S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview

S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation (NO+) and a thiolate (RS−), the base of the corresponding acids RSH. The smallest S-nitrosothiol is HSNO and derives from hydrogen sulfide (HSH, H2S). The most common physiological S-nitrosothiols are derived from the amino acid L-cysteine (CysSH). Thus, the simplest S-nitrosothiol is S-nitroso-L-cysteine (CysSNO). CysSNO is a spontaneous potent donor of nitric oxide (NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate (cGMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation. Like NO, CysSNO is a short-lived species and occurs physiologically at concentrations around 1 nM in human blood. CysSNO can be formed from CysSH and higher oxides of NO including nitrous acid (HONO) and its anhydride (N2O3). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NO+ group is reversibly transferred to another thiolate. By this way numerous RSNO can be formed such as the low-molecular-mass S-nitroso-N-acetyl-L-cysteine (SNAC) and S-nitroso-glutathione (GSNO), and the high-molecular-mass S-nitrosol-L-cysteine hemoglobin (HbCysSNO) present in erythrocytes and S-nitrosol-L-cysteine albumin (AlbCysSNO) present in plasma at concentrations of the order of 200 nM. All above mentioned RSNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free RSNO. Thus, we prepared the ethyl ester of SNAC, the S-nitroso-N-acetyl-L-cysteine ethyl ester (SNACET), from synthetic N-acetyl-L-cysteine ethyl ester (NACET). Both NACET and SNACET have improved pharmacological features over N-acetyl-L-cysteine (NAC) and S-nitroso-N-acetyl-L-cysteine (SNAC), respectively, including higher oral bioavailability. SNACET exerts NO-related activities which can be utilized in the urogenital tract and in the cardiovascular system. NACET, with high oral bioavailability, is a strong antioxidant and abundant precursor of GSH, unlike its free acid N-acetyl-L-cysteine (NAC). Here, we review the chemical and pharmacological properties of SNACET and NACET as well as their analytical chemistry. We also report new results from the ingestion of S-[15N]nitroso-N-acetyl-L-cysteine ethyl ester (S15NACET) demonstrating the favorable pharmacological profile of SNACET

Surgical Data Science - from Concepts toward Clinical Translation

Recent developments in data science in general and machine learning in particular have transformed the way experts envision the future of surgery. Surgical Data Science (SDS) is a new research field that aims to improve the quality of interventional healthcare through the capture, organization, analysis and modeling of data. While an increasing number of data-driven approaches and clinical applications have been studied in the fields of radiological and clinical data science, translational success stories are still lacking in surgery. In this publication, we shed light on the underlying reasons and provide a roadmap for future advances in the field. Based on an international workshop involving leading researchers in the field of SDS, we review current practice, key achievements and initiatives as well as available standards and tools for a number of topics relevant to the field, namely (1) infrastructure for data acquisition, storage and access in the presence of regulatory constraints, (2) data annotation and sharing and (3) data analytics. We further complement this technical perspective with (4) a review of currently available SDS products and the translational progress from academia and (5) a roadmap for faster clinical translation and exploitation of the full potential of SDS, based on an international multi-round Delphi process