Introduction: SARS-CoV-2 (COVID-19) patients who develop acute respiratory distress syndrome (ARDS) can suffer acute lung injury, or even death. Early identification of severe disease is essential in order to control COVID-19 and improve prognosis. Oxidative stress (OS) appears to play an important role in COVID-19 pathogenesis; we therefore conceived a study of the potential discriminative ability of serum biomarkers in patients with ARDS and those with mild to moderate disease (non-ARDS). Method: 60 subjects were enrolled in a single-centre, prospective cohort study of consecutively admitted patients: 29 ARDS/31 non-ARDS. Blood samples were drawn and marker levels analysed by spectrophotometry and immunoassay techniques. Results: C-reactive protein (CRP), lactate dehydrogenase (LDH), and ferritin were significantly higher in ARDS versus non-ARDS cases at hospital admission. Leukocytes, LDH, ferritin, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) were also significantly elevated in ARDS compared to non-ARDS patients during the hospital stay. Total thiol (TT) was found to be significantly lower in ARDS. Conversely, D-dimer, matrix metalloproteinase-9 (MMP-9) and advanced glycosylated end products (AGE) were elevated. Leukocytes, LDH, CRP, ferritin and IL-6 were found to be significantly higher in non-survivors. However, lymphocyte, tumour necrosis factor beta (TGF-β), and TT were lower. Conclusion: In summary, our results support the potential value of TT, ferritin and LDH as prognostic biomarkers for ARDS development in COVID-19 patients, distinguishing non-ARDS from ARDS (AUCs = 0.92; 0.91; 0.89) in a fast and cost-effective manner. These oxidative/inflammatory parameters appear to play an important role in COVID-19 monitoring and can be used in the clinical management of patients.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug−drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions. KEYWORDS: SERT, NET, dual, reuptake inhibitor, SNRI, SERT RO, α-MMT, pain M anipulation of central nervous system (CNS) levels of the neurotransmitters serotonin (5-HT) and norepinephrine (NE), through inhibition of the corresponding reuptake transporters SERT (serotonin transporter) and NET (norepinephrine transporter), has been a successful strategy for treating several CNS disorders including depression, generalized anxiety disorder, and several chronic pain conditions. 1−6 Several compounds that selectively inhibit these transporters (known as serotonin norepinephrine reuptake inhibitors or SNRIs) are available on the market (compounds 5−8, see Figure 1) and have proven to be safe and effective drugs for the treatment of pain and/or mood disorders. However, these molecules often show more potent inhibition of SERT than NET in vitro (Table 1). Published studies have demonstrated that selective SERT and NET inhibitors can show additive or synergistic analgesic efficacy. 7,8 For our targeted indication of pain, we hypothesized that a SNRI that inhibited SERT and NET with comparable potency would lead to a compound with a superior efficacy and safety profile. Therefore, we undertook to develop a new SNRI that, in a single molecule, improved NET activity versus current SNRIs, retained potent and balanced in vivo activity at both transporters, had good brain exposure, was metabolically stable, and provided minimal drug−drug interaction (DDI) risk to patients on other therapies.Our search for a balanced SNRI led to the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Amine containing compounds have long been a fertile source of reuptake inhibitors with a variety of profiles. 9 SNRIs 5−8 all show a similar pharmacophore, with an amine and an aryl group separated by 2−4 sp 3 hybridized atoms. The pyrrolidines we synthesized and tested represent a conformationally constrained version of this general pharmacophore that maintains potent transporter inhibition. 10 Compound 1 contains several innovative features that make it an improvement over earlier scaffolds. The pyrrolidine ring provided the secondary amine that is common to many reuptake inhibitors, but in a novel constrained geometry. Introduction of the pyridine ring, in place of a phenyl ring, was a key change that delivered both our desired pharmacological profile and...

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