1. S-Nitroso- N-acetyl-l-cysteine Ethyl Ester (SNACET) Catheter Lock Solution to Reduce Catheter-Associated Infections
Rajnish Kumar, Hamed Massoumi, Manjyot Kaur Chug, Elizabeth J Brisbois ACS Appl Mater Interfaces. 2021 Jun 9;13(22):25813-25824. doi: 10.1021/acsami.1c06427. Epub 2021 May 24.
Antimicrobial-lock therapy is an economically viable strategy to prevent/reduce the catheter-related bloodstream infections (CRBSI) that are associated with central venous catheters (CVCs). Herein, we report the synthesis and characterization of the S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), a nitric oxide (NO)-releasing molecule, and for the first time its application as a catheter lock solution to combat issues of bacterial infection associated with indwelling catheters. Nitric oxide is an endogenous gasotransmitter that exhibits a wide range of biological properties, including broad-spectrum antimicrobial activity. The storage stability of the SNACET and the NO release behavior of the prepared lock solution were analyzed. SNACET lock solutions with varying concentrations exhibited tuneable NO release at physiological levels for >18 h, as measured using chemiluminescence. The SNACET lock solutions were examined for their efficacy in reducing microbial adhesion after 18 h of exposure toStaphylococcus aureus (Gram-positive bacteria) andEscherichia coli (Gram-negative bacteria). SNACET lock solutions with 50 and 75 mM concentrations were found to reduce >99% (ca. 3-log) of the adhered S. aureus and E. coli adhesion to the catheter surface after 18 h. The SNACET lock solutions were evaluated in a more challenging in vitro model to evaluate the efficacy against an established microbial infection on catheter surfaces using the same bacteria strains. A >90% reduction in viable bacteria on the catheter surfaces was observed after instilling the 75 mM SNACET lock solution within the lumen of the infected catheter for only 2 h. These findings propound that SNACET lock solution is a promising biocidal agent and demonstrate the initiation of a new platform technology for NO-releasing lock solution therapy for the inhibition and treatment of catheter-related infections.
2. Safety assessment of lactate esters
J J Clary, V J Feron, J A van Velthuijsen Regul Toxicol Pharmacol. 1998 Apr;27(2):88-97. doi: 10.1006/rtph.1997.1175.
Lactate esters have an oral LD50 greater than 2000 mg/kg and the inhalation LC50 is generally above 5000 mg/m3 and they may be potential eye and skin irritants, but not skin sensitizers. No evidence of teratogenicity or maternal toxicity was observed in an inhalation (2-ethylhexyl-l-lactate) or dermal study (ethyl-l-lactate). Subacute inhalation studies have been conducted at concentration up to 600 mg/m3 or higher on four lactate esters (ethyl, n-butyl, isobutyl, and 2-ethylhexyl-l-lactate). Degenerative and regenerative changes in the nasal cavity were noted in all studies. The NOAEL in ethyl, n-butyl, and isobutyl-l-lactate vapor studies was 200 mg/m3. For aerosol exposure, 2-ethylhexyl-l-lactate, the most toxic of the lactates, minimal damage to the nasal epithelium was noted at 75 mg/m3 with vapor being slightly less toxic than the aerosol. Lactates do not appear to cause systemic toxicity, except at very high concentrations (1800 mg/m3 or higher). These systemic effects may be secondary to severe irritation seen at high doses. Sensory irritation tests suggest that a vapor exposure limit of 75 mg/m3 ( approximately 15 ppm) should prevent irritation in humans and therefore an occupational exposure level for vapor of 75 mg/m3 is recommended. However, aerosol exposure should be kept as low as possible. The low vapor pressure of the higher molecular weight esters would tend to keep vapor exposure low and the odor of lactate esters serves as a warning of exposure. These lactate esters are readily biodegradable, suggesting little concern from an environmental point of view.
3. Omega-3 and cardiovascular prevention - Is this still a choice?
Massimiliano Ruscica, Cesare R Sirtori, Stefano Carugo, Philip C Calder, Alberto Corsini Pharmacol Res. 2022 Aug;182:106342. doi: 10.1016/j.phrs.2022.106342. Epub 2022 Jul 4.
There is currently growing attention being paid to the role of elevated triglycerides (TGs) as important mediators of residual atherosclerotic cardiovascular disease (ASCVD) risk. This role is supported by genetic studies and by the persistent residual risk of ASCVD, even after intensive statin therapy. Although TG lowering drugs have shown conflicting results when tested in cardiovascular outcome trials, data from the REDUCE-IT study with the ethyl ester of ω-3 eicosapentaenoic acid (EPA) have revived hope in this area of research. The aim of the present review is to critically discuss the most recent large trials with ω-3 fatty acids (FAs) trying to elucidate mechanistic and trial-related differences, as in the case of REDUCE-IT and STRENGTH studies. The ω-3 FAs may lower cardiovascular risk through a number of pleiotropic mechanisms, e.g., by lowering blood pressure, by mediating antithrombotic effects, by providing precursors for the synthesis of specialized proresolving mediators that can inhibit inflammation or by modulating the lipid rafts enriched in cholesterol and sphingolipids. In conclusion, in a field fraught with uncertainties, the ω-3 FAs and especially high dose icosapent ethyl (the ethyl ester of EPA) are at present a most valuable therapeutic option to reduce the ASCVD risk.
