In Vivo Evaluation of the Oral Toxicity of the Chlorobutanol

Chlorobutanol (CB) is used as a preservative in cosmetics and has antibacterial activity. This study investigated the single- and repeated-dose 28-day oral toxicity of a CB solvent in Sprague Dawley (SD) rats. For the single-dose oral toxicity study, a dose of 62.5, 125, or 250 mg per kg of body weight (mg/kg b.w.) of CB was given once orally via gavage. For the repeated-dose 28-day toxicity study, the high dose was set as 100 mg/kg b.w./day, and the middle, middle-low, and low doses were set to 50, 25, and 12.5 mg/kg b.w./day, respectively. Body weight was not significantly changed in the repeated-dose toxicity study. Relative liver and kidney weights were significantly increased in both sexes of the 100 mg/kg b.w./day treatment group. However, there were histopathological changes in liver and kidney for females and males, respectively. These data suggested that the approximate lethal dose (ALD) of CB was over 250 mg/kg b.w./day in the single-dose study, and the no adverse effect level (NOAEL) for CB was over 50 and 12.5 mg/kg b.w./day for female and male rats in the repeated-dose toxicity study.

Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections

Cardiotonic steroids are steroid-like natural compounds known to inhibit Na+/K+-ATPase pumps. To develop a broad-spectrum antiviral drug against the emerging coronavirus infection, this study assessed the antiviral properties of these compounds. The activity of seven types of cardiotonic steroids against the MERS-CoV, SARS-CoV, and SARS-CoV-2 coronavirus varieties was analyzed using immunofluorescence antiviral assay in virus-infected cells. Bufalin, cinobufagin, and telocinobufagin showed high anti-MERS-CoV activities (IC50, 0.017~0.027 μM); bufalin showed the most potent anti-SARS-CoV and SARS-CoV-2 activity (IC50, 0.016~0.019 μM); cinobufotalin and resibufogenin showed comparatively low anti-coronavirus activity (IC50, 0.231~1.612 μM). Differentially expressed genes in Calu3 cells treated with cinobufagin, telocinobufagin, or bufalin, which had high antiviral activity during MERS-CoV infection were analyzed using QuantSeq 3′ mRNA-Seq analysis and data showed similar gene expression patterns. Furthermore, the intraperitoneal administration of 10 mg/kg/day bufalin, cinobufagin, or digitoxin induced 100% death after 1, 2, and 4 days in 5-day repeated dose toxicity studies and it indicated that bufalin had the strongest toxicity. Pharmacokinetic studies suggested that telocinobufagin, which had high anti-coronavirus activity and low toxicity, had better microsomal stability, lower CYP inhibition, and better oral bioavailability than cinobufagin. Therefore, telocinobufagin might be the most promising cardiotonic steroid as a therapeutic for emerging coronavirus infections, including COVID-19.

Antifungal Activity and Acute and Repeated-Dose Toxicity Study of Geranyl Cinnamate Ester in Mice

In the present study, the antifungal activity and toxicity of the geranyl cinnamate ester (GCE) were investigated. The GCE showed antifungal activity at a minimum concentration of 0.16 μL/mL against Candida albicans and at concentrations greater than 2.5 μL/mL against Aspergillus niger. In acute toxicity studies, the administration of GCE (2.000 mg/kg) affected the body weight gain and food intake but did not induce the mortality of the animals studied. After the investigation of repeated-dose toxicity of GCE at 2 and 4 mg/kg, the hematological and biochemical parameters were changed. In addition, the adrenal weight of male mice treated with GCE at 4 mg/kg was affected. In conclusion, according to the Organization for Economic Cooperation and Development (OECD) acute toxicity parameters, the geranyl cinnamate ester can be classified into safety category number 5. The results of this study suggested that the geranyl cinnamate ester may be a source of natural antifungals.

Using a micro-physiological system to prolong the preservation of ex vivo lung tissue

Current in vitro and in vivo disease models have been reported to lack sufficient translation to human. Precision-Cut Lung Slices (PCLS) are viable sections of lung tissue and have been described to be a translational model for the ex vivo assessment of pharmacological and toxicological compounds. In most studies PCLS were cultured under static conditions. These lung sections, however, suffer from the limited viability. Here we present a novel modular microphysiological system (MPS) to prolong the cultivation of ex vivo lung tissue. A tailored MPS setup was designed using the PDMS free modular plug&play MPS construction kit. PCLS from mice were cultivated for up to one week under static versus perfused conditions. Using the MPS technology enabled a prolonged culture period with improved viability as shown by lowered lactate dehydrogenase release and improved membrane integrity. Using this technology might allow us to use PCLS for longer culture periods such as e.g. repeated dose toxicity or pharmacology studies.

Acute and Repeated Dose Toxicity Study of Clevira Syrup – A Polyherbal Formulation

Aim and Objectives: This study evaluated the acute and repeated dose toxicity effects of Clevira Syrup Polyherbal formulation (CSPHF), which was prepared from ten different herbs, well known and widely used in traditional medicine for the management of viral infections and other inflammatory disease conditions. Individually these herbs (Carica papaya, Melia azedarach, Andrographis paniculata, Vetiveria zizanioides, Trichosanthes dioica, Cyperus rotundus, Zingiber officinale, Piper nigrum, Mollugo Cerviana and Tinospora cordifolia )were completely safe, but the polyherbal formulation effects were not known. Thus, this study was done for the investigation of toxicological profile of CSPHF in Wistar Albino rats. Methods: As per OECD(Organisation for Economic Co-operation and Development) guidelines 423 and 407, Acute and Repeated dose toxicity study were proceeded. In the acute toxicity study a single dose of CSPHF (2000mg/kg) was administered orally to female Wistar rats and in repeated dose toxicity study, CSPHF was administered orally in Control group and three different doses (1000, 500 and 250mg/kg body weight) to both male and female wistar albino rats for 28 days. At the end of the study, the animals were euthanized, observed the external and internal morphology (Acute Toxicity) and assessed the effect of CSPHF on histopathological and biochemical parameters (Repeated Dose toxicity study). Results: In acute toxicity study, there were no visual signs of toxicity of CSPHF (2000mg/kg) observed, whereas in Repeated dose toxicity study Ischaemia, inflammation and hematoma of the internal organs were observed at 1000mg/kg dose, but no such toxic features were seen at 500 and 250mg/kg dose of CSPHF. Conclusion: The results of the Acute and Repeated Dose toxicity study could be authenticated in future studies, which will be more useful and evidence based for the management of Viral infectionsduring pandemics.