/mL). All four extracts demonstrated strong antioxidant activity, compared to the positive control (ascorbic acid, 1.3 µg/mL), with the dried plant ethanol extract being the most potent (1.6 µg/mL). Analysis of the dried plant aqueous extract confirmed the identity of seven phytochemicals, five lignans and two triterpenes. Individual screening of these phytochemicals against the activity of CYP1A2 identified yatein as a moderate inhibitor (71.9 μM), likely to contribute to the plant extract’s potent bioactivity. Further analysis on the impact of this plant on key drug metabolizing enzymes in vivo appears warranted for likely ADRs, as well as furthering development as a potential chemopreventive agent

Concurrent use of prescription drugs and herbal medicinal products in older adults: A systematic review

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The use of herbal medicinal products (HMPs) is common among older adults. However, little is known about concurrent use with prescription drugs as well as the potential interactions associated with such combinations. Objective Identify and evaluate the literature on concurrent prescription and HMPs use among older adults to assess prevalence, patterns, potential interactions and factors associated with this use. Methods Systematic searches in MEDLINE, PsycINFO, EMBASE, CINAHL, AMED, Web of Science and Cochrane from inception to May 2017 for studies reporting concurrent use of prescription medicines with HMPs in adults (≥65 years). Quality was assessed using the Joanna Briggs Institute checklists. The Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) three stage approach to mixed method research was used to synthesise data. Results Twenty-two studies were included. A definition of HMPs or what was considered HMP was frequently missing. Prevalence of concurrent use by older adults varied widely between 5.3% and 88.3%. Prescription medicines most combined with HMPs were antihypertensive drugs, beta blockers, diuretics, antihyperlipidemic agents, anticoagulants, analgesics, antihistamines, antidiabetics, antidepressants and statins. The HMPs most frequently used were: ginkgo, garlic, ginseng, St John’s wort, Echinacea, saw palmetto, evening primrose oil and ginger. Potential risks of bleeding due to use of ginkgo, garlic or ginseng with aspirin or warfarin was the most reported herb-drug interaction. Some data suggests being female, a lower household income and less than high school education were associated with concurrent use. Conclusion Prevalence of concurrent prescription drugs and HMPs use among older adults is substantial and potential interactions have been reported. Knowledge of the extent and manner in which older adults combine prescription drugs will aid healthcare professionals can appropriately identify and manage patients at risk.Peer reviewedFinal Published versio

Frequency of complementary and alternative medicine utilization in hypertensive patients attending an urban tertiary care centre in Nigeria

<p>Abstract</p> <p>Background</p> <p>To study the frequency and pattern of use of complementary and alternative medicine (CAM) in patients with essential hypertension attending a tertiary hypertension clinic.</p> <p>Methods</p> <p>Two hundred and twenty-five consecutive hypertensive patients attending the hypertension clinic of the Lagos University Teaching Hospital over a 3-month period were interviewed. Socio-demographic data, duration of hypertension, clinic attendance, current blood pressure, and compliance to conventional medications was documented. CAM utilization was explored using both structured and open-ended questions.</p> <p>Results</p> <p>There were 90 (40%) male and 135 (60%) female patients with mean age ± SD overall was 55.1 ± 12.4 years. 88 (39.1%) of the respondents used CAM. Herbal products were the most commonly used CAM type. Amongst the CAM users, the most common herbal product used was garlic (69.3%). Others were native herbs (25%), ginger (23.9%), bitter leaf (<it>Vernonia amygdalina</it>) (9.1%), and aloe vera (4.5%). 2.5% used spiritual therapy. There was no difference in the clinical characteristics, socio-economic status, and blood pressure control of CAM users and non-users. Patients who utilized CAM had higher BMI compared with those who did not, but the difference was not statistically significant (mean BMI ± SD of 29.1 ± 5.6 vs 27.1 ± 5.9 kg/m²; P = 0.05).</p> <p>Conclusion</p> <p>A significant proportion of hypertensive patients attending our tertiary facility and receiving conventional treatment also use CAM therapies. Clinicians need to be aware of this practice, understand the rationale for this health-seeking behaviour, proactively enquire about their use, and counsel patients regarding the potential of some of the therapies for adverse reactions and drug interactions.</p

Selective cytotoxic and anti-metastatic activity in DU-145 prostate cancer cells induced by 'Annona muricata' L. bark extract and phytochemical, annonacin

Background: Annona muricata L. was identified as a popular medicinal plant in treatment regimens among cancer patients in Jamaica by a previously conducted structured questionnaire. Ethnomedically used plant parts, were examined in this study against human prostate cancer cells for the first time and mechanisms of action elucidated for the most potent of them, along with the active phytochemical, annonacin. Methods: Nine extracts of varying polarity from the leaves and bark of A. muricata were assessed initially for cytotoxicity using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on PC-3 prostate cancer cells and the ethyl acetate bark (EAB) extract was identified as the most potent. EAB extract was then standardized for annonacin content using High-performance Liquid Chromatography - Mass Spectrometry (HPLC-MS) and shown to be effective against a second prostate cancer cell line (DU-145) also. The mode of cell death in DU-145 cells were assessed via several apoptotic assays including induction of increased reactive oxygen species (ROS) production, reduction of mitochondrial membrane potential, activation of caspases and annexin V externalization combined with morphological observations using confocal microscopy. In addition, the potential to prevent metastasis was examined via inhibition of cell migration, vascular endothelial growth factor (VEGF) and angiogenesis using the chorioallantoic membrane assay (CAM). Results: Annonacin and EAB extract displayed selective and potent cytotoxicity against the DU-145 prostate carcinoma cells with IC50 values of 0.1 ± 0.07 μM and 55.501 ± 0.55 μg/mL respectively, without impacting RWPE-1 normal prostate cells, in stark contrast to chemotherapeutic docetaxel which lacked such selectivity. Docetaxel’s impact on the cancerous DU-145 was improved by 50% when used in combination with EAB extract. Insignificant levels of intracellular ROS content, depolarization of mitochondrial membrane, Caspase 3/7 activation, annexin V content, along with stained morphological evaluations, pointed to a non-apoptotic mode of cell death. The extract at 50 μg/mL deterred cell migration in the wound-healing assay, while inhibition of angiogenesis was displayed in the CAM and VEGF inhibition assays for both EAB (100 μg /mL) and annonacin (0.5 μM). Conclusions: Taken together, the standardized EAB extract and annonacin appear to induce selective and potent cell death via a necrotic pathway in DU-145 cells, while also preventing cell migration and angiogenesis, which warrant further examinations for mechanistic insights and validity in-vivo

Novel Natural Inhibitors of CYP1A2 Identified by in Silico and in Vitro Screening

Inhibition of cytochrome P450 (CYP) is a major cause of herb–drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb–drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb–drug interactions at an early stage of the drug development process

Potential chemopreventive, anticancer and anti-inflammatory properties of a refined artocarpin-rich wood extract of 'Artocarpus heterophyllus' Lam

Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives. A crude methanol extract from the wood pulp of Artocarpus heterophyllus was found to be the most bioactive among multiple others, and an enriched extract containing 84% (w/v) artocarpin (determined by HPLC–MS–DAD) was prepared. The enriched extract irreversibly inhibited the activity of human cytochrome P450 CYP2C9, an enzyme previously shown to be overexpressed in CRC models. In vitro evaluations on heterologously expressed microsomes, revealed irreversible inhibitory kinetics with an IC50 value of 0.46 μg/mL. Time- and concentration-dependent cytotoxicity was observed on human cancerous HCT116 cells with an IC50 value of 4.23 mg/L in 72 h. We then employed the azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-induced model in C57BL/6 mice, which revealed that the enriched extract suppressed tumor multiplicity, reduced the protein expression of proliferating cell nuclear antigen, and attenuated the gene expression of proinflammatory cytokines (Il-6 and Ifn-γ) and protumorigenic markers (Pcna, Axin2, Vegf, and Myc). The extract significantly (p = 0.03) attenuated (threefold) the gene expression of murine Cyp2c37, an enzyme homologous to the human CYP2C9 enzyme. These promising chemopreventive, cytotoxic, anticancer and anti-inflammatory responses, combined with an absence of toxicity, validate further evaluation of A. heterophyllus extract as a therapeutic agent

A study of arylamine N-acetyltransferase from Salmonella typhimurium

SIGLEAvailable from British Library Document Supply Centre-DSC:D206450 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

An integrated optimization approach for operations of irrigation networks

© 2015 Dr. Dilini Kaushalya DelgodaA significant amount of water losses in farms occurs due to over-irrigation. Moreover, large numbers of farmlands suffer from under-irrigation. Both over-irrigation and under-irrigation cause water shortages, environmental and crop damage, competition and legal conflicts among stakeholders. Thus, optimization of irrigation operations is a very important task. The simple phenomenon behind over-irrigation or under-irrigation is the mismatch between actual water requirement and the supply. At the farm-scale, this means the inequality between the delivered amount and the field water demand. At the field-scale, this is the imbalance between the estimated water demand and the actual crop water deficit. Mismatch at any scale would make the optimization efforts at the other scale useless by reducing the net optimization outcome. This thesis focuses on proposing a theoretical framework for integrated optimization of irrigation operations in a typical irrigation network (farm), consisting of several fields supplied by a canal system. A linear time series model for root zone soil moisture deficit is identified through data analysis. It uses direct measurements of rainfall, irrigation and crop evapotranspiration as inputs. The simplicity of the model reduces calibration efforts significantly and when it is applied in irrigation control, provides convenience in analysis and implementation. The changes to the model identification procedure under the presence of saturation, rule-based irrigation control methods, and measurement noise in soil moisture data are investigated. The adequacy of the model is verified through standard tests, using synthetic data generated from the physics-based AQUACROP model and two field datasets. A novel methodology based on the proposed model is developed for irrigation control at field-scale, which minimizes both root zone soil moisture deficit and irrigation amount. Existing robust model predictive control principles are analyzed for their ability to form the basis of the irrigation control method and modified in the context of irrigation systems. The control method guarantees optimum operation above the wilting point at all times, under the uncertainty in weather forecasts subject to water availability. The method is validated using AQUACROP model, real weather forecasts and data. The performance of the method is verified through three performance indicators. A preliminary sensitivity analysis of the performance is also carried out. A generic method to optimize irrigation canal scheduling is developed. It provides optimization of objectives at higher hierarchical layers in a canal network without disrupting the optimization at lower layers. It also offers flexibility to the canal operator to visualize the entire situation by quantifying the impact of optimizing multiple conflicting objectives. It also utilizes the available infrastructure and traditional canal scheduling methods. The method is demonstrated in a hypothetical example with six objectives and three hierarchical layers, and a real scenario with four objectives and two layers. Due to its flexibility, the canal scheduling method allows to synchronize the scheduling and control without compromising the optimization results obtained at field- and farm-scales. Two potential approaches of synchronization are demonstrated and the performance is quantified through the three above mentioned performance indicators. This removes the bottleneck in the water saving process at the two scales. In summary, the proposed integrated approach can serve as a starting point for making large-scale water savings in irrigation networks a reality