Status of novel drug delivery technology for phytotherapeutics

Herbal medicines have been widely used all over the world since ancient times and have been recognized by physicians and patients for their better therapeutic value as they have fewer adverse effects as compared with modern medicines. However, phytotherapeutics needs a scientific approach to deliver the components in a sustained manner to increase patient compliance and avoid repeated administration. This can be achieved by designing novel drug delivery systems for herbal constituents. Novel drug delivery systems not only reduce the repeated administration to overcome non-compliance, but also help to increase the therapeutic value by reducing toxicity and increasing the bioavailability, and so on. Recently, pharmaceutical scientists have shifted their focus to designing a drug delivery system for herbal medicines using a scientific approach. For a long time herbal medicines were not considered for development as novel formulations owing to lack of scientific justification and processing difficulties, such as standardization, extraction and identification of individual drug components in complex polyherbal systems. However, modern phytopharmaceutical research solves the scientific needs for herbal medicines as in modern medicine, which gives way for developing novel formulations such as nanoparticles, microemulsions, matrix systems, solid dispersions, liposomes, solid lipid nanoparticles, and so on. This article summarizes various drug delivery technologies for herbal actives, which are gaining more attention for better therapeutic response.     

Metabolic activation in drug-induced liver injury

It is generally believed that metabolic bioactivation of drug molecules to form reactive metabolites, followed by their covalent binding to endogenous macromolecules, is one of the mechanisms that can lead to hepatotoxicity or idiosyncratic adverse drug reactions (IADRs). Although the role of bioactivation in drug-induced liver injury has been reasonably well established and accepted, and methodologies (e.g., structural alerts, reactive metabolite trapping, and covalent binding) continue to emerge in an attempt to detect the occurrence of bioactivation, the challenge remains to accurately predict the likelihood for idiosyncratic liver toxicity. Recent advances in risk-assessment methodologies, such as by the estimate of total body burden of covalent binding or by zone classification, taking the clinical dose into consideration, are positive steps toward improving risk assessment. The ability to better predict the potential of a drug candidate to cause IADRs will further be dependent upon a better understanding of the pathophysiological mechanisms of such reactions. Until a thorough understanding of the relationship between liver toxicity and the formation of reactive metabolites is achieved, it appears, at present, that the most practical strategy in drug discovery and development to reduce the likelihood of idiosyncratic liver toxicity via metabolic activation is to minimize or eliminate the occurrence of bioactivation and, at the same time, to maximize the pharmacological potency (to minimze the clinical dose) of the drug of interest.     

Pharmacology and Toxicology of Herbs

S11StudiesontoxicityofChinesemedicines anddecreasedvirulencethroughthecompatibili tyofherbalingredients LIPeng Tao(CST)(BeijingUniversityofTraditionalChineseMedicine,Beijing100029,China)Beginningfromthereportoftherenalinjuryin ducedbyaristolochicacid,thepoisonoussideeffects ofChinesemedicineshaveattractedmoreandmoreat tentions,whichhaveproducedhugeinfluenceontheprogressoftraditionalChinesemedicines.Itbecomesa vitallyimportantissuetounderstandanduseChinese medicinescorrectly.Thetoxicity…     

Herb-drug interactions: methods to identify potential influence of genetic variations in genes encoding drug metabolizing enzymes and drug transporters

Herbal supplements are often used concomitantly with conventional medications resulting in considerable potential for herb-drug interactions. These interactions, which are generally through interfering with pharmacokinetic and/or pharmacodynamic pathways, may result in beneficial effects or more often adverse reactions such as toxicity or treatment failure and may be influenced by multiple environmental and/or genetic factors. The pharmacogenetic approach may help to identify some interactions which may be more pronounced or only occur in specific groups of subjects although the complex nature of the herbal medicines may limit the discovery of such an interaction. Preclinical studies such as gene expression profiling in rodent liver may help to define metabolic pathways influenced by herbal medicines and facilitate more accurate targeting of human in vivo studies. This review discusses the mechanisms of herb-drugs interaction and the potential influence of genetic variation on herb-drug interactions based on available clinical evidence.     

EMA对草药产品申请上市许可或注册的非临床资料的要求

EMA于2017年8月发布了"公认和传统草药产品申请上市许可或注册的非临床文件的指导原则（草案）"。该指导原则指出传统和公认的草药物质或制剂,在获得人体充分而详实经验的情况下,单次给药和重复给药毒性、毒代动力学研究、免疫毒性以及局部耐受性试验是不必要的;而其生殖毒性、遗传毒性和致癌性,如果发表的文献不能用或不足,附加非临床试验是必要的。详细介绍该指导原则主要内容,以期对拟在欧盟上市的中草药产品有所帮助,也对我国草药监管有所启发。     

Herb-drug interactions: Focus on metabolic enzymes and transporters

As the uses of herbal medicines from traditional natural products are increased, the need for pharmacokinetic studies and relevant data are also increased for safe pharmacotherapy. The market entry for the traditional herbal medicine is easier compared with that for synthetic drugs because of a lower regulatory barrier. Thus, the exact mechanisms for the absorption, distribution, metabolism and excretion of active components in herbal medicines and the potential herb-drug interactions are not always fully understood. Recently, there has been an increasing interest in pharmacokinetic studies of herbal remedies and relevant data of commonly used herbal remedies are accumulating in this field. In this review, the effects of nine botanicals (ginkgo, green tea, grapes, licorice, saw palmetto, garlic milk thistle, ginseng and St. John’s wort) on metabolic enzymes and transporters affecting absorption and disposition of herbal products are summarized. The source of samples (extracts and individual components), the species (human and animal) and in vivo and in vitro systems were separately reviewed for a better understanding of herb-drug interactions.     

Bioactivation of herbal constituents: mechanisms and toxicological relevance

Abstract

The increase in the application of herbal medicines and dietary products over the last decades has been accompanied with a substantial increase in case reports of herb-induced toxicities. Metabolic activation of relatively inert functional groups to chemically reactive metabolites is often considered to be an obligatory event in the etiology of drug-induced adverse reactions. Circumstantial evidence suggests that several herb-induced toxicities are a result of transformation of herbal constituents to electrophilic reactive metabolites that can covalently bind to vital macromolecules in the body, exemplified by aristolochic acids and pyrrolizidine alkaloids. At physiologically relevant concentrations, bioactivation of furanocoumarins and methylenedioxyphenyl compounds leads to mechanism-based inactivation of drug metabolizing enzymes and clinically manifested herb-drug interactions. Of particular interest is that several organic functional groups embedded in herbal constituents act as a toxicophore as well as a pharmacophore, resembling the electrophilic warheads in the development of targeted covalent inhibitors. The aim of this review is to provide a cataloging of bioactivation mechanisms of herbal substructures, structure-activity relationships, biological targets, and assist in circumventing the structural liability in the development of more effective and safer herb-based NCEs.     

生殖毒性试验的质量保证

生殖毒性试验是毒理学试验中最为复杂、繁琐,技术要求最高的试验,在药品非临床研究质量管理规范（GLP）和质量保证（QA）检查方面有其特殊性.现从实验室资质的确认、试验关键阶段的检查、研究资料和报告的审查、特殊评价项目的质量保证和现场检查等5个方面介绍生殖毒性试验质量保证的程序、要求和注意事项.     

Safety concerns of herbal products and traditional Chinese herbal medicines: dehydropyrrolizidine alkaloids and aristolochic acid

In many countries, including the United States, herbal supplements, tisanes and vegetable products, including traditional Chinese medicines, are largely unregulated and their content is not registered, monitored or verified. Consequently, potent plant toxins including dehydropyrrolizidine alkaloids and other potential carcinogens can contaminate these products. As herbal and food supplement producers are left to their own means to determine the safety and purity of their products prior to marketing, disturbingly often good marketing practices currently in place are ignored and content is largely undocumented. Historical examples of poisoning and health issues relating to plant material containing dehydopyrrolizidine alkaloids and aristolochic acids were used as examples to demonstrate the risk and potential toxicity of herbal products, food supplements, or traditional medicines. More work is needed to educate consumers of the potential risk and require the industry to be more responsible to verify the content and insure the safety of their products. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

Drug interactions with herbal medicines

In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John's wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms.     

Evaluation of metabolism-mediated herb-drug interactions

As the use of herbal medicines increases, the public health consequences of drug-herb interactions are becoming more significant. Herbal medicines share the same drug metabolizing enzymes and drug transporters, including cytochrome P450 enzymes (CYPs), glucuronosyltransferases (UGTs), and P-glycoprotein, with several clinically important drugs. Interactions of several commonly used herbal medicines, such as Ginko biloba, milk thistle, and St. John’s wort, with therapeutic drugs including warfarin, midazolam, alprazolam, indinavir, saquinavir, digoxin, nifedipine, cyclosporine, tacrolimus, irinotecan, and imatinib in humans have been reported. Many of these drugs have very narrow therapeutic indices. As the herb-drug interactions can significantly alter pharmacokinetic and pharmacodynamic properties of administered drugs, the drugs interacting with herbal medicines should be identified by appropriate in vitro and in vivo methods. A good understanding of the mechanisms of herb-drug interactions is also essential for assessing and minimizing clinical risks. In vitro methods are useful for providing mechanistic information and evaluating multiple components in herbal medicines. This review describes major factors affecting the metabolism of herbal medicines, mechanisms of herb-drug interactions mediated by CYPs and UGTs, and several in vitro methods to assess the herb-drug interactions. Finally, drug interactions of Ginkgo biloba and St. John’s wort, as representative herbal medicines, are described.     

Drug interactions with herbal medicines

The use of herbal medicines (HM) is on the rise among the global population. Although the safety profile of many herbal medicines is promising, accumulated data show evidence of significant interactions with medications, which can place individual patients at great risk. A range of electronic databases have been reviewed for articles published in this field: Medline, Allied and Complementary Medicine Database, HealthSTAR, AMBASE, CINHAL, Cochrane Library, as well as Internet documents and manually searched references in medical journals. In this review, we examined the literature from 1966 to 2006 and focused on the importance of the risk of drug interactions and potential side effects when HM are involved. We discuss these in light of the documented findings. A review of the problematic issues is given and recommendations are made in order to encourage the setting up of clinical trials on HM and herb-drug interactions.     

ADME properties of herbal medicines in humans: evidence, challenges and strategies

Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are generally not needed for herbal remedy discovery and development. For the majority of herbal medicines, data on their ADME and pharmacokinetic properties in humans are lacking or scant. An extensive literature search indicates that there are limited data on ADME properties of herbal medicines in humans. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp/MDR1/ABCB1) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are critical determining factors for the in vivo ADME processes of herbal remedies. There are increasing ADME studies of herbal remedies, but these studies are mainly focused on a small number of herbal medicines including St John's wort, milk thistle, curcumin, echinacea, ginseng, ginkgo, and ginger. For an herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and ADME processes of active herbal components in the body govern their target-site concentrations and thus the therapeutic responses. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their ADME profiles. To optimize the use of herbal remedies, further studies to explore their ADME properties in humans are certainly warranted.     

In vitro anti-microbial and in vivo cytokine modulating effects of different prepared Chinese herbal medicines

The toxicity, antimicrobial and cytokine modulating effects of herbal medicines in treating periodontal diseases were evaluated in this study. Using the broth dilution method and disc agar diffusion test, in individual and combined decocted preparations, different concentrations of Ching–Wei–San and its individual herbal components, Coptidis rhizoma, Angelicae sinensis radix, Rehmanniae radixet rhizom, Moutan radicis cortex, and Cimicifuga foetida, were tested for in vitro inhibitory effects on three well-known plaque-causing bacteria, Porphyromonas gingivialis, Streptococcus sanguis, and Streptococcus mutans, and two common pathogens, Staphylococcus aureus and Escherichia coli. The cytokine modulating effects were evaluated in Balb/c mice. The results suggested that one milliliter Ching–Wei–San at the 25,000 mg/mL concentration daily for the mice had significantly high levels in the liver function indexes in the 3-day acute toxicity test and in both the liver and kidney function indexes in the 28-day subacute toxicity test (P < 0.01). The 250 mg/mL Ching–Wei–San is comparable to 250 mg/mL of tetracycline, and had similar inhibitory effects on the tested bacteria. Coptidis rhizoma (62.5 mg/mL) was the only individual herbal component to show 100% inhibitory effects. The mean cytokine ratios of IL-2, IL-4, IFN-γ, and TNF- in Balb/c mice treated with individual herbal components were shown to be different from each other. Ching–Wei–San modulated the immunity of mice, up-regulated IL-2, IL-4 and TNF-, but down-regulated IFN-γ. The effects of none of the individual herbal components alone can substitute for the cumulative effect of Ching–Wei–San.     

Active phytochemicals from Chinese herbs as therapeutic agents for the heart

Naturally occurring plant alkaloids, in particular those identified from herbal medicines, are finding therapeutic use. Heart diseases can be well managed with specific formulations of herbal medicines. The combined action of multiple constituents of herbal medicines works with therapeutic benefits in humans. The established formulations of Traditional Chinese medicines show efficacy in treatment of diseases. However, individual herbal principles seldom show pharmacological activity. Nevertheless, some of the active alkaloids and terpenoids from medicinal herbs have been identified. The pharmacological activities of these herbal compounds have been studied. These active constituents of herbal medicine are also used in nutrient supplements, but the modes of action of the active component remain sketchy. The present review describes the recent development of those active principles from herbal medicines as cardiovascular agents. The study will provide insights into herbal medicines for drug development for the treatment of cardiovascular disease.     

黄芩苷化合物现代常用测定方法的分析比较

黄芩的主要有效成分黄芩苷具有抗菌消炎、解热镇痛、抗病毒、抗肿瘤、降压及利尿等作用。黄芩苷是许多复方中药制剂的主要成分,而中药成分复杂,对分析技术也有特定的要求。本文对黄芩苷测定技术分光光度法、色谱法、红外光谱分析法等进行了综述。     

A decades-long investigation of acute metabolism-based hepatotoxicity by herbal constituents: a case study of pennyroyal oil

Abstract

Herbal supplements are often regarded as “natural”, and are, therefore, considered by many to be safer than pharmaceuticals; however, the adverse effects of these supplements are under-reported in many cases. Many herbal supplements, such as pyrrolizidine alkaloids, kava, chaparral and germander, are known to induce liver injury, which, in general, is one of the main toxicity liabilities observed in the clinic and accounts for about half of total liver failures. One example is the hepatotoxicity of pennyroyal oil, which is ingested as an abortifacient, among other uses. For three decades, the late Professor Sidney Nelson contributed to our understanding of the mechanism of toxicity of pennyroyal and broadened our understanding of chemical toxicology. Here we present the studies and review the findings on acute hepatotoxicity of pennyroyal oil. These studies involved the isolation and characterization of pennyroyal components, determination of the appropriate animal models, identification of the structural requirement for toxicity and determination of the target enzymes and the enzymes involved in the process of bioactivation. Studies with stable isotope labeled pennyroyal metabolites, pulegone and menthofuran, furthered our understanding of the role of cytochrome P450 in the oxidation of these compounds. This review presents the investigational tools used in the study of pennyroyal oil, allowing the reader to not only appreciate these methods but also utilize them to tackle and better understand metabolism-based toxicity in their own projects.     

The year's new drugs and biologics--2006

This annual series presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2006, 41 new medicines--this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents and, for the first time this year, an important new herbal medicine--reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006. This year's edition of the article also includes several new features: a deeper insight into the five first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines; and an analysis of the market for these new medicines. New generic drug approvals are also reviewed, as well as a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future.