Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications.

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.

Improving the rigor and utility of botanical toxicity studies: Recommended resources.

Interest in botanicals, particularly as dietary supplement ingredients, is growing steadily. This growth, and the marketing of new ingredients and combination products as botanical dietary supplements, underscores the public health need for a better understanding of potential toxicities associated with use of these products. This article and accompanying template outline the resources to collect literature and relevant information to support the design of botanical toxicity studies. These resources provide critical information related to botanical identification, characterization, pre-clinical and clinical data, including adverse effects and interactions with pharmaceuticals. Toxicologists using these resources should collaborate with pharmacognosists and/or analytical chemists to enhance knowledge of the botanical material being tested. Overall, this guide and resource list is meant to help locate relevant information that can be leveraged to inform on decisions related to toxicity testing of botanicals, including the design of higher quality toxicological studies.

Considerations for determining safety of probiotics: A USP perspective.

A history of safe use is a backbone of safety assessments for many current probiotic species, however, there is no global harmonization regarding requirements for establishing probiotic safety for use in foods and supplements. As probiotic manufacturers are increasingly seeking to use new strains, novel species, and next-generation probiotics, justification based on a significant history of use may be challenged. There are efforts underway by a variety of stakeholders, including the United States Pharmacopeia (USP), to develop best practices guidelines for assessing the quality and safety of probiotics. A current initiative of the USP seeks to provide expert advice specific to safety considerations for probiotics. Toward this goal, this review provides a helpful summary guide to global regulatory guidelines. We question the suitability of traditional animal toxicology studies designed for testing chemicals for relevance in assessing probiotic safety. This includes discussion of the use of excessive dose levels, the length of repeated dose toxicity studies needed, and the most suitable animal species used in toxicology studies. In addition, the importance of proper manufacturing practices with regard to final product safety are also included. Thus, an outline of essential parameters of a comprehensive safety assessment for a probiotic are provided.

Prospective molecular and morphological assessment of testicular prepubertal-type teratomas in postpubertal men.

In 2016, the World Health Organization classification system of testicular tumors included the new entity prepubertal-type teratoma based on its morphological and molecular profile, and the realization that these tumors may occur in postpubertal men. For treatment and prognostic purposes, it is important to distinguish prepubertal-type teratoma from the usual postpubertal-type teratoma, because the former is benign unlike the latter. The distinction may be challenging. In this study, we investigated clinical, morphological, and molecular criteria for distinguishing prepubertal-type teratoma from postpubertal-type teratoma in a prospective series of pure testicular teratomas. All cases of pure teratoma in postpubertal men assessed at Barts Health NHS Trust or in consultation since the introduction of routine investigation of chromosome 12p status in 2010 were reviewed. Morphological features suggestive of prepubertal-type teratoma were observed in 14 out of 35 cases. All underwent molecular testing and none displayed 12p amplification. Mean tumor size was 16 mm (range 7-28 mm). None had associated germ cell neoplasia in situ or significant atrophy. Four incorporated a well-differentiated neuroendocrine tumor, 1-2 mm in size. Of the ten patients with follow-up information, none have recurred or metastasized. Twenty-one of the 35 cases were diagnosed as postpubertal-type teratoma, mean tumor size 40 mm (range 6-90 mm). One case underwent molecular testing: a tumor of pure skeletal muscle differentiation and possessed 12p amplification. Three cases presented with clinical metastases. Eight cases contained immature areas, ten cases had associated germ cell neoplasia in situ, and 17 cases had severe atrophy of the parenchyma. One case with neither germ cell neoplasia in situ nor atrophy showed necrosis. We conclude that both morphological and molecular features are of help in differentiating prepubertal-type teratoma from postpubertal-type teratoma. In nearly all postpubertal-type teratomas, molecular testing was unnecessary, and merely confirmed the morphological impression in the prepubertal-type teratomas. Our study confirmed the high incidence of well-differentiated neuroendocrine tumors in the prepubertal-type.

"Natural" is not synonymous with "Safe": Toxicity of natural products alone and in combination with pharmaceutical agents.

During the 25 years since the US Congress passed the Dietary Supplement Health and Education Act (DSHEA), the law that transformed the US Food and Drug Administration's (FDA's) authority to regulate dietary supplements, the dietary supplement market has grown exponentially. Retail sales of herbal products, a subcategory of dietary supplements, have increased 83% from 2008 to 2018 ($4.8 to $8.8 billion USD). Although consumers often equate "natural" with "safe", it is well recognized by scientists that constituents in these natural products (NPs) can result in toxicity. Additionally, when NPs are co-consumed with pharmaceutical agents, the precipitant NP can alter drug disposition and drug delivery, thereby enhancing or reducing the therapeutic effect of the object drug(s). With the widespread use of NPs, these effects can be underappreciated. We present a summary of a symposium presented at the Annual Meeting of the Society of Toxicology 2019 (12 March 2019) that discussed potential toxicities of NPs alone and in combination with drugs.

A Review of the Toxicity of Compounds Found in Herbal Dietary Supplements.

Use of herbal dietary supplements by the public is common and has been happening for centuries. In the United States, the Food and Drug Administration has a limited scope of regulation over marketed herbal dietary supplements, which may contain toxic botanical compounds that pose a public health risk. While the Food and Drug Administration has made efforts to prohibit the sale of unsafe herbal dietary supplements, numerous reports have proliferated of adverse events due to these supplements. This literature review investigates bioactive plant compounds commonly used in herbal dietary supplements and their relative toxicities. Using primarily the National Library of Medicine journal database and SciFinder for current reports, 47 toxic compounds in 55 species from 46 plant families were found to demonstrate harmful effects due to hepatic, cardiovascular, central nervous system, and digestive system toxicity. This review further contributes a novel and comprehensive view of toxicity across the botanical dietary market, and investigates the toxicity of the top ten botanical dietary supplements purchased in the United States of America to gauge the exposure risk of toxicity to the public. The criteria of measuring toxicity in this review (plant compound, family, quantity, and toxicity effects) across the entire market in the United States, with special attention to those supplements whose exposure to the consumer is maximal, provides a unique contribution to the investigation of botanical supplements.

Therapeutic Perspectives on Chia Seed and Its Oil: A Review.

The attraction of novel foods proceeds alongside epidemic cardiovascular disease, diabetes, obesity, and related risk factors. Dieticians have identified chia (Salvia hispanica) as a product with a catalog of potential health benefits relating to these detriments. Chia is currently consumed not only as seeds, but also as oil, which brings about similar effects. Chia seeds and chia seed oil are used mainly as a food commodity and the oil is also used popularly as a dietary ingredient used in various dietary supplements available in the U. S. market. Chia seed is rich in α-linolenic acid, the biological precursor to eicosapentaenoic acid, a polyunsaturated fatty acid, and docosahexaenoic acid. Because the body cannot synthesize α-linolenic acid, chia has a newfound and instrumental role in diet. However, the inconclusive nature of the scientific community's understanding of its safety warrants further research and appropriate testing. The focus of this work is to summarize dietary health benefits of S. hispanica seed and oil to acknowledge concerns of adverse events from its ingestion, to assess current research in the field, and to highlight the importance of quality compendial standards to support safe use. To achieve this end, a large-scale literature search was partaken on the two well-known databases, PubMed and SciFinder. Hundreds of articles detailing such benefits as decreased blood glucose, decreased waist circumference and weight in overweight adults, and improvements in pruritic skin and endurance in distance runners have been recorded. These benefits must be considered within the appropriate circumstances.

Prediction of Clinically Relevant Herb-Drug Clearance Interactions Using Sandwich-Cultured Human Hepatocytes: Schisandra spp. Case Study.

The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans, especially schizandrins, deoxyschizandrins, and gomisins. In China, Schisandra sphenanthera extract (SSE) is often coadministered with immunosuppressant treatment of transplant recipients. In cases of coadministration, the potential for herb-drug interactions (HDIs) increases. Clinical studies have been used to assess HDI potential of SSE. Results demonstrated that chronic SSE administration reduced midazolam (MDZ) clearance by 52% in healthy volunteers. Although clinical studies are definitive and considered the "gold standard," these studies are impractical for routine HDI assessments. Alternatively, in vitro strategies can be used to reduce the need for clinical studies. Transporter-certified sandwich-cultured human hepatocytes (SCHHs) provide a fully integrated hepatic cell system that maintains drug clearance pathways (metabolism and transport) and key regulatory pathways constitutive active/androstane receptor and pregnane X receptor (CAR/PXR) necessary for quantitative assessment of HDI potential. Mechanistic studies conducted in SCHHs demonstrated that SSE and the more commonly used dietary supplement Schisandra chinensis extract (SCE) inhibited CYP3A4/5-mediated metabolism and induced CYP3A4 mRNA in a dose-dependent manner. SSE and SCE reduced MDZ clearance to 0.577- and 0.599-fold of solvent control, respectively, in chronically exposed SCHHs. These in vitro results agreed with SSE clinical findings and predicted a similar in vivo HDI effect with SCE exposure. These findings support the use of an SCHH system that maintains transport, metabolic, and regulatory functionality for routine HDI assessments to predict clinically relevant clearance interactions.

The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline.

The increasing consumption of amino acids from a wide variety of sources, including dietary supplements, natural health products, medical foods, infant formulas, athletic and work-out products, herbal medicines, and other national and international categories of nutritional and functional food products, increases the exposure to amino acids to amounts far beyond those normally obtained from the diet, thereby necessitating appropriate and robust safety assessments of these ingredients. Safety assessments of amino acids, similar to all food constituents, largely rely on the establishment of an upper limit [Tolerable Upper Intake Level (UL)] considered to be a guide for avoiding high intake, above which adverse or toxic effects might occur. However, reliable ULs have been difficult or impossible to define for amino acids because of inadequate toxicity studies in animals and scarce or missing clinical data, as well as a paucity or absence of adverse event reporting data. This review examines 2 amino acids that have been associated with in-market adverse events to show how quality specifications might have helped prevent the adverse clinical outcomes. We further highlight the importance of various factors that should be incorporated into an overall safety assessment of these and other amino acids. In addition to the traditional reliance on the established UL, well-defined quality specifications, review of synthesis and production strategies, potential interactions with drugs, contraindications with certain disease states, and cautionary use within certain age groups should all be taken into consideration.

A practice analysis of toxicology.

In 2015, the American Board of Toxicology (ABT), with collaboration from the Society of Toxicology (SOT), in consultation with Professional Examination Service, performed a practice analysis study of the knowledge required for general toxicology. The purpose of this study is to help assure that the examination and requirements for attainment of Diplomate status are relevant to modern toxicology and based upon an empirical foundation of knowledge. A profile of the domains and tasks used in toxicology practice was developed by subject-matter experts representing a broad range of experiences and perspectives. An on-line survey of toxicologists, including Diplomates of the ABT and SOT members, confirmed the delineation. Results of the study can be used to improve understanding of toxicology practice, to better serve all toxicologists, and to present the role of toxicologists to those outside the profession. Survey results may also be used by the ABT Board of Directors to develop test specifications for the certifying examination and will be useful for evaluating and updating the content of professional preparation, development, and continuing education programs.

Assessing Natural Product-Drug Interactions: An End-to-End Safety Framework.

The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach.

A Review of Probiotic Ingredient Safety Supporting Monograph Development Conducted by the United States Pharmacopeia (USP).

The United States Pharmacopeia (USP) is an independent, nonprofit science-based organization whose mission is to improve global health through public standards and related products for medicines, food and dietary supplements. Probiotic-based dietary supplements are increasingly popular in the marketplace and USP has developed fourteen monographs specific to probiotic ingredients, including representatives from the Genera Lactobacillus, Bacillus, Streptococcus, and Bifidobacterium. These monographs include the definition of the article, tests for identification, quantification assays (enumeration in the case of probiotics), limits for contaminants, and other quality parameters when appropriate. In addition to quality, the USP also considers the safety of probiotics for monograph development. This report includes an overview of the USP admission evaluation process for probiotics as well as a tabular summary of the probiotic monographs currently available. Pharmacopeia monographs can guide manufacturers and brand owners and protect consumers through establishment of quality standards.

Inhibition of Toxic Shock Syndrome-Associated Staphylococcus aureus by Probiotic Lactobacilli.

Staphylococcus aureus is a human pathogen with many infections originating on mucosal surfaces. One common group of S. aureus is the USA200 (CC30) clonal group, which produces toxic shock syndrome toxin-1 (TSST-1). Many USA200 infections occur on mucosal surfaces, particularly in the vagina and gastrointestinal tract. This allows these organisms to cause cases of menstrual TSS and enterocolitis. The current study examined the ability of two lactobacilli, Lactobacillus acidophilus strain LA-14 and Lacticaseibacillus rhamnosus strain HN001, for their ability to inhibit the growth of TSST-1 positive S. aureus, the production of TSST-1, and the ability of TSST-1 to induce pro-inflammatory chemokines from human vaginal epithelial cells (HVECs). In competition growth experiments, L. rhamnosus did not affect the growth of TSS S. aureus but did inhibit the production of TSST-1; this effect was partially due to acidification of the growth medium. L. acidophilus was both bactericidal and prevented the production of TSST-1 by S. aureus. This effect appeared to be partially due to acidification of the growth medium, production of H2O2, and production of other antibacterial molecules. When both organisms were incubated with S. aureus, the effect of L. acidophilus LA-14 dominated. In in vitro experiments with HVECs, neither lactobacillus induced significant production of the chemokine interleukin-8, whereas TSST-1 did induce production of the chemokine. When the lactobacilli were incubated with HVECs in the presence of TSST-1, the lactobacilli reduced chemokine production. These data suggest that these two bacteria in probiotics could reduce the incidence of menstrual and enterocolitis-associated TSS. IMPORTANCE Toxic shock syndrome (TSS) Staphylococcus aureus commonly colonize mucosal surfaces, giving them the ability to cause TSS through the action of TSS toxin-1 (TSST-1). This study examined the ability of two probiotic lactobacilli to inhibit S. aureus growth and TSST-1 production, and the reduction of pro-inflammatory chemokine production by TSST-1. Lacticaseibacillus rhamnosus strain HN001 inhibited TSST-1 production due to acid production but did not affect S. aureus growth. Lactobacillus acidophilus strain LA-14 was bactericidal against S. aureus, partially due to acid and H2O2 production, and consequently also inhibited TSST-1 production. Neither lactobacillus induced the production of pro-inflammatory chemokines by human vaginal epithelial cells, and both inhibited chemokine production by TSST-1. These data suggest that the two probiotics could reduce the incidence of mucosa-associated TSS, including menstrual TSS and cases originating as enterocolitis.

VelcroVax: a "Bolt-On" Vaccine Platform for Glycoprotein Display.

Having varied approaches to the design and manufacture of vaccines is critical in being able to respond to worldwide needs and newly emerging pathogens. Virus-like particles (VLPs) form the basis of two of the most successful licensed vaccines (against hepatitis B virus [HBV] and human papillomavirus). They are produced by recombinant expression of viral structural proteins, which assemble into immunogenic nanoparticles. VLPs can be modified to present unrelated antigens, and here we describe a universal "bolt-on" platform (termed VelcroVax) where the capturing VLP and the target antigen are produced separately. We utilize a modified HBV core (HBcAg) VLP with surface expression of a high-affinity binding sequence (Affimer) directed against a SUMO tag and use this to capture SUMO-tagged gp1 glycoprotein from the arenavirus Junín virus (JUNV). Using this model system, we have solved the first high-resolution structures of VelcroVax VLPs and shown that the VelcroVax-JUNV gp1 complex induces superior humoral immune responses compared to the noncomplexed viral protein. We propose that this system could be modified to present a range of antigens and therefore form the foundation of future rapid-response vaccination strategies. IMPORTANCE The hepatitis B core protein (HBc) forms noninfectious virus-like particles, which can be modified to present a capturing molecule, allowing suitably tagged antigens to be bound on their surface. This system can be adapted and provides the foundation for a universal "bolt-on" vaccine platform (termed VelcroVax) that can be easily and rapidly modified to generate nanoparticle vaccine candidates.

The Safety and Efficacy of Botanicals with Nootropic Effects.

Recent estimates for the global brain health supplement category, i.e. nootropic market size, will grow to nearly $5.8 billion by 2023. Overall, nearly one-quarter (23%) of adults currently take a supplement to maintain or improve brain health or delay and reverse dementia. Not surprisingly, the use of such supplements increases with age - more than one-third of the oldest generation (ages 74 and older) takes a supplement for brain health. This widespread use is being driven by a strong desire both in the younger and older generations to enhance cognitive performance and achieve healthy aging. The most prevalent botanicals currently dominating the nootropic marketplace include Gingko biloba, American ginseng, and Bacopa monnieri. However, other botanicals that affect stress, focus, attention, and sleep have also been procured by dietary supplement companies developing products for improving both, short and long-term brain health. This review focuses on efficacy data for neuroactive botanicals targeted at improving cognitive function, stress reduction, memory, mood, attention, concentration, focus, and alertness, including Bacopa monnieri, Ginkgo biloba, Holy basil, American ginseng, Gotu kola, Lemon balm, Common and Spanish sages and spearmint. Botanicals are discussed in terms of available clinical efficacy data and current safety profiles. Data gaps are highlighted for both efficacy and safety to bring attention to unmet needs and future research.

United States Pharmacopeia (USP) Safety Review of Gamma-Aminobutyric Acid (GABA).

Gamma-amino butyric acid (GABA) is marketed in the U.S. as a dietary supplement. USP conducted a comprehensive safety evaluation of GABA by assessing clinical studies, adverse event information, and toxicology data. Clinical studies investigated the effect of pure GABA as a dietary supplement or as a natural constituent of fermented milk or soy matrices. Data showed no serious adverse events associated with GABA at intakes up to 18 g/d for 4 days and in longer studies at intakes of 120 mg/d for 12 weeks. Some studies showed that GABA was associated with a transient and moderate drop in blood pressure (<10% change). No studies were available on effects of GABA during pregnancy and lactation, and no case reports or spontaneous adverse events associated with GABA were found. Chronic administration of GABA to rats and dogs at doses up to 1 g/kg/day showed no signs of toxicity. Because some studies showed that GABA was associated with decreases in blood pressure, it is conceivable that concurrent use of GABA with anti-hypertensive medications could increase risk of hypotension. Caution is advised for pregnant and lactating women since GABA can affect neurotransmitters and the endocrine system, i.e., increases in growth hormone and prolactin levels.

United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts.

As part of the United States Pharmacopeia's ongoing review of dietary supplement safety data, a new comprehensive systematic review on green tea extracts (GTE) has been completed. GTEs may contain hepatotoxic solvent residues, pesticide residues, pyrrolizidine alkaloids and elemental impurities, but no evidence of their involvement in GTE-induced liver injury was found during this review. GTE catechin profiles vary significantly with manufacturing processes. Animal and human data indicate that repeated oral administration of bolus doses of GTE during fasting significantly increases bioavailability of catechins, specifically EGCG, possibly involving saturation of first-pass elimination mechanisms. Toxicological studies show a hepatocellular pattern of liver injury. Published adverse event case reports associate hepatotoxicity with EGCG intake amounts from 140 mg to ∼1000 mg/day and substantial inter-individual variability in susceptibility, possibly due to genetic factors. Based on these findings, USP included a cautionary labeling requirement in its Powdered Decaffeinated Green Tea Extract monograph that reads as follows: "Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes)."

Safety of Guarana Seed as a Dietary Ingredient: A Review.

The seeds of the guarana plant (Paullinia cupana Kunth, family Sapindaceae) are well-known to many cultures as a stimulant, aphrodisiac, and astringent. Its rhizome was traditionally boiled into a tea by Amazonian cultures. Today, guarana seeds are ground to a fine powder and sold as powder, tablets, and capsules. This review focuses on the traditional uses, phytochemistry, and biological activities of the guarana seed to evaluate its safety as a dietary ingredient. A comprehensive review of published literature was conducted to identify articles that focused on the phytochemistry, pharmacology, and safety of guarana. On the basis of this review, guarana is not currently known to be associated causally with any serious health risks when consumed properly. Overall, guarana is generally recognized as safe as a dietary ingredient marketed for its flavor and caffeine content. If guidelines for caffeine intake are respected, guarana consumption is not likely to be associated with any serious health risks.

Development of a consensus approach for botanical safety evaluation - A roundtable report.

Botanical safety science continues to evolve as new tools for risk assessment become available alongside continual desire by consumers for "natural" botanical ingredients in consumer products. Focusing on botanical food/dietary supplements a recent international roundtable meeting brought together scientists to discuss the needs, available tools, and ongoing data gaps in the botanical safety risk assessment process. Participants discussed the key elements of botanical safety evaluations. They provided perspective on the use of a decision tree methodology to conduct a robust risk assessment and concluded with alignment on a series of consensus statements. This discussion highlighted the strengths and vulnerabilities in common assumptions, and the participants shared additional perspective to ensure that this end-to-end safety approach is sufficient, actionable and timely. Critical areas and data gaps were identified as opportunities for future focus. These include, better context on history of use, systematic assessment of weight of evidence, use of in silico approaches, inclusion of threshold of toxicological concern considerations, individual substances/matrix interactions of plant constituents, assessing botanical-drug interactions and adaptations needed to apply to in vitro and in vivo pharmacokinetic modelling of botanical constituents.