Nonclinical Safety Testing of RNA Vaccines.

In this chapter, we will first consider the overall goal of nonclinical safety testing during drug development and have a brief overview of its regulatory background. We will then discuss some basic requirements of safety/toxicity testing before concentrating on the safety testing of RNA vaccines and developing a sample RNA vaccine safety testing program.

A Systematic Review of the Design and Applications of Antimicrobial Peptides in Wound Healing.

The sources of antimicrobial peptides (AMPs), also known as peptide-based antibiotics, are diverse, such as plants, animals, microorganisms including human leukocytes, saliva, human defense peptides, and human sweat. These natural sources provide a rich variety of AMPs with unique characteristics and potential therapeutic applications, including wound-healing and antimicrobial properties. AMPs derived from these sources have shown promise in combating a wide range of pathogens, making them valuable targets for further research and potential clinical applications. The design of AMPs for wound healing involves a meticulous process of structurally optimizing peptides to possess a unique combination of antibacterial and wound-healing characteristics. This systematic review was produced to show the design and applications of AMPs in wound healing. The terms "antimicrobial peptides AND wound healing" were used to search for articles published between September 2023 and January 2010. In the search, we found a total of 12958 articles, of which 12898 were excluded, and the remaining 60 articles were chosen for further study. This systematic review underscores the potential of AMPs as valuable tools in infection control and wound healing, showcasing their versatility and effectiveness in combating a wide range of pathogens. Overall, AMPs in wound healing display a diverse mechanism of action, influencing the inflammatory response, encouraging tissue regeneration, and aiding tissue remodeling, along with strong antibacterial activity. Furthermore, this systematic review addresses AMP toxicity studies, which include rigorous in vitro and in vivo examinations to determine potential cytotoxic effects, systemic toxicity, and any adverse responses connected with its usage in wound-healing applications.

A Systematic Review on Marine Algae-Derived Fucoxanthin: An Update of Pharmacological Insights.

Fucoxanthin, belonging to the xanthophyll class of carotenoids, is a natural antioxidant pigment of marine algae, including brown macroalgae and diatoms. It represents 10% of the total carotenoids in nature. The plethora of scientific evidence supports the potential benefits of nutraceutical and pharmaceutical uses of fucoxanthin for boosting human health and disease management. Due to its unique chemical structure and action as a single compound with multi-targets of health effects, it has attracted mounting attention from the scientific community, resulting in an escalated number of scientific publications from January 2017 to February 2022. Fucoxanthin has remained the most popular option for anti-cancer and anti-tumor activity, followed by protection against inflammatory, oxidative stress-related, nervous system, obesity, hepatic, diabetic, kidney, cardiac, skin, respiratory and microbial diseases, in a variety of model systems. Despite much pharmacological evidence from in vitro and in vivo findings, fucoxanthin in clinical research is still not satisfactory, because only one clinical study on obesity management was reported in the last five years. Additionally, pharmacokinetics, safety, toxicity, functional stability, and clinical perspective of fucoxanthin are substantially addressed. Nevertheless, fucoxanthin and its derivatives are shown to be safe, non-toxic, and readily available upon administration. This review will provide pharmacological insights into fucoxanthin, underlying the diverse molecular mechanisms of health benefits. However, it requires more activity-oriented translational research in humans before it can be used as a multi-target drug.

Bibliometric Analysis of Chimeric Antigen Receptor-Based Immunotherapy in Cancers From 2001 to 2021.

Background: Chimeric antigen receptor (CAR)-based immunotherapy has shown great potential for the treatment of both hematopoietic malignancies and solid tumors. Nevertheless, multiple obstacles still block the development of CAR-based immunotherapy in the clinical setting. In this study, we aimed to summarize the research landscape and highlight the front lines and trends of this field. Methods: Literature published from 2001 to 2021 was searched in the Web of Science Core Collection database. Full records and cited references of all the documents were extracted and screened. Bibliometric analysis and visualization were conducted using CiteSpace, Microsoft Excel 2019, VOSviewer and R software. Results: A total of 5981 articles and reviews were included. The publication and citation results exhibited increasing trends in the last 20 years. Frontiers in Immunology and Blood were the most productive and most co-cited journals, respectively. The United States was the country with the most productive organizations and publications in the comprehensive worldwide cooperation network, followed by China and Germany. June, C.H. published the most papers with the most citations, while Maude, S.L. ranked first among the co-cited authors. The hotspots in CAR-based therapy research were multiple myeloma, safety and toxicity, solid tumors, CAR-engineered immune cells beyond T cells, and gene editing. Conclusion: CAR-based immunotherapy is a promising treatment for cancer patients, and there is an emerging movement toward using advanced gene modification technologies to overcome therapeutic challenges, especially in solid tumors, and to generate safer and more effective universal CAR-engineered cell products.

Kidney tonifying traditional Chinese medicine: Potential implications for the prevention and treatment of osteoporosis.

The aging global population is increasingly affected by osteoporosis (OP), which is one of the most significant threats to the elderly. Moreover, its prevention and treatment situations have become increasingly severe. Therefore, it is imperative to develop alternatives or complementary drugs for preventing and treating osteoporosis. Kidney tonifying traditional Chinese medicine (KTTCM) has been used for the treatment of osteoporosis for a long time. Pharmacological studies have shown that kidney tonifying traditional Chinese medicine can promote osteoblasts, inhibit osteoclasts, and regulate the level of estrogen and plays vital roles in stimulating osteogenesis, restraining adipogenesis of marrow mesenchymal stem cells (MSCs), regulating the metabolism of calcium and phosphorus, and inhibiting oxidative stress. These effects are mediated by OPG/RANKL/RANK, BMP/Smads, MAPKs, and Wnt/ß-catenin systems. To develop a safe, synergistic, effective, and homogenized TCM formula with robust scientific evidence to provide faster and more economical alternatives, the anti-osteoporosis ingredients and pharmacological mechanisms of kidney tonifying traditional Chinese medicine are recapitulated from the perspective of molecular and cell biology, and the safety and toxicity of kidney tonifying traditional Chinese medicine have also been reviewed in this paper.

The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies.

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.

Nutraceuticals: Transformation of Conventional Foods into Health Promoters/Disease Preventers and Safety Considerations.

Nutraceuticals are essential food constituents that provide nutritional benefits as well as medicinal effects. The benefits of these foods are due to the presence of active compounds such as carotenoids, collagen hydrolysate, and dietary fibers. Nutraceuticals have been found to positively affect cardiovascular and immune system health and have a role in infection and cancer prevention. Nutraceuticals can be categorized into different classes based on their nature and mode of action. In this review, different classifications of nutraceuticals and their potential therapeutic activity, such as anti-cancer, antioxidant, anti-inflammatory and anti-lipid activity in disease will be reviewed. Moreover, the different mechanisms of action of these products, applications, and safety upon consumers including current trends and future prospect of nutraceuticals will be included.

Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects.

Withania somnifera, commonly known as "Ashwagandha" or "Indian ginseng" is an essential therapeutic plant of Indian subcontinent regions. It is regularly used, alone or in combination with other plants for the treatment of various illnesses in Indian Systems of Medicine over the period of 3,000 years. Ashwagandha (W. somnifera) belongs to the genus Withania and family Solanaceae. It comprises a broad spectrum of phytochemicals having wide range of biological effects. W. somnifera has demonstrated various biological actions such as anti-cancer, anti-inflammatory, anti-diabetic, anti-microbial, anti-arthritic, anti-stress/adaptogenic, neuro-protective, cardio-protective, hepato-protective, immunomodulatory properties. Furthermore, W. somnifera has revealed the capability to decrease reactive oxygen species and inflammation, modulation of mitochondrial function, apoptosis regulation and improve endothelial function. Withaferin-A is an important phytoconstituents of W. somnifera belonging to the category of withanolides been used in the traditional system of medicine for the treatment of various disorders. In this review, we have summarized the active phytoconstituents, pharmacologic activities (preclinical and clinical), mechanisms of action, potential beneficial applications, marketed formulations and safety and toxicity profile of W. somnifera.

In vitro and In vivo toxicity analysis of zinc selenium/zinc sulfide (ZnSe/ZnS) quantum dots.

Despite the versatility of quantum dots (QDs) in optoelectronics and biomedical field, their toxicity risks remain a considerable hindrance for clinical applications. Cytotoxicity of Cadmium containing QDs is well documented and reveals that they are toxic to cells. Reports suggest that the presence of toxic elements at the QD core (e.g., cadmium, selenium) is responsible for its toxicity in in vivo and in vitro levels. Hence, here the toxicity of heavy metal free ZnSe/ZnS QDs on two scenarios were assessed, (i) HEK cells as in vitro system and (ii) Swiss Albino mice as in vivo model. Before toxicity analysis, QDs subjected to various optical and physico-chemical characterization methods such as absorption and emission spectra analysis, observation under U.V light, TEM, DLS, Zeta potential, FTIR, Raman and XPS spectra, ICP-OES, TGA and DTG curve. It is very necessary to characterize the synthesized QDs because their toxicity greatly influenced by the physico-chemical properties. On checking the vulnerability of HEK cells on exposure to ZnSe/ZnS QDs, the obtained results disclose that ZnSe/ZnS QDs showed merest impact on cellular viability at a concentration less than 100 µg/ml. Acute toxicity of 10 mg/kg ZnSe/ZnS QDs was studied in mice and no clinical or behavioural changes were observed. It did not induce any changes in haematological parameters and any loss of body or organ weight. Moderate pathological changes were evident only in the liver, all others organs like kidney, spleen and brain did not show any manifestations of toxicity. Current work lays substantial bedrock for safe biomedical and environmental application of ZnSe/ZnS QDs in near future.

Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis.

BACKGROUND: India accounts for a quarter of the world's multidrug-resistant tuberculosis (MDR-TB); with less than 50% having successful treatment outcomes. Bedaquiline (BDQ) was approved for use under conditional access program in India in 2015. OBJECTIVE: We evaluate the effectiveness, safety, and tolerability of a BDQ containing regimen used under field settings in India. METHOD: Interim analysis of a prospective cohort of MDR-TB patients on a BDQ containing regimen at six sites in the country. RESULTS: Six hundred and twenty MDR-TB patients [349 (56%) males; 554 (89%) between 18 and 50 years and 240 (39%) severely malnourished] were started on BDQ containing regimen between June 2016 and August 2017. There 354 (57%) patients had MDR-TB with additional drug resistance to fluoroquinolone (MDRFQ); 31 (5%) with additional resistance to second-line injectable (MDRSLI) and 101 (16%) extensively drug-resistant TB. After 6 months of treatment, culture conversion was achieved in 513 of 620 (83%) patients. The median time to culture conversion was 60 days. Higher body mass index was the only factor associated with faster culture conversion (HR 1.97; 95% CI 1.24-2.9). Around 100 patients (16.3%) experienced a ≥60-ms increase in QTc interval during the treatment. Seventy-three (12%) deaths were reported, the majority of them (56%) occurring within the first 6 months of treatment. CONCLUSIONS: BDQ with a background regimen has the potential to achieve higher and faster culture conversion rates with a lower toxicity profile among DR-TB patients. Use of BDQ with additional monitoring may be safe and effective even in the field settings.

Next tier in vitro and in vivo nonclinical studies further elucidating the safety and toxicity profile of MB-102, a novel fluorescent tracer agent for measurement of glomerular filtration rate.

MB-102 was designed for measurement of real-time glomerular filtration rate (GFR). Previously reported in vitro and in vivo nonclinical studies clearly demonstrated negligible toxicity, resulting in FDA clearance for First-in Human, proof of concept clinical studies. The next tier of safety and toxicity studies are reported herein. MB-102 did not demonstrate any phototoxic potential in a BALB/c 3T3 mouse fibroblast study. Co-administration of MB-102 and iohexol resulted in pharmacokinetic parameters virtually identical to the values observed upon individual administration in beagle dogs. A single dose of MB-102 administered either intravenously (18.6 mg/mL) or perivenously (0.25 mL) was well-tolerated in NZ white rabbits, with no adverse inflammation or irritation. MB-102 did not induce micronuclei in polychromatic erythrocytes for rat bone marrow cells treated up to 450 mg/kg/day, the maximum feasible dose. Two separate optical imaging studies demonstrated that MB-102 distributes rapidly and thoroughly throughout the test subjects, followed by rapid clearance from the body without any preferential localization in any particular tissue or organ, with the exception of the bladder, which is totally consistent with a known GFR agent. In addition, two-week repeat intravenous (once-daily) toxicity and toxicokinetic studies were conducted in rats and beagles, with no MB-102- related effects. Thus, for the studies reported herein, there were no toxicological effects of concern for MB-102.

Vandetanib-eluting Radiopaque Beads: In vivo Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization.

PURPOSE: To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine. MATERIALS AND METHODS: In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads. RESULTS: The peak plasma levels of VTB (Cmax) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the in vitro IC50 for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug. CONCLUSIONS: Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity.

Nonclinical Safety Testing of RNA Vaccines.

In this chapter, we first consider the overall goal of nonclinical safety testing during drug development and have a brief overview of its regulatory background. We then discuss some basic requirements of safety/toxicity testing before concentrating on the safety testing of RNA vaccines and developing a sample RNA vaccine safety testing program.

Preclinical evaluation of the safety and pathogenicity of a live attenuated recombinant influenza A/H7N9 seed strain and corresponding MF59-adjuvanted split vaccine.

Developing a safe and effective H7N9 influenza vaccine was initiated in early spring 2013, following human infections with a novel avian influenza A (H7N9) virus. In this study, a candidate H7N9 vaccine seed strain is produced using reverse genetics, with HA and NA derived from a human H7N9 virus and the remaining genes from the PR8 backbone virus which grows well in eggs. We verified that the virulence and transmissibility of the recombinant H7N9 vaccine seed strain were decreased as compared to wild-type H7N9 virus, to levels comparable with PR8. Using the seed virus, we produced a monovalent split influenza A (H7N9) MF59-adjuvanted vaccine that was immunogenic in mice. Our H7N9 vaccine is selected for clinical investigation and potential human use. To assess the safety of our H7N9 vaccine, we performed acute toxicity, repeated dose toxicity and active systemic anaphylaxis tests. Our results showed that, under the conditions used in this study, the NOEAL (no obvious adverse effect level) was 30 µg/0.5 mL.

Safety and toxicity of nanomaterials for ocular drug delivery applications.

Multifunctional nanomaterials are rapidly emerging for ophthalmic delivery of therapeutics to facilitate safe and effective targeting with improved patient compliance. Because of their extremely high area to volume ratio, nanomaterials often have physicochemical properties that are different from those of their larger counterparts. There exists a complex relationship between the physicochemical properties (composition, size, shape, charge, roughness, and porosity) of the nanomaterials and their interaction with the biological system. The eye is a very sensitive accessible organ and is subjected to intended and unintended exposure to nanomaterials. Currently, various ophthalmic formulations are available in the market, while some are underway in preclinical and clinical phases. However, the data on safety, efficacy, and toxicology of these advanced nanomaterials for ocular drug delivery are sparse. Focus of the present review is to provide a comprehensive report on the safety, biocompatibility and toxicities of nanomaterials in the eye.

The relevance and potential roles of microphysiological systems in biology and medicine.

Microphysiological systems (MPS), consisting of interacting organs-on-chips or tissue-engineered, 3D organ constructs that use human cells, present an opportunity to bring new tools to biology, medicine, pharmacology, physiology, and toxicology. This issue of Experimental Biology and Medicine describes the ongoing development of MPS that can serve as in-vitro models for bone and cartilage, brain, gastrointestinal tract, lung, liver, microvasculature, reproductive tract, skeletal muscle, and skin. Related topics addressed here are the interconnection of organs-on-chips to support physiologically based pharmacokinetics and drug discovery and screening, and the microscale technologies that regulate stem cell differentiation. The initial motivation for creating MPS was to increase the speed, efficiency, and safety of pharmaceutical development and testing, paying particular regard to the fact that neither monolayer monocultures of immortal or primary cell lines nor animal studies can adequately recapitulate the dynamics of drug-organ, drug-drug, and drug-organ-organ interactions in humans. Other applications include studies of the effect of environmental toxins on humans, identification, characterization, and neutralization of chemical and biological weapons, controlled studies of the microbiome and infectious disease that cannot be conducted in humans, controlled differentiation of induced pluripotent stem cells into specific adult cellular phenotypes, and studies of the dynamics of metabolism and signaling within and between human organs. The technical challenges are being addressed by many investigators, and in the process, it seems highly likely that significant progress will be made toward providing more physiologically realistic alternatives to monolayer monocultures or whole animal studies. The effectiveness of this effort will be determined in part by how easy the constructs are to use, how well they function, how accurately they recapitulate and report human pharmacology and toxicology, whether they can be generated in large numbers to enable parallel studies, and if their use can be standardized consistent with the practices of regulatory science.

The STEP (Safety and Toxicity of Excipients for Paediatrics) database: part 2 - the pilot version.

The screening and careful selection of excipients is a critical step in paediatric formulation development as certain excipients acceptable in adult formulations, may not be appropriate for paediatric use. While there is extensive toxicity data that could help in better understanding and highlighting the gaps in toxicity studies, the data are often scattered around the information sources and saddled with incompatible data types and formats. This paper is the second in a series that presents the update on the Safety and Toxicity of Excipients for Paediatrics ("STEP") database being developed by Eu-US PFIs, and describes the architecture data fields and functions of the database. The STEP database is a user designed resource that compiles the safety and toxicity data of excipients that is scattered over various sources and presents it in one freely accessible source. Currently, in the pilot database data from over 2000 references/10 excipients presenting preclinical, clinical, regulatory information and toxicological reviews, with references and source links. The STEP database allows searching "FOR" excipients and "BY" excipients. This dual nature of the STEP database, in which toxicity and safety information can be searched in both directions, makes it unique from existing sources. If the pilot is successful, the aim is to increase the number of excipients in the existing database so that a database large enough to be of practical research use will be available. It is anticipated that this source will prove to be a useful platform for data management and data exchange of excipient safety information.

New Progress in Modern Research on Chinese Herbal Medicines Published in Chinese Traditional and Herbal Drugs in 2010: Annual Highlights and Comments / 中草药·英文版

As a series of and continuous publication,the papers published on Chinese Traditional and Herbal Drugs in 2010 were selectively and briefly highlighted to reflect the new progress on modern research of Chinese herbal medicines.Within 617 articles,chemical constituents (127),pharmaceutics and technology (149),pharmacological studies and clinical observation,and medicinal materials are still major categories.Some comments have also been personally provided.