The Therapeutic Potential of the Essential Oil of Thymbra capitata (L.) Cav., Origanum dictamnus L. and Salvia fruticosa Mill. And a Case of Plant-Based Pharmaceutical Development.

This review performs a comprehensive assessment of the therapeutic potential of three native herbs of Crete (Thymbra capitata (L.) Cav., Salvia fruticosa Mill. and Origanum dictamnus L.), their phytochemical constituents, health benefits and issues relevant to their safety, within a translational context. Issues discussed comprise: 1) Ethnopharmacological uses of the three herbs, reviewed through an extensive search of the literature; 2) Systematic analysis of the major phytochemical constituents of each plant, and their medicinal properties; 3) To what extent could the existing medicinal properties be combined and produce an additive or synergistic effect; 4) Possible safety issues. We conclude with a specific example of the use of a combination of the essential oils of these plants as an effective anti-viral product and the experience gained in a case of a plant-based pharmaceutical development, by presenting the major steps and the continuum of the translational chain.

Nutraceuticals' Novel Formulations: The Good, the Bad, the Unknown and Patents Involved.

Traditional nutraceuticals and cosmeceuticals hold pragmatic nature with respect to their definitions, claims, purposes and marketing strategies. Their definitions are not well established worldwide. They also have different regulatory definitions and registration regulatory processes in different parts of the world. Global prevalence of nutraceuticals and cosmeceuticals is noticeably high with large market share with minimal regulation compared to traditional drugs. The global market is flooded with nutraceuticals and cosmeceuticals claiming to be of natural origin and sold with a therapeutic claim by major online retail stores such as Amazon and eBay. Apart from the traditional formulations, many manufacturers and researchers use novel formulation technologies in nutraceutical and cosmeceutical formulations for different reasons and objectives. Manufacturers tend to differentiate their products with novel formulations to increase market appeal and sales. On the other hand, researchers use novel strategies to enhance nutraceuticals and cosmeceuticals activity and safety. The objective of this review is to assess the current patents and research adopting novel formulation strategies in nutraceuticals and cosmeceuticals. Patents and research papers investigating nutraceutical and cosmeceutical novel formulations were surveyed for the past 15 years. Various nanosystems and advanced biotechnology systems have been introduced to improve the therapeutic efficacy, safety and market appeal of nutraceuticals and cosmeceuticals, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of nutraceuticals and cosmeceuticals current technologies, highlighting their pros, cons, misconceptions, regulatory definitions and market. This review also aims in separating the science from fiction in the nutraceuticals and cosmeceuticals development, research and marketing.

Ragweed allergy immunotherapy tablet MK-3641 (Ragwitek®) for the treatment of allergic rhinitis.

INTRODUCTION: Allergic rhinitis (AR) is among the most common chronic conditions affecting both children and adults. It is the cause of significant morbidity from the symptoms and interference with sleep. It results in major impairment of performance both at school and at work. In the U.S. and certain parts of Europe, ragweed pollen is a major cause of seasonal AR. In 2014, the U.S. Food and Drug Administration (FDA) approved a sublingual ragweed tablet (MK-3641) for use in adults with ragweed-induced AR. Areas covered: This paper will review the impact of ragweed-induced AR and available treatments including subcutaneous immunotherapy and studies with MK-3641. The principal search method was PubMed. Expert commentary: One dosing finding, two 28-day safety and two 52-week safety and efficacy studies have been conducted with MK-3641. The 12-U (12µg Amb a 1) tablet was the most effective. Local application site reactions were common but usually not serious. Only one, non-serious systemic reaction was reported in four safety studies. MK-3641 is a safe and effective treatment for ragweed-pollen-induced AR when treatment is initiated ≥ 12 weeks prior to the onset of the ragweed pollen season.

The Brazilian market of herbal medicinal products and the impacts of the new legislation on traditional medicines.

ETHNOPHARMACOLOGICAL RELEVANCE: the herbal medicinal products (HMP) market is expanding in the world, an expansion that has not occurred in Brazil when considering the number of licensed products. Despite being a megadiverse country, the number of HMP licensed in Brazil is small, and the number of HMP obtained from native species is even smaller. A new legislation for herbal products licensing, which divides the products into two categories, Herbal Medicine (HM) and Traditional Herbal Product (THP) was launched in Brazil focusing on traditional use, as well as a law regulating the use of biodiversity and traditional knowledge. AIM OF THE STUDY: to evaluate the situation of HMP licensed in Brazil and to make a comparison with the data obtained in 2008 and 2011, discussing the evolution of the licensed products and the possible impacts of the new legislation. MATERIALS AND METHODS: a survey was carried out in the Brazilian Health Regulatory Agency (Anvisa) database to verify the HMP licensed in Brazil in September 2016. The data obtained were compared with two surveys previously published. RESULTS: There are 332 single, and 27 combined HM, totaling 359 HM licensed in Brazil. There is no THP notified in Anvisa's system yet. There are 214 HM classified as nonprescription (OTC), while 145 are sold under prescription, one of them with prescription retention. There are 101 plant species licensed as active in HM in Brazil, 39 of which are native, adapted or cultivated. The most licensed plant species is Mikania glomerata Spreng., with 25 HM licensed. The article includes tables with plant species that have derivatives licensed as simple and combined HM, their therapeutic classification, the native plant species indication and the distribution of the companies by Brazilian regions. CONCLUSIONS: There are few licensed HM in Brazil, and this number has been decreasing in recent years. It is expected that the data obtained, together with the changes promoted in sanitary and environmental rules, will help to develop and regulate HMP chain in Brazil.

Regulatory Forum.

Revision of the International Council for Harmonization (ICH) S1 guidance for rat carcinogenicity studies to be more selective of compounds requiring a 2-year rat carcinogenicity study has been proposed following extensive evaluation of rat carcinogenicity and chronic toxicity studies by industry and drug regulatory authorities. To inform the ICH S1 expert working group in their potential revision of ICH S1, a prospective evaluation study was initiated in 2013, in which sponsors would assess the pharmacologic and toxicologic findings present in the chronic toxicity studies and predict a positive or negative carcinogenicity outcome using a weight of evidence argument (a carcinogenicity assessment document [CAD]). The Scientific and Regulatory Policy Committee was asked by the Society of Toxicology Pathology (STP) executive committee to track these changes with ICH S1 and inform the STP membership of status changes. This commentary is intended to provide a brief summary of recent changes to the CAD guidance and highlight the importance of STP membership participation in the process of CAD submissions.

Perception and understanding of health claims on milk powder for children: A focus group study among mothers in Indonesia, Singapore and Thailand.

Health claim regulations and guidelines on food products have been established in some Southeast Asia (SEA) countries. Health claims on food products aim to help consumers make informed food choices to achieve a healthy diet. This study aimed to investigate the perception and understanding of health claims and the associated regulatory frameworks of SEA mothers using semi-structured focus groups conducted in Indonesia, Singapore and Thailand. Milk powder for children for three years and above was used as product focus. The mothers recognised and recalled some specific nutrients and food constituents by name but lacked full understanding of their function. The findings indicated that the mothers in all three countries trusted health claims made on the products which was, in part, explained by their trust in their governments and the international brand manufacturers. Their understanding of health claims was influenced by several factors such as their familiarity of the nutrient, previous knowledge of the nutrients, the perceived relevance of the nutrient, the use of scientific terms, the choice of words, and also the phrasing and length of the claims. Consumer education efforts via Public, Private Partnerships could be an approach to educate SEA consumers and help them to better understand health claims. The findings of this study may be relevant to different stakeholders such as local regulatory bodies, policy makers, food industry, academia and non-profit organisations that aim to effectively communicate health claims.

From medical tradition to traditional medicine: A Tibetan formula in the European framework.

ETHNOPHARMACOLOGICAL RELEVANCE: The increasing prevalence of complex multi-factorial chronic diseases and multimorbidity reveals the need for an enlargement of the therapeutic options. Potent multicompound herbal formulations from traditional medicine systems such as Tibetan Medicine might meet the requirements. With its practice over the centuries Tibetan Medicine is one of the important medical heritages of the world. In the 20th century Tibetan formulas came to Switzerland, where the formula Gabur-25 was then registered as medicine in 1977 (Padma 28, Swissmedic No 35872). The new European directive 2004/24/EC opened the avenue for traditional herbal medicinal products and registrations followed in Austria (HERB-00037) and the UK (39568/0001). The aim of this review was to analyse not only the critical points and hazards but also chances that occur in the endeavour of bringing a ethnopharmacological based preparation to the market within a modern Western medical and regulatory framework and to discuss the necessary transformation steps from a traditional herbal formula towards a modern pharmaceutical product with the example of the Tibetan formula Gabur-25. METHODS: The historic transformation process from the 19th to the 21st century is analysed, using the registration documents and other material from the library of Padma AG, Hinwil, Switzerland. RESULTS: The transformation of a traditional formula into a modern traditional herbal medicinal product according to the present EU regulations is a multi faceted process. The modern indication represents only a small part of the possible traditional indications. Quality and product labelling has to be adopted to modern standards. The formula, once registered, is a fixed combination of herbal and mineral ingredients. Contrary to this the concept of Asian medical tradition allows a certain flexibility in the composition of an herbal formula. The ingredients are constantly adapted to local conditions, availability of raw material and therapeutic situation. CONCLUSIONS: The example shows that in principle complex herbal formulas from Asian medicine can meet the requirements of the European regime of traditional herbal medicinal products. A structured process of transformation from a traditional herbal formula to a modern medicinal product has to include selection of a suitable formula, development of an analytic concept and selection of a suitable indication with regard to the empirical set of possible indications. To extend the range of high quality medicinal products from other medical traditions within the European context the European legislators have to re-evaluate the imposed restrictions given in directive 2004/24/EC. Without amendment of the prerequisite of 15 years documented use in the EU and the limitation of indications for traditional herbal medicinal products, European citizens will be excluded from access to high quality medical traditions with their accumulated empirical knowledge.

Quality standards of the European Pharmacopoeia.

ETHNOPHARMACOLOGICAL RELEVANCE: The European Pharmacopoeia (Ph. Eur.) provides a legal and scientific reference for the quality control of medicines. It is legally binding in the 38 signatory parties of the Convention on the elaboration of a European Pharmacopoeia (37 member states and the European Union). MATERIALS AND METHODS: The requirements for a specific herbal drug are prescribed in the corresponding individual monograph and the relevant general monographs. Criteria for pesticides and heavy metals for example are defined in the general monograph on Herbal drugs. The Ph. Eur. also provides general methods including methods for determination of aflatoxins B1 and ochratoxin A. Screening methods for aristolochic acids are applied for herbal drugs that may be subject to adulteration or substitution with plant material containing aristolochic acids. CONCLUSION: The Ph. Eur. collaborate in many areas with the European Medicines Agency (EMA) to ensure close collaboration as regards the respective work programmes and approach.

The role of the pathologist in GLP studies.

This continuing education course presented at the Society of Toxicologic Pathology's 31st Annual Symposium explored and defined the many roles that toxicologic pathologists serve Good Laboratory Practice (GLP)-conducted toxicology and carcinogenicity studies.

Regulatory forum opinion piece: Clarification and simplification of the pathology peer review documentation process.

The transparency and documentation of the peer review process have been discussed recently. Our position is that transparency is best achieved when peer review is a collaborative process, in which both parties are open-minded but both also realize that the study pathologist retains complete control over the findings (raw data) and over the content of the pathology report. For these reasons, we believe that histopathology raw data should be defined as the observations made by the study pathologist (printed and/or electronic formats) rather than as the tissue slides recommended by the Organisation for Economic Co-operation and Development (OECD). Also, because the study pathologist retains control over the histopathology raw data, any notes or tabulations of findings by the study pathologist and peer review pathologist during the peer review are interim notes and should not be included as an appendix to the pathology report though they may be retained if desired, as currently recommended. Because the histopathology raw data have not been created until completion of the peer review, the performance of a peer review should be documented in the study report, as currently recommended, but that it not be a GLP-compliant process.

Role of the study pathologist.

Toxicologic pathology relies on many disciplines of toxicology and basic sciences and often requires other fields and skills such as biostatistics, study design, guidelines, and knowledge of Good Laboratory Practices (GLP) regulations. Pathology is an integrative discipline where specific training and experience are required in order to integrate chemical or biological structures, molecular biology, physiology, and morphology for candidate selection and early development of a test article and to help in the design of appropriate preclinical/toxicology studies. Experience does matter and successful learning is determined by personal behavior; pathologists who not only read slides but research their topics and keep current with the literature are apt to be successful.

Pathology working groups.

Pathology Working Groups (PWG) are a specialized form of review consisting of a panel of expert pathologists who provide an independent, unbiased assessment of specific questions concerning study results. PWGs may concentrate on pivotal studies with controversial end points, address questions that are of concern to a regulatory agency, or compare the results of multiple studies that may have been conducted and evaluated by different laboratories and/or pathologists. The PWG does not review the entire study but always includes a preliminary review by a peer review pathologist. The PWG chairperson needs to thoroughly understand the issue in question, reviews all relevant data and study results, and is responsible for the organization and conduct of the PWG. The members of the PWG examine coded slides without knowledge of treatment group or previous diagnosis and arrive at a consensus diagnosis by majority vote. Once the results are decoded, the PWG evaluates the results and provides discussion and conclusions that are reflected in the final PWG report. Specific examples of PWG issues are provided.

The study pathologist's role in GLP studies: a regulator's perspective.

Results of early nonclinical "General Toxicology" studies are used to set a safe starting dose for first-in-human (FIH) clinical trials. In FIH trials, the research subjects are typically healthy volunteers who have little to gain but much to lose if a trial goes wrong. With that in mind, good laboratory practice regulations require that a standardized system be used for the conduct, documentation, and retention of study-related materials. The study pathologist, working within that system of standards, documentation, and oversight, is key to the identification of potential target organs of toxicity and other toxicologically significant findings.