Safety Of Herbal Medicinal Products Research Articles

Inductively Coupled Plasma-Atomic Emission Spectrometry for the Analysis of Heavy Metals and Arsenic in Tinctures

To ensure the safety of herbal medicinal products, particularly in liquid dosage forms, it is necessary to control environmental toxins to acceptable levels. However, there is no methodology for individual elemental impurities in tinctures. The aim of the study was to select sample preparation conditions for quantitative determination of heavy metals and arsenic in tinctures. Materials and methods : the study used tinctures of anomalous peony, motherwort and valerian sampled from pharmacies. Sample preparation involved microwave-assisted digestion of pre-concentrated aliquots. Quantitative determination of 16 elemental impurities (As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Sb, Sr, Ti, V, Zn, Hg) was carried out using inductively coupled plasma–atomic emission spectrometry. Results : according to the study results, quantitative analysis of most elemental impurities requires sample concentration at the preparation step. Due to the method sensitivity, direct quantification of individual elements in a sample is possible only at levels of not less than 0.1 mg/kg. The optimal volume of a tincture for concentration is 25 ml, both in terms of time efficiency and recovery of toxic elements. Conclusions : the proposed procedure showed the possibility of quantification of 16 elemental impurities in the tinctures. The concentrations of heavy metals and arsenic in the tinctures of anomalous peony, motherwort and valerian did not exceed 0.722 mg/kg. Zinc and manganese were the most abundant elemental impurities in the studied samples.

Pharmaco-epidemiological research on herbal medicinal products in the paediatric population: data from the PhytoVIS study

In paediatrics, clinical study data are limited, especially on herbal medicinal products. To address this gap, 2063 datasets from the paediatric population were evaluated in the PhytoVIS data base. By screening for paediatric data, information on indication, gender, treatment, co-medication and tolerability were evaluated. The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety. The perceived effect of the therapy was rated in 84% of the patients as very good or good without adverse events. The data shed light on a still neglected field of phyto-pharmacotherapy by giving information on the use of herbal medicines in an unselected cohort of paediatric patients. The results confirm the good clinical effects and safety of herbal medicinal products in this patient population and show that they are widely used in Germany.What is Known:• In Germany, about 85% of children receive one or more herbal medicinal products per year.• Despite international initiatives to promote clinical research in paediatrics, there are still many gaps of knowledge in the use of drugs in paediatrics.What is New:• The PhytoVIS project evaluated 2063 data sets from the paediatric population using herbal medicinal products.• The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety, and 84% of the patients rated the therapy as very good or good without adverse events.

Silymarin content in Silybum marianum extracts as a biomarker for the quality of commercial tinctures

Silybum marianum (L.) Gaertner (Milk thistle) extracts have been widely used for the treatment of liver pathologies and as a hepatoprotectant against alcohol-induced liver diseases and other harmful drug metabolites or toxins. Silymarin, the active fraction of Silybum marianum tinctures, accounts for 70–80% of the plant's hydro-alcoholic extract and consists of a mixture of flavonolignans and a flavonoid. Silybum marianum tinctures are commonly prescribed by herbal practitioners for the treatment of liver diseases. However, previous studies have showed inconsistency in the therapeutic efficacy of Silybum marianum tinctures, which is believed to have arisen from the content variability of silymarin, resulting from lack of standardized and regulated manufacturing processes. This work was conducted to quantify the silymarin content in commercial Silybum marianum tinctures in order to evaluate their quality. In this study, we report the determination of the total silymarin content in eleven different commercial tinctures retailed in the U.K. using a convenient and accurate HPLC-UV method. The tinctures analyzed differed in the ratio between herb and liquid as well as percentage of ethanol used during the extraction process. Our results showed a direct correlation between the silymarin content in tinctures and the alcohol strength. Following our protocol, silymarin could not be detected in tinctures extracted with 25% ethanol. Effective therapeutic doses were found only in tinctures with a concentration ratio herb to liquid 1:1 (kg/L) and an alcoholic content of 70%. To guarantee quality and safety of herbal medicinal products, legal requirements to produce plant-based products under regulatory frameworks are needed.

Safety of Herbal Medicinal Products: Echinacea and Selected Alkylamides Do Not Induce CYP3A4 mRNA Expression

A major safety concern with the use of herbal medicinal products (HMP) is their interactions with conventional medicines, which are often mediated via the cytochrome P450 (CYP) system. Echinacea is a widely used over-the-counter HMP, with proven immunomodulatory properties. Its increasing use makes research into its safety an urgent concern. Previously, we showed that Echinacea extracts and its alkylamides (thought to be important for Echinacea's immunomodulatory activity) mildly inhibit the enzymatic activity of the main drug metabolising CYP isoforms, but to this date, there is insufficient work on its ability to alter CYP expression levels. We now report for the first time the effect of a commercial Echinacea extract (Echinaforce) and four Echinacea alkylamides on the transcription of the major drug metabolizing enzyme CYP3A4. HepG2 cells were exposed for 96 h to clinically relevant concentrations of Echinaforce (22, 11.6 and 1.16 μg mL−1) or the alkylamides (1.62 and 44 nM). CYP3A4 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). Neither Echinaforce nor the alkylamides produced any significant changes in the steady-state CYP3A4 mRNA levels, under these conditions. In contrast, treatment with 50 μM rifampicin resulted in a 3.8-fold up-regulation over the vehicle control. We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs.

Safety of herbal medicinal products—Regulatory approach

Safety of herbal medicinal products—Regulatory approach

The Development of Herbal Medicinal Products

Physicians are increasingly recommending the use of plant-derived products, partly because of a growing dissatisfaction among consumers with conventional medicines, but also because of the progress made in the chemical, pharmacological and clinical study of herbal medicinal products, the use of innovative galenical forms and the growing importance of self medication. Quality is a key issue in the development of herbal medicinal products that have consistent safety and efficacy, and quality can only be achieved if it is prioritized from the earliest stages of the development process. Problems in the development of herbal remedies include the frequent lack of standardized products (leading to a poor reproducibility of results and lack of batch-to-batch uniformity), a lack of toxicology, pharmacokinetic and pharmacodynamic data, as well as of dose-response and interaction studies. In addition, the placebo effect in trials with herbal remedies is often very high. Research involving herbal medicinal products must progress from the use of traditional evidence and/or open, observational trials to randomized, double-blind, placebo-controlled trials, the ‘gold standard’ of clinical and scientific research. Over time, the development process for herbal medicinal products should become more closely aligned with the development of new chemical entities. Pharmacovigilance is also slowly becoming a standard tool to monitor the safety of herbal medicinal products. Yet we should not discard the legacy of traditional wisdom because ethnopharmacology and knowledge provided by existing clinical trials (be they open, observational studies or small, double-blind investigations) is a source of invaluable insight into the safety and efficacy of herbal remedies. Ideally, a registration dossier for any herbal medicinal product should include both the results of appropriate preclinical and clinical studies, and the wealth of knowledge that has accumulated from the traditional use of the product.

Regulatory Checks Ensuring Safety of Herbal Substances, Herbal Preparations and Herbal Medicinal Products

Global and national markets for medicinal herbs have been growing rapidly and significant economic gains are being realized [1]. As a consequence, the safety and quality of herbal medicines have become increasingly important concerns for Health Authorities including WHO [1]. Safety can be ensured by imposing stringent control on the herbal substances, herbal preparations and herbal medicinal products. This includes practicing of Good Agricultural and Collection Practices (GACP) [1,2] using pesticides to minimum, soil with minimum contamination with heavy metals (arsenic, cadmium, lead and mercury) and minimum microbial contaminants etc. The control on the microbial/fungal contaminants including aflatoxin becomes a critical part of post-harvesting of herbal substances [3–6]. The botanical identification/authentication and control on adulterants, and foreign matter play an equally important role in ensuring the safety of herbal substances. The control on solvents used for making herbal extracts also play a very important role in ensuring safety. Further, the control on residual solvents such as dichloromethane, isopropyl alcohol used as granulating or film coating agent also help to ensure the safety of the herbal medicinal products. The water used in the making of herbal extracts and the herbal medicinal products should be controlled for microbial limits and heavy metals. The individual herbal substances though having been reported safe in reported literature but when used in fixed dose combination needs to be proved to be safe by means of toxicity studies. When assessing safety, documented experience of long-term use without evidence of safety problems should form the basis of risk assessment. If toxicological risk is known, toxicity data must be generated and evidence that it does not occur in therapeutic dose and justification of advantages of the combination with increased efficacy outweighing such disadvantages should be studied [7].

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

In recent years, studies on evaluation of the therapeutic and toxic activity of herbal medicinal products became available and popular. The advances in modern biotechnology have led to discovery of many new active constituents. However, it is a constant challenge to establish the pharmacological basis for efficacy and safety of herbal medicinal products. A better understanding of the effects and bioavailability of phytopharmaceuticals can help in discovering suitable and rational therapies. In this review, we present the bioavailability studies in immune system that has been conducted for some of the more important or widely used phytopharmaceuticals. Furthermore, various new drug targets worthy of using for drug development in immunomodulating herbal medicine area and their regulatory mechanisms are also discussed. Adverse effects, drug interactions, and contraindications are also discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived pharmaceutical components.

European Legislation on Herbal Medicines

Harmonization of the market for herbal medicines is a fundamental requirement for European industries and health professionals and it will also be useful for consumers. Herbal medicines are generally sold as food supplements, but a common regulatory status in the various European countries does not exist. As a consequence, information on clinical indications for use, efficacy and safety are influenced by different opinions, according to the clinical or traditional experience of various folk medicines available in each European country. The European Directive 2004/24/EC released in 2004 by the European Parliament and by the Council of Europe provides the basis for the use of herbal medicines in Europe going forward. The Directive establishes that herbal medicines released in the market need authorization by the national regulatory authorities of each European country and that these products must have a recognized level of safety and efficacy. The safety of herbal medicinal products will be evaluated on the basis of existing scientific literature (data from clinical studies, case reports, pre-clinical studies). When data on safety are not sufficient, it will be communicated to consumers. According to the criteria of safety and efficacy, we will have two kinds of herbal medicinal products in the future: (i) 'well established use herbal medicinal products' (medicinal herbs with a recognized level of safety and efficacy); and (ii) 'traditional use herbal medicinal products'. The later category will include those medicinal herbs that do not have a recognized level of efficacy but are acceptably safe. Even though the fundamental objective of the new European herbal legislation is the harmonization of the market of herbal medicines, important regulations have been introduced, which will contribute to safer use of herbal substances if adopted by the whole of the European community.

The Safety of Herbal Medicinal Products Derived from Echinacea Species

Echinacea spp. are native to North America and were traditionally used by the Indian tribes for a variety of ailments, including mouth sores, colds and snake-bites. The three most commonly used Echinacea spp. are E. angustifolia, E. pallida and E. purpurea. Systematic literature searches were conducted in six electronic databases and the reference lists of all of the papers located were checked for further relevant publications. Information was also sought from the spontaneous reporting programmes of the WHO and national drug safety bodies. Twenty-three manufacturers of echinacea were contacted and asked for data held on file. Finally our own departmental files were searched. No language restrictions were imposed. Combination products and homeopathic preparations were excluded. Data from clinical studies and spontaneous reporting programmes suggest that adverse events with echinacea are not commonly reported. Gastrointestinal upsets and rashes occur most frequently. However, in rare cases, echinacea can be associated with allergic reactions that may be severe. Although there is a large amount of data that investigates the efficacy of echinacea, safety issues and the monitoring of adverse events have not been focused on. Short-term use of echinacea is associated with a relatively good safety profile, with a slight risk of transient, reversible, adverse events. The association of echinacea with allergic reactions is supported by the present evaluation. While these reactions are likely to be rare, patients with allergy or asthma should carefully consider their use of echinacea. The use of echinacea products during pregnancy and lactation would appear to be ill-advised in light of the paucity of data in this area.

The Significance of Quality for Efficacy and Safety of Herbal Medicinal Products

The efficacy and safety of any pharmaceutical product is determined by the compounds (desired and undesired) which it contains. The purpose of quality control is to ensure that each dosage unit of the drug product delivers the same amount of active ingredients and is, as far as possible, free of impurities. As herbal medicinal products are complex mixtures which originate from biological sources, great efforts are necessary to guarantee a constant and adequate quality. By carefully selecting the plant material and a standardized manufacturing process the pattern and concentration of constituents of herbal medicinal products should be kept as constant as possible as this is a prerequisite for reproducible therapeutic results. With the increasing use of herbal products, particularly in the United States, the future worldwide labeling practice for herbal products should adequately address quality aspects.