Plant-derived medicines: a novel class of immunological adjuvants

Plant-derived medicines have a long history of use for the prevention and treatment of human disease. Today, many pharmaceuticals currently approved by the Food and Drug Administration (FDA) have origins to plant sources. A major role for plant-derived compounds based on the reported immunomodulatory effects has emerged in recent times and has led to the rigorous scientific examination to determine efficacy and safety. The discovery of novel plant compounds with immune system modulating activities has become an increasingly important area of research, particularly in the search for new-generation vaccine adjuvants. This review discusses the important role of plant-derived medicines as immunomodulators and provides evidence in support of the continued investigation of this new class of drugs for the maintenance of human health. The identification and characterization of plant compounds that augment new or existing vaccines, and in particular mucosally administered vaccines, will be of significant interest to vaccinologists and immunologists.     

Transgenic plants in the biopharmaceutical market

Many of our 'small-molecule-drugs' are natural products from plants, or are synthetic compounds based on molecules found naturally in plants. However, the vast majority of the protein therapeutics (or biopharmaceuticals) we use are from animal or human sources, and are produced commercially in microbial or mammalian bioreactor systems. Over the last few years, it has become clear that plants have great potential for the production of human proteins and other protein-based therapeutic entities. Plants offer the prospect of inexpensive biopharmaceutical production without sacrificing product quality or safety, and following the success of several plant-derived technical proteins, the first therapeutic products are now approaching the market. In this review, the different plant-based production systems are discussed and the merits of transgenic plants are evaluated compared with other platforms. A detailed discussion is provided of the development issues that remain to be addressed before plants become an acceptable mainstream production technology. The many different proteins that have already been produced using plants are described, and a sketch of the current market and the activities of the key players is provided. Despite the currently unclear regulatory framework and general industry inertia, the benefits of plant-derived pharmaceuticals are now bringing the prospect of inexpensive veterinary and human medicines closer than ever before.     

Transgenic plants in the biopharmaceutical market

Many of our ‘small-molecule-drugs’ are natural products from plants, or are synthetic compounds based on molecules found naturally in plants. However, the vast majority of the protein therapeutics (or biopharmaceuticals) we use are from animal or human sources, and are produced commercially in microbial or mammalian bioreactor systems. Over the last few years, it has become clear that plants have great potential for the production of human proteins and other protein-based therapeutic entities. Plants offer the prospect of inexpensive biopharmaceutical production without sacrificing product quality or safety, and following the success of several plant-derived technical proteins, the first therapeutic products are now approaching the market. In this review, the different plant-based production systems are discussed and the merits of transgenic plants are evaluated compared with other platforms. A detailed discussion is provided of the development issues that remain to be addressed before plants become an acceptable mainstream production technology. The many different proteins that have already been produced using plants are described, and a sketch of the current market and the activities of the key players is provided. Despite the currently unclear regulatory framework and general industry inertia, the benefits of plant-derived pharmaceuticals are now bringing the prospect of inexpensive veterinary and human medicines closer than ever before.     

Pyrrolizidine alkaloids in plants used in the traditional medicine of Madagascar and the Mascarene islands

Pyrrolizidine alkaloids (PAs) can be hazardous to the health of humans and animals. Although their toxicity has been known for a long time, PA containing plants are still in use in many traditional medicines. Traditional healing systems have become of increasing interest as many people believe that they can be used without any risk and side effects. This also applies to the traditional medicine of Madagascar and the Mascarene island (Mauritius, Reunion, Rodriguez). Recent literature reports have recommended this traditional medicine because of its good efficacy and pharmacological properties. However, several plants are listed there which have already been described to contain toxic PAs or are suspected of containing them.     

Plant secondary metabolites in cancer chemotherapy: where are we?

Nowadays we have a number of chemical and biological agents at our disposal to treat chronic pathologies such as cancer. Although most drugs display significant activity, thus improving the clinical outcome, side-effects and emergence of resistances cannot be looked down. From an historical point of view, higher plants have been very important in the search of new therapeutic agents and they were in the origin of the first medicines used in human health. The contribute of plants to treat pathologies such as cancer is far from being over, mainly due to the high number of new drugs that are currently being evaluated in clinical trials. Metabolomics-based studies have rendered several new chemical entities, some of them with remarkable complex chemistry, which sometimes results in novel mechanisms of action, higher potency and lower toxicity. In this review, we will focus the most important plant-derived classes of compounds in clinical use, as well as those currently in clinical trials, with special focus on vinca alkaloids, taxanes, combretastatins, podophylotoxins and camptothecins. The molecular mechanism of action and spectrum of activity will also be discussed.     

The One Health Perspective in Trace Elements Biomonitoring

Health risks in both animals and humans are associated with chronic exposures to levels of trace elements (TE) eliciting toxic and/or antinutritional effects, including excess exposures to some essential elements. Interferences with essential TE may also lead to secondary nutritional deficiencies and/or imbalances. Although research is still required, biomarkers of exposure, including bioavailability, for TE are established tools for human biomonitoring that can also be applied to animal surveillance. Biomarkers of effect as well as, where available, of susceptibility and bioavailability are necessary to understand whether an ongoing exposure may pose a current or future health concern. In the field of animal health the use of biomarkers is less developed and less widespread than in human health; however, under a One Health perspective, animal biomonitoring can provide important information on the interfaces among humans, animals, and the environment, supporting the prevention and management of health risks. Therefore, a transfer of knowledge from human biomonitoring to farm or free-ranging animals is critical in a risk assessment framework from farm to humans. Advantages and critical aspects in designing and conducting integrative biomonitoring activities in humans and animals were critically reviewed focusing on biomarkers of exposure, effect, susceptibility, and bioavailability for toxic and essential TE. Highlighted aspects include TE metabolism, bioaccessibility, and interactions. Farm or free-ranging animals may provide noninvasive matrices suitable for evaluating animal welfare, environmental stressors, food safety, and potential risks for human health, as proposed by the interdisciplinary concept of One Health.     

Natural products from plants as drug candidates and lead compounds against leishmaniasis and trypanosomiasis

Millions of people in the developing world are affected by diseases caused by the kinetoplastid parasites: the leishmaniases, African trypanosomiasis, and Chagas disease. In many cases the drugs employed for treatment are toxic, marginally effective, given by injection, and/or compromised by the development of resistance. Since safe, effective, and affordable chemotherapeutic agents for leishmaniasis and trypanosomiasis are clearly needed, the identification of new antikinetoplastid drug candidates should be an urgent priority. Numerous plant-derived natural products from different structural classes have been investigated as antileishmanial and antitrypanosomal candidates, including various alkaloids, terpenoids, flavonoids, and quinonoids. This review outlines the antikinetoplastid activities of plant-derived natural products reported in the literature and also provides an overview of mechanistic studies that have been conducted with these compounds. Given the activities of these agents and their diverse range of effects on parasite biology, natural products are a potentially rich source of drug candidates and leads against leishmaniasis and trypanosomiasis.     

Adverse drug reactions for medicine newly approved in Japan from 1999 to 2013: Syncope/loss of consciousness and seizures/convulsions

Many approved medicines are used with their adverse drug reactions (ADRs) appropriately managed in the clinical setting based on their risks and benefits. In this survey, the correlation between human ADR (specifically syncope/loss of consciousness and seizures/convulsions) and safety signals reported in animal studies has been investigated for 393 Japanese medicines which were approved between September 1999 and March 2013. Clinically important drug-induced ADR, syncope/loss of consciousness and seizures/convulsions are reported in this paper. Of 393 medicines, 101 (25.7%) showed syncope/loss of consciousness and 105 (26.7%) showed seizures/convulsions. Syncope/loss of consciousness and seizures/convulsions were reported for many medicines affecting the central nervous system. The animal toxicity concordance ratio with syncope/loss of consciousness and seizures/convulsions was 4.0% (4/101) and 23.8% (25/105), respectively. The underlying cases of syncope/loss of consciousness attributed to hypotension, arrhythmia, hypoglycemia or acute toxic reaction was 16.8%, 5.0%, 4.0% or 4.0%, respectively. Mechanism of seizures/convulsions for the remaining 101 medicines was not identified except for four local anesthetics. This survey suggested that the careful attention to and understanding of medicine profiles is necessary for the appropriate use of recently approved medicines in Japan.     

欧洲药品局对在第三国进行临床试验的伦理和GCP问题的考虑

众所周知,欧洲药品管理局(EMA)是欧盟的一个非集权实体,主要职责是通过审评和监督人用药品和兽用药品保护并促进公众和动物健康。欧洲药品管理局负责对药品的欧洲上市许可申请(集中程序)进行技术审评。对来源于欧盟以外的临床研究数据,如何保证受试者的合法权益,保证临床研究符合伦理和GCP的要求,成为欧洲药品局关注的一个问题。2009年,EMA起草了"对在第三国进行的人用药品临床试验中以及向欧洲药品管理局递交的上市许可申请中的伦理和GCP草案"并广泛征求意见,2010年9月在伦敦召开会议对草案进行了讨论。本文主要介绍该草案的基本情况以及会议讨论要点。     

Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment.

Sanguinaria canadesis, Chelidonium majus and Macleya cordata have been used for centuries as alternative medicines. Currently the extracts from these medicinal plants are components of veterinary and human phytopreparations, and of oral-hygiene agents. Sanguinarine and chelerythrine (SA/CHE) are biologically active components of these extracts. They display distinct antibacterial and anti-inflammatory properties, but, on the other hand, they have been reported as having adverse effects - genotoxicity and hepatotoxicity. This paper is aimed at evaluation of the effects of daily administration of the extract from Macleya cordata (2 mg and 100 mg in 1 kg feed, sanguinarine:chelerythrine 3:1) in the diet on the health status of swine. After 90-day administration, alkaloids were retained to a different extent in tissues. The highest SA/CHE retention was detected in the gingiva (0.55 microg/g) and liver (0.15 microg/g), no SA/CHE were detected in muscles. Plasma SA levels attained 0.11 microg/ml. Treated animals did not display any results of hematological, biochemical or histological assay different from controls. A (32)P-postlabeling assay proved that no DNA-adducts with SA/CHE were detected in pig livers. We did not observe any symptom linked to epidemic dropsy syndrome often attributed to sanguinarine. In conclusion, an average daily oral dose of alkaloids up to 5 mg per 1 kg animal body weight proved to be safe.     

Adverse Drug Reactions for Medicines Newly Approved in Japan from 1999 to 2013: Hypertension and Hypotension

In this survey, the correlation between adverse drug reactions (ADRs) in human and animal toxicities was investigated for 393 medicines which were approved in Japan from September 1999 to March 2013. ADRs were collected from each Japanese package insert. Comparable animal toxicities with ADRs were collected by thorough investigation of common technical documents. The results of this survey show that hypertension and/or hypotension were mainly observed in medicines affecting the central nervous system. Hypertension was also observed in antipyretics, analgesics, anti‐inflammatory agents, vasoconstrictors and agents using antibody. Concordance between human ADRs and animal toxicities was analysed. True‐positive rate for hypertension and hypotension is 0.29 and 0.52, respectively. Positive likelihood ratio and inverse negative likelihood ratio are 1.98 and 1.21, respectively, in hypertension and 1.67 and 1.44, respectively, in hypotension. Concordance between human ADRs and animal toxicities is not so high in hypertension and hypotension. Identified mechanisms as on‐target for hypertension and hypotension are 29.8% and 30.5%, respectively. More than half of the causative factors of hypertension and hypotension were unable to be elucidated. Our results show that the intake of medicines is often linked to blood pressure variations that are not predicted in animal toxicity studies. Improvement of drug development processes may be necessary to provide safer medicines because current animal toxicity studies are insufficient to predict all ADRs in human beings.     

红火蚁毒素物质基础研究进展

红火蚁是一种对农业、生态、环境和人类健康造成严重危害的入侵性害虫。红火蚁主要利用螯针中的毒液攻击人类，对红火蚁毒液过敏的患者会出现全身性过敏反应，甚至出现过敏性休克，危及患者生命。国内外的科研人员对红火蚁毒液中的物质成分进行了大量细致的研究，红火蚁毒液主要组成成分包括水、生物碱和少量的蛋白，生物碱是造成灼烧感和水泡的主要原因，过敏反应则是由毒液中的蛋白质或多肽类物质造成的。本文综述了目前对红火蚁毒液中毒素物质的研究进展以及各组分的作用和功能。     

Hypotensive natural products: current status

Hypertension is a common and progressive disorder that possesses a major risk for cardiovascular and renal disease. Recent data have revealed that the global burden of hypertension is an important and increasing public health problem worldwide and that the level of awareness, treatment and control of hypertension varies considerably among countries. Hypertension is often called a 'silent killer' because persons with this pathological condition can be asymptomatic for years and then have a fatal heart attack or stroke. The field of naturally occurring antihypertensive agent is a research area rapidly expanding due to the high potential of such molecules as new antihypertensive drugs. Recently, a great number of plant-derived substances have been evaluated as possible antihypertensive agents through different mechanisms of action such as alkaloids, flavonoids and terpenoids. In this mini-review we will discuss the medicinal chemistry of these compounds.     

An overview of mycotoxin contamination in foods and its implications for human health

Mycotoxins are natural contaminants of cereals and other food commodities throughout the world and they significantly impact human and animal health. Mycotoxins are toxic secondary metabolites produced by species of filamentous fungi growing on grains before harvest and in storage. When ingested, inhaled, or absorbed through skin, mycotoxins may reduce appetite and general performance, and cause sickness or death in humans. Mycotoxins subject to government regulation in most countries include aflatoxins, fumonisins, ochratoxins, deoxynivalenol, zearalenone, and patulin, produced by species of Aspergillus, Fusarium, and Penicillium. Aflatoxins, fumonisins, and ochratoxins pose the most serious threats to human health worldwide. This review describes the prevalence of mycotoxins in foods and its implications on human health, which may help in establishing and carrying out proper management strategies. Data from detailed investigations of food mycotoxins worldwide help provide safer food for consumption and help prioritize future research programs.     

Control of ochratoxin A production in grapes

Ochratoxin A (OTA) is a mycotoxin commonly present in cereals, grapes, coffee, spices, and cocoa. Even though the main objective of the food and feed chain processors and distributors is to avoid the extended contamination of plant-derived foods and animal feeds with mycotoxins, until now, complete OTA removal from foods and feedstuffs is not feasible. Prevention through pre-harvest management is the best method for controlling mycotoxin contamination. However, in the case that the contamination occurs after this stage, the hazards associated with OTA must be managed through post-harvest strategies. Due to the increasing number of fungal strains resistant to chemical fungicides and the impact of these pesticides on the environment and human health, maximum levels of chemical residues have been regulated in many products. Alternative methods are necessary to substitute or complement treatments with fungicides to control fungi under field or storage conditions. Yeasts are considered one of the most potent biocontrol agents due to their biology and non-toxic properties. Epiphytic yeasts are the major component of the microbial community on the surface of grape berries and they are evolutionarily adapted to this ecological niche. Nowadays, several yeast species included in different genera are considered as potential biocontrol agents to control both, growth of ochratoxigenic Aspergillus species and OTA accumulation.     

Analysis of Ergot Alkaloids

The principles and application of established and newer methods for the quantitative and semi-quantitative determination of ergot alkaloids in food, feed, plant materials and animal tissues are reviewed. The techniques of sampling, extraction, clean-up, detection, quantification and validation are described. The major procedures for ergot alkaloid analysis comprise liquid chromatography with tandem mass spectrometry (LC-MS/MS) and liquid chromatography with fluorescence detection (LC-FLD). Other methods based on immunoassays are under development and variations of these and minor techniques are available for specific purposes.     

Taxines: a review of the mechanism and toxicity of yew (Taxus spp.) alkaloids.

This literature review summarizes relevant information and recent progress regarding the scientific investigations of taxine alkaloids. Taxines are the active, poisonous constituents in yew plants (Taxus spp.) and have been implicated in animal and human poisonings. Several taxine alkaloids have been isolated and characterized through the use of high performance liquid chromatography, mass spectroscopy, and nuclear magnetic resonance. Recently, as a result of electrophysiological investigations, significant progress has been made with regard to their pharmacological and toxicological mechanisms of action. Current investigations suggest that their chief action is on cardiac myocytes resulting in heart failure and death in instances of animal and human poisoning.     

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.