Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: Toxicology and pain efficacy assessments

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.     

The Global Educational Toxicology Uniting Project (GETUP): an Analysis of the First Year of a Novel Toxicology Education Project

The international boundaries to medical education are becoming less marked as new technologies such as multiuser videoconferencing are developed and become more accessible to help bridge the communication gaps. The Global Educational Toxicology Uniting Project (GETUP) is aimed at connecting clinicians in countries with established clinical toxicology services to clinicians in countries without clinical toxicologists around the globe. Centers that manage or consult on toxicology cases were registered through the American College of Medical Toxicology website via Survey Monkey®. Data was analyzed retrospectively from February 2014 to January 2015. Google hangouts® was used as the main conferencing software, but some sites preferred the use of Skype®. Registration data included contact details and toxicology background and qualifications. Thirty sites in 19 different countries in Australasia, Europe, Africa, and America were registered. Twenty-eight (93 %) sites were located in a major urban center, one (3.5 %) site in a major rural center and one (3.5 %) a private practice. Expectations of GETUP included sharing toxicology cases and education (30, 100 % of sites), assistance with toxicology management guidelines (2, 7 %), assistance with providing a toxicology teaching curriculum in languages other than English (2, 7 %), and managing toxicology presentations in resource-poor settings, international collaboration, and toxicovigilance (2 sites, 7 %). Twenty-two conferences were performed during the first 12 months with a mean of 3 cases per conference. GETUP has connected countries and clinical units with and without toxicology services and will provide a platform to improve international collaboration in clinical toxicology.     

Preclinical evaluation of a plant-derived SARS-CoV-2 subunit vaccine: Protective efficacy,immunogenicity, safety,and toxicity

Coronavirus disease 2019 (COVID-19) is an acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The prevention of SARS-CoV-2 transmission has become a global priority. Previously, we showed that a protein subunit vaccine that was developed based on the fusion of the SARS-CoV-2 receptor-binding domain (RBD) to the Fc portion of human IgG1 (RBD-Fc), produced in Nicotiana benthamiana, and adjuvanted with alum, namely, Baiya SARS-CoV-2 Vax 1, induced potent immunological responses in both mice and cynomolgus monkeys. Hence, this study evaluated the protective efficacy, safety, and toxicity of Baiya SARS-CoV-2 Vax 1 in K18-hACE2 mice, monkeys and Wistar rats. Two doses of vaccine were administered three weeks apart on Days 0 and 21. The administration of the vaccine to K18-hACE2 mice reduced viral loads in the lungs and brains of the vaccinated animals and protected the mice against challenge with SARS-CoV-2. In monkeys, the results of safety pharmacology tests, general clinical observations, and a core battery of studies of three vital systems, namely, the central nervous, cardiovascular, and respiratory systems, did not reveal any safety concerns. The toxicology study of the vaccine in rats showed no vaccine-related pathological changes, and all the animals remained healthy under the conditions of this study. Furthermore, the vaccine did not cause any abnormal toxicity in rats and was clinically tolerated even at the highest tested concentration. In addition, general health status, body temperature, local toxicity at the administration site, hematology, and blood chemistry parameters were also monitored. Overall, this work presents the results of the first systematic study of the safety profile of a plant-derived vaccine, Baiya SARS-CoV-2 Vax 1; this approach can be considered a viable strategy for the development of vaccines against COVID-19.     

术德兼修视角下医学院校专业课程思政的探索与实践

高校立身之本在于立德树人。以钟南山院士为首的广医人在抗击“非典”、防控“新冠”等重大公共事件中体现的人文情怀是我校课程思政的重要基石。该文以临床药学专业药物毒理学为例,阐述了在医学院校中对于专业课程开展课程思政的教学理念、教学策略以及在实践中的运用方法与反思。     

Potential of biofluid components to modify silver nanoparticle toxicity

Establishing realistic exposure scenarios is critical for cytotoxic investigation of silver nanoparticles (AgNP) in the gastrointestinal tract. This study investigated the potential interaction with and effect of biofluid components, namely cholic acid, deoxycholic acid and ursodeoxycholic acid, on AgNP toxicity. Two cell lines corresponding to organs related to the biofluid components were employed. These were HepG‐2 a hepatocellular carcinoma derived from liver tissue and Hep2 an epithelial cell line. Physiochemical and cytotoxic screening was performed and the ability of biofluid components to modify AgNP cytotoxicity was explored. No alteration to the physiochemical characteristics of AgNP by biofluid components was demonstrated. However, biofluid component addition resulted in alteration of AgNP toxicity. Greater reactive oxygen species induction was noted in the presence of cholic acid and deoxycholic acid. Ursodeoxycholic acid demonstrated no modification of toxicity in HepG‐2 cells; however, significant modification was noted in Hep2 cells. It is concluded that biofluid components can modify AgNP toxicity but this is dependent on the biofluid component itself and the location where it acts. Copyright © 2015 John Wiley & Sons, Ltd.