Sensitivity of SARS-CoV-2 towards Alcohols: Potential for Alcohol-Related Toxicity in Humans

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative organism that is highly contagious and has been responsible for more than 240 million cases and 5 million deaths worldwide. Using masks, soap-based hand washing, and maintaining social distancing are some of the common methods to prevent the spread of the virus. In the absence of any preventive medications, from the outset of pandemic, alcohol-based hand sanitizers (ABHS) have been one of the first-line measures to control transmission of Coronavirus Disease 2019 (COVID-19). The purpose of this narrative review is to evaluate the sensitivity of SARS-CoV-2 towards ABHS and understand their potential adverse effects on humans. Ethanol and isopropanol have been the most commonly used alcohols in ABHS (e.g., gel, solution, spray, wipes, or foam) with alcohol in the range of 70–85% v/v in World Health Organization or Food and Drug Administration-approved ABHS. The denaturation of proteins around the envelope of SARS-CoV-2 positive sense single-stranded RNA virus is the major mechanism of action of ABHS. Due to frequent use of high-percentage alcohol-containing ABHS over an extended period of time, the oral, dermal, or pulmonary absorption is a possibility. In addition to the systemic toxicity, topical adverse effects such as contact dermatitis and atopic dermatitis are plausible and have been reported during COVID-19. ABHS appear to be effective in controlling the transmission of SARS-CoV-2 with the concern of oral, dermal, or pulmonary absorption.

The Effect of Absorption-Enhancement and the Mechanism of the PAMAM Dendrimer on Poorly Absorbable Drugs

The polyamidoamine (PAMAM) dendrimer is a highly efficient absorption promoter. In the present study, we studied the absorption-enhancing effects and the mechanism of PAMAM dendrimers with generation 0 to generation 3 (G0–G3) and concentrations (0.1–1.0%) on the pulmonary absorption of macromolecules. The absorption-enhancing mechanisms were elucidated by microarray, western blotting analysis, and PCR. Fluorescein isothiocyanate-labeled dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption-enhancing effects of PAMAM dendrimers on the pulmonary absorption of FDs were in a generation- and concentration-dependent manner. The G3 PAMAM dendrimer with high effectiveness was considered to the best absorption enhancer for improving the pulmonary absorption of FDs. G3 PAMAM dendrimers at three different concentrations were non-toxic to Calu-3 cells. Based on the consideration between efficacy and cost, the 0.1% G3 PAMAM dendrimer was selected for subsequent studies. The results showed that treatment with a 0.1% G3 PAMAM dendrimer could increase the secretion of organic cation transporters (OCTs), OCT1, OCT2, and OCT3, which might be related to the absorption-enhancing mechanisms of the pulmonary absorption of FDs. These findings suggested that PAMAM dendrimers might be potentially safe absorption enhancers for improving absorption of FDs by increasing the secretion of OCT1, OCT2, and OCT3.

Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers

Background Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. Methods Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. Results The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min–1 (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. Conclusions We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.