Aconitum in treatment of rheumatoid arthritis: benefit-risk assessment / 中国中药杂志

Rheumatoid arthritis (RA) has the characteristics of long course of disease and difficulty in treatment. The conventional therapy may easily induce adverse drug reactions or events (ADR/ADE) due to the long-time medication. Thus, it should be given special attentions to treatment benefit and medication risk of RA patients. Aconitum, a kind of toxic traditional Chinese herbs, is an important complement therapy for RA, with some controversy in clinical application. Coming straight to the practical problem of combined use of traditional Chinese medicines (TCM) and Western medicines (WM), this study conducted quantitative assessment on the benefits and risks of Aconitum using combined with WM or not, which was carried out by the method of multi-criteria decision analysis model. RevMan 5.2 software was used to separately analyze the results of every index of 21 random clinical trials (RCTs) of Aconitum exclusive use in the treatment of RA, and 49 RCTs of Aconitum combined use with WM. The merged results indicated that as compared with the conventional therapy of WM, no matter the exclusive use or the combined use of Aconitum could improve the efficacy and decrease the incidence of ADR/ADEs. Based on the benefit-risk assessment decision tree of RA treatment, Hiview 3 software and Crystal Ball Monte Carlo simulation were used to calculate the benefit value, risk value and benefit-risk value of Aconitum exclusive use and the combined use of Aconitum with WM. The results showed that the combination therapy had significantly better benefits than Aconitum exclusive using, difference value was 15, (95%CI[9.72, 20.25]), but the risk of combined use was higher difference value=23, （95%CI[15.57, 30.55]）. In comprehensive consideration of the benefit and risk, the total benefit-risk value of using Aconitum alone was 58, while that of the combination therapy was 55, and the probability of the former superior to the latter was 81.07%. The study showed that Aconitum was the important therapy to supply RA treatment. In clinical application, the patient's acceptability of benefit and risk need to be considered; if patients cannot bear the risk, the combination use of Aconitum and WM is not recommended.

Revisión sistemática de nuevos anticoagulantes orales frente a warfarina en fibrilación auricular no valvular / Systematic review of new oral anticoagulants versus warfarin in non valvular atrial fibrillation

RESUMEN INTRODUCCIÓN: Los nuevos anticoagulantes orales son el más reciente avance en anticoagulación oral. Existen suficientes estudios publicados, pero muy poca síntesis de la información. MÉTODOS: Se realizó una búsqueda sistemática de los estudios en Medline, Cochrane y Embase con los términos predefinidos. Se aplicaron los criterios de inclusión y exclusión definidos, se definieron las variables utilizadas en este estudio según el beneficio (reducción de la mortalidad y reducción del ACV) y el riesgo en la anticoagulación (sangrado intracraneal, sangrado gastrointestinal, sangrado mayor y otros sangrados). Se seleccionaron los artículos y se extrajo la información en una hoja de cálculo para análisis. RESULTADOS: Se incluyeron 24 meta-análisis y 62 subanálisis; 77 % de los meta-análisis mostraron reducción de ACV, 65 % mortalidad, 71 % reportó disminución de hemorragia intracraneal y 45 % de sangrado mayor, pero hubo aumento de sangrado gastrointestinal en el 5 4% de los estudios. En relación a los resultados de los subanálisis, 4 estudios mostraron algún dato estadísticamente significativo para apixabán, 5 para dabigatrán, 3 para edoxabán y 5 estudios para rivaroxabán. Existen diferencias en algunas variables como sexo, riesgo de ACV, resultados a 30 días, función renal; diferentes dosis (dabigatrán y edoxabán), según la edad, síntomas gastrointestinales, relación con el INR; niveles séricos del medicamento, uso de amiodarona, uso previo de warfarina; enfermedad arterial periférica, transición a warfarina; factores de riesgo de HGI y sangrado mayor para cada anticoagulante en particular. CONCLUSIONES: Los nuevos anticoagulantes orales muestran mejor perfil de seguridad y de eficacia frente a warfarina.

SUMMARY INTRODUCTION: New oral anticoagulants are the latest advancement in oral anticoagulation. Several studies are published, but a few studies of synthesis information. METHODS: A systematic review of the studies in MEDLINE, COCHRANE and EMBASE was performed with the predefined terms. The defined inclusion and exclusion criteria were applied; variables used in this study were defined according to benefits (reduction of mortality and reduction of stroke) and anticoagulation risks (intracranial bleeding, gastrointestinal bleeding, major bleeding and other bleeding). Articles were selected and information was extracted into a spreadsheet for analysis. RESULT: Were included 24 meta-analyzes and 62 sub-analyzes; 77% of meta-analyzes showed stroke reduction, 65% in mortality, 71% reported decreased of intracranial hemorrhage and 45% in major bleeding, but there was an increase in gastrointestinal bleeding in 54% of the studies. Regarding the results of the sub-analysis, 4 studies for apixaban, 5 for dabigatran, 3 for edoxaban and 5 studies for rivaroxaban showed some statistically significant data. There are differences in some variables such as sex, stroke risk, 30-day results, renal function; Different doses (dabigatran and Edoxaban), according to age, gastrointestinal symptoms, relation with INR; Serum levels of the drug, use of amiodarone, prior use of warfarin; Peripheral arterial disease, transition to warfarin; Risk factors for gastrointestinal bleeding and major bleeding for each particular anticoagulant. CONCLUSION: The new oral anticoagulants shows better safety and efficacy profile against Warfarin.

Benefit and Risk Assessment of Breastmilk for Infant Health in Norway.

The present benefit and risk assessment of breastmilk and contaminants in breastmilk was initiated by the Norwegian Scientific Committee for Food Safety (VKM). The overall objective is to provide a balanced assessment of the benefits of breastmilk against the possible risks from exposure to contaminants in breastmilk with focus on Norwegian conditions. The aim is to contribute to a foundation for decision-makers when providing recommendations on the length of exclusive and partial breastfeeding. The composition of breastmilk is tailored for the needs of the newborn. Provided that the nutritional needs of the mother are met during pregnancy and breastfeeding, breastmilk covers all the nutritional requirements of the infant the first months of life, with the exception of vitamin D. Breastmilk also contains a number of specialised components, including growth factors, factors with anti-microbial and anti-inflammatory properties and selected immunological components which boost the maturation of the infant’s immune system. Infant formula fulfils the infant’s established nutritional needs, but does not provide the specific protective factors which are present only in breastmilk. However, studies over the last four decades have shown that polluting chemicals have accumulated in the environment, biomagnified in the food chain, are in our bodies, and consequently in breastmilk. The levels of lipid-soluble persistent contaminants in the foetus, the newborn child and in breastmilk largely reflect the amount of these in the mother’s body. Thus, breastmilk contains nutrients and protective immunological factors which have a positive effect on infant health, but may also contain contaminants. Particularly lipid-soluble and persistent contaminants accumulate in the infant during breastfeeding. This has contributed to a debate among experts agreeing that breastfeeding is beneficial, but discussing the advisable length of breastfeeding. Breastfeeding in Norway Breastfeeding prevalence is higher in Norway than in most European countries. 80% of the infants are breastfed at 6 months of age and 46% at 12 months. Mean breastfeeding duration is about 10 months. Norwegian health authorities recommend that infants are exclusively breastfed for 6 months with a total duration of at least 12 months. However, only a minority of Norwegian mothers breastfeed exclusively for the recommended 6 months. The prevalence of exclusive breastfeeding declines rapidly from 3 months onwards with only 9% being exclusively breastfed at 6 months. Mean breastmilk consumption in exclusively breastfed infants increases from approximately 700 ml/day at age 1 month to 850 ml/day at age 6 months. The amount of breastmilk provided to the child is not very different between the partially and exclusively breastfed infants during the first 4 months. From 7 months, breastmilk consumption in partially breastfed infants may be about 500 ml/day. There are a few conditions where breastfeeding is contraindicated. Among these are some metabolic disorders, infections and use of certain pharmaceuticals. Nutrients and Immunological Components in Breastmilk The positive health effects of breastmilk relates to nutritious as well as immunological properties. An infant who is exclusively breastfed for the first 6 months of life has, provided adequate nutrition of the mother, all the nutritional needs covered with the exception of vitamin D. Therefore, worldwide, the recommended daily intake of nutrients for infants is derived from the nutrient concentrations in breastmilk multiplied with the average intake of breastmilk. The composition of nutrients in breastmilk varies by stage of lactation, the time of day and during a given feeding. The concentration of some nutrients also varies according to the mother’s diet. The energy content of breastmilk varies, but has been estimated to be about 700 kcal/L. The content of proteins and carbohydrates is relatively stable, while the fat content has large variations. The fatty acid composition and concentrations of most vitamins reflect the maternal intake, while the concentrations of most minerals are not affected by the maternal diet, except for selenium and iodine. Breastmilk has protective properties. It contains a number of specialised components, including factors with anti-microbial and anti-inflammatory properties as well as constituents boosting the maturation of the infant’s immune system. This benefits health in childhood and most likely also later in life. The milk antibodies are targeted against potential pathogens and other antigens to which the mother has been exposed. Moreover, maturation of the infant’s immune system is influenced by contact with the immune-modulating factors in breastmilk as well as dietary and microbial constituents in the infant’s gut. Different components in breastmilk facilitate the establishment of a beneficial intestinal microbiota, which is important for induction of a balanced mucosal immune system. Through all these mechanisms, breastfeeding represents an ingenious immunologic integration of mother and child. Nutrients in Infant Formula If breastfeeding is not possible or if there is a need for more milk in addition to breastmilk, infant formula is recommended until the child is 12 months of age. Infant formula fulfills the infant´s established nutritional needs, but does not provide maternal antibodies and innate defence factors or immunity-promoting components. The majority of the infant formulas on the Norwegian market are cow’s milk-based. Data from a national dietary survey among infants (Spedkost, 2006) showed that at 6 months of age, 43% of the infants in Norway had been introduced to infant formula, and 36% used it regularly. At 1 year of age, 43% of the infants received infant formula regularly. Infant formulas in Norway are subject to EU regulations that cover the composition, labelling, marketing and distribution of the product. The regulations give minimum and maximum limits for nutrients for infant formulas and include some of the provisions of the WHO Code1. Contaminants and Microbiological Organisms in Breastmilk and Infant Formula Breastmilk, as a reflection of the mother’s body, contains low concentrations of a mixture of different contaminants. Only the most prevalent contaminants in breastmilk have been determined chemically and even fewer have been studied in humans with regard to impact on early life health. The main focus of the present benefit and risk assessment of breastmilk are contaminants which are included in the Stockholm convention on Persistent Organic Pollutants (POPs)2. They can be divided into the three main groups; pesticides (DDT and HCB), other halogenated organic pollutants (dioxins and dioxin-like PCBs, non-dioxin-like PCBs, brominated flame retardants (PBDE), perfluorinated compounds (PFOS/PFOA)) and heavy metals (lead, mercury and cadmium). In the identification and characterisation of negative health effects, combined exposures to multiple contaminants3 from breastmilk have to some extent been taken into consideration, as several of the cohorts have been investigating the impact on health outcomes of PCBs and dioxins in combination with DDT or HCB and some in combination with mercury. Additionally, it should be noted that the contaminants studied may be considered as markers for the combined exposure of multiple contaminants, since their occurrences are often correlated. Metal concentrations in both breastmilk and infant formula (e.g. mercury and lead) are generally low and not at levels associated with concern. Due to national and international restrictions and bans on use, the levels of dioxins, PCBs, and pesticides (like DDTs and HCB) have declined substantially (more than 60%) in the environment and in humans the last three decades. Compared to DDTs, HCB, dioxins and PCBs, the concentration of PBDEs in breastmilk in Norway increased until approximately year 2000, after which a decline has been observed. The fluorinated surfactants PFOS and PFOA have shown a similar time trend as the PBDEs. There are limited Norwegian data on levels of persistent organic pollutants in infant formula, but the levels reported are generally much lower than in breastmilk. Some contaminants which do not accumulate in the food chain may also be relevant in both breastmilk and infant formula. Substances from food packaging materials, e.g. phthalates, may be present in both breastmilk and infant formula, as well as process-generated substances such as acrylamide, PAHs, furan and 3-MDCP. The hormone active substance bisphenol A (BPA) used in plastic has recently been banned in infant feeding bottles in EU and Norway. Occurrence data in breastmilk and infant formula for these substances in Norway are scarce. The main difference between the contaminants in breastmilk and those provided by infant formula or bottle-feeding is that breastmilk generally contains higher levels of persistent organic pollutants, while most of the unwanted substances imposed by infant formula and bottle-feeding have a shorter half-life. Infant formula may contain microbial contamination of concern, which may lead to diarrhea and in severe cases bacteraemia and meningitis. Cronobacter spp. (formerly Enterobacter sakazakii) is a rare cause of invasive infection with high death rates in newborn infants. Possible outbreak from microbiological hazards in infant formula itself or due to contaminated water is an issue in developing countries, but no such outbreaks have been registered in Norway. Methodological Approach to this Benefits and Risk Assessment The benefit assessment is based on positive health effects reported in systematic reviews and meta-analyses published within the last 10 years. This implies that VKM has not conducted its own specific literature search to reveal the epidemiological studies that have examined positive health effects of breastmilk, but summarises and discu

Benefit-risk Assessment of Fish and Fish Products in the Norwegian Diet – An Update.

Request from the Norwegian Food Safety Authority (NFSA) In September 2013, the Norwegian Food Safety Authority requested VKM to update relevant parts of the benefit-risk assessment of fish in the Norwegian diet published by VKM in 2006. The background for the request was new knowledge and data on the content of some nutrients and contaminants both for wild and farmed fish since 2006. The proportion of vegetable ingredients used in farmed fish feed has in recent years increased, and new national dietary surveys for adults and children have been conducted. The Norwegian Food Safety Authority referred to VKM’s report from 2006, which pointed out that the positive impact of fish consumption on public health was especially due to the content of polyunsaturated fatty acids and vitamin D in fish. Further, VKM concluded that the contaminants that could pose a potential risk to public health through fish consumption mainly were methylmercury, dioxins and dioxin-like PCBs (dl-PCBs). The request included a reassessment of fish consumption in Norway with focus on specific nutrients; n-3 fatty acids (eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), vitamin D, and the minerals iodine and selenium, and on specific contaminants; mercury, dioxins and dl-PCBs. VKM was asked to address the main changes in the use of raw materials in farmed fish feed and how these affect the levels of nutrients, mercury, dioxins and dl-PCBs and in fish feed. Further, VKM was asked to address to what extent levels of nutrients and contaminants in fish have changed since 2006, to describe these changes and estimate the human intake of the substances in question on the basis of recent dietary data. VKM was also requested to consider the benefits of eating fish with regard to the intake of nutrients and the risks associated with the intake of mercury, dioxins and dl-PCBs and comment on whether this change the conclusions from the report in 2006. Additionally, on the basis of updated knowledge, VKM was asked to comment whether other substances, like pesticide and residues of veterinary medicinal products, could affect the conclusions with regard to the impact on public health. The Norwegian Food Safety Authority and the Directorate of Health will use the updated assessment as a basis for public recommendations concerning the consumption of fish and fish products. How VKM has Addressed the Request The VKM appointed a working group consisting of VKM members and external experts to answer the request. Several of the scientific panels of VKM reviewed the report during its preparation. The Scientific Steering Committee of VKM has given their final assessment and approval of the current report. In the current report, VKM has mainly used data from national surveillance and monitoring programs for nutrient and contaminant concentrations in fish feed, farmed fish and wild caught fish, but occurrence data have also been derived from peer reviewed articles. VKM has estimated fish consumption in three population groups (2-year-olds, adults and pregnant women). The estimated fish consumption was compared to national dietary guidelines. To assess health effects of fish consumption, the current estimated fish intakes were also compared with assessments done by recognised international bodies and results from epidemiological studies addressing possible associations between fish consumption and specific health outcomes. Literature searches were done to identify relevant epidemiological studies. VKM has not systematically assessed reviews or meta-analyses nor individual studies for weight of evidence, but merely summarised the studies retrieved from the literature search. It was considered being beyond the scope of this assessment to review individual studies included in reviews or meta-analyses. Furthermore, based on current fish consumption in the various population groups, intake of nutrients and exposure to contaminants from fish were estimated. For benefit characterisation of the specific nutrients the estimated nutrient intake was compared with national recommendations of nutrients intake and for EPA and DHA a comparison was also done with European recommendations. For risk characterization of contaminant exposure from fish, VKM used health based guidance values set by international risk assessment bodies (WHO, EFSA). VKM noted that the request from NFSA was restricted to fish, whereas the VKM report in 2006 included both fish and other seafood. VKM focused on specific nutrients and contaminants as requested by the NFSA. In addition, VKM also commented on other substances that could affect the risk assessment, such as residues of veterinary medicinal products including residues of antibiotics, new contaminants from fish feed like the pesticide endosulfan, polycyclic aromatic hydrocarbons (PAHs), mycotoxins, the synthetic antioxidants ethoxyquin, butylhydroxyanisole (BHA) and butylhydroxytoluene (BHT), as well as environmental contaminants like brominated flame retardants and perfluorated organic compounds Background In the Norwegian diet fish is important source of well-balanced proteins, and important nutrients such as EPA and DHA, vitamin D, iodine and selenium. On the other hand, fish is also a source of exposure to chemical contaminants like dioxins, PCBs and mercury. Over the last 10 years there has been a great change in raw materials used in fish feeds, and in 2013 terrestrial plant proteins and vegetable oils accounted for 70% of the feed. The changes in concentrations of nutrients and contaminants in fish feed for farmed Atlantic salmon and trout are reflected in changed concentrations and compositions of the same nutrients and contaminants in the farmed fish fillet. The current national dietary guideline is to eat fish as dinner meals 2-3 times per week for all age groups, representing 300-450 g fish per week for adults, including at least 200 g fatty fish, such as salmon, trout, mackerel and herring. Fish is also recommended as bread spread. Further, a daily supplement of vitamin D to infants from 4 weeks of age is recommended, and if this supplement is taken as cod liver oil it will in addition ensure an adequate supply of EPA and DHA. The present benefit-risk assessment is comprised of three elements, i.e. benefit assessment, risk assessment and benefit-risk comparison. This methodology is in accordance with the guidance given by EFSA in 2010. Fish Consumption in Norway and Comparison with National Dietary Guidelines VKM has used information about fish consumption from more recent national dietary surveys among 2-year-olds (Småbarnskost 2007) and adults at 18-70 years of age (Norkost 3, 2010/2011), as well as information for pregnant women who answered the Norwegian Mother and Child Cohort Study (MoBa2, 2002-2008) food frequency questionnaire. The national food consumption survey Ungkost 2000, which covers the age groups 4-, 9-, and 13-year-old children, was considered too old to be used and it is therefore not known if their fish consumption patterns have changed, neither in amount consumed nor type of fish consumed. Even though there are methodological differences between the dietary surveys used in 2006 and 2014, the amount of fish consumed appears to be unchanged for all population groups. Furthermore, in 2014, lean fish and fatty fish contribute with about 60 and 40 percent, respectively, of the total fish consumption, which is similar to 2006. Given a portion size of 150 g fish, the average adult eats fish equivalent to 2-3 dinner servings per week and the average pregnant woman eats fish equivalent to 1-2 dinner servings per week, while the average two-year-old eats fish equivalent to 1-2 dinner servings per week given a portion size of 75 g. The table below describes fish intake in the selected populations. Fish consumption (expressed as raw fish), mean grams (g) per week in 2-year-olds (Småbarnskost 2007, n=1674), adults (Norkost 3, n=1787) and pregnant women (MoBa, n=86277) Population groups Mean fish consumption g/week Fish roe Fish, total Lean fish (≤ 5% fat) Fatty fish (> 5% fat) and liver 2-year-olds 112 70 35 7 Adults 364 210 147 7 Pregnant women 217 126 77 14 VKM concludes that of the different population groups, only adults (18-70 years of age) with an average or higher fish consumption reach the national food based dietary guidelines for total fish consumption. Mean total fish consumption and fatty fish consumption in children (2-year-olds) and pregnant women, as well as the mean fatty fish consumption in adults are lower than recommended. In pregnant women and 2-year-olds, fish consumption is too low to meet the food based dietary guidelines Health Effects of Fish Consumption VKM is of the opinion that according to epidemiological studies, the net effects of the present average fish consumption in Norway for adults including pregnant women is beneficial for specific cardiovascular diseases (particularly cardiac mortality, but also with regard to ischaemic stroke, non-fatal coronary heart disease events, congestive heart failure and atrial fibrillation), as well as for optimal neurodevelopment of foetus and infants. Furthermore, VKM is of the opinion that those with fish consumption less than one dinner serving per week may miss these beneficial effects. The health benefit of fish consumption is reported from 1-2 dinner servings per week and up to 3-4 dinner servings per week. For higher fish intake per week, the limited number of consumers in epidemiological studies does not allow for drawing firm conclusions about the actual balance of risk and benefit. More knowledge is needed to reveal the beneficial mechanisms of fish consumption. Benefit Characterisation of Nutrients in Fish VKM is of the opinion that there has been minor or no changes of the composition and concentrations of nutrients in wild caught fish since 2006. Due to replacement of fish oil and fish protein with plant prote

<b>Pharmacovigilance and Regulatory Science</b> / 薬剤疫学

The concept of regulatory science (RS) was proposed in 1987 by Dr. Mitsuru Uchiyama. He describes “RS is the science of optimizing scientific and technological developments according to objectives geared toward human health. It is also the science of predictive evaluation. In properly carrying out the mission of regulation, we must engage in appropriate research activities and harmonize technology with society's needs. This can be accomplished only by accurately comprehending and carefully exploiting the characteristics and trends of new technologies, reactions, materials, and substances”. This article describes the development and the present status of RS in Japan, US and EU. FDA (US authority) defines RS as the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products, and considers RS as a useful tool to accelerate the approval of new drugs and their delivery to patients. On the other hand, PMDA (Japanese authority) takes RS as the norms of regulatory activities in assessment and approval of useful drugs to meet the needs of patients. Pharmacovigilance (PV), defined by WHO, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products. PV focuses on safety of drugs and, therefore, can be a part of RS which deals with all aspects of pharmaceutical products including efficacy, safety and quality. The occurrence rate of adverse effects leading to death is revealed quite high by the studies in US and in Japan. Prediction and prevention of adverse effects are urgent matter that RS and PV should deal with.

The Benefit Risk Assessment of Consumption of Marine Species Based on Benefit-Risk Analysis for Foods (BRAFO)-tiered Approach / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To assess the net health effect caused by the consumption of specific marine species based on Benefit-Risk Analysis for Foods (BRAFO)-tiered approach.</p><p><b>METHODS</b>Twenty species were collected from the Zhoushan Archipelago, China. Concentrations of n-3 long-chain polyunsaturated fatty acids, methyl mercury (MeHg), and dioxin-like compounds (DLCs) in the samples were analyzed for benefit risk assessment based on BRAFO-tiered approach.</p><p><b>RESULTS</b>Based on the BRAFO-tiered approach, reference scenario (no intake) and alternative scenario (intake of specific species of 200 g/week) were determined. The exposure to MeHg/DLCs via alternative scenario of all studied species did not exceed provisional tolerable weekly/monthly intake. However, the adult population with high DLCs exposure in China would significantly exceed the upper limit of DLCs via an additional alternative scenario of some species such as Auxis thazard. The results of deterministic computation showed that alternative scenario of all studied species generated clear net beneficial effects on death prevention and child IQ gain.</p><p><b>CONCLUSION</b>The alternative scenario of all studied species could be recommended to population with average DLCs exposure, and the reference scenario of species with relatively high DLCs concentration could be recommended to population exposed to high DLCs.</p>

Benefit-Risk Analysis for Foods (BRAFO)- Executive Project Summary.

BRAFO, Benefit-Risk Analysis for Foods, was a European Commission project funded within Framework Six as a Specific Support Action and coordinated by ILSI Europe. BRAFO developed a tiered methodology for assessing the benefits and risks of foods and food components, utilising a quantitative, common scale for health assessment in higher tiers. A methodology group reviewed and assembled the methodologies available developing a guidance document that describes a tiered (‘stepwise’) approach for performing a risk and benefit assessment of foods. In parallel, three expert groups on natural foods, dietary interventions and heat processing applied the tiered approach to several case studies. Finally a consensus group reported on the implications of the experience gained during the development of the project for the further improvement.