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Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5 ) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1 . Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (-/-) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD.

Purpose: The Pain assessment using a novel digital application (Panda) is a smartphone application that contains the digital versions of the visual analogue scale (VAS-100) and numeric rating scale (NRS-11). This study aimed to investigate if the Panda versions of these two pain scales are equivalent to the paper versions in adult patients., Methods: This was a prospective, randomized, cross-over-controlled trial of subjects aged 19-75 yr undergoing procedures with anticipated post-surgical pain. Each subject used both the Panda and paper versions of VAS-100 or NRS-11 pain scores after emergence from anesthesia and after meeting postanesthesia care unit (PACU) discharge criteria. Correlations between the two tools were analyzed, and Bland-Altman agreement was calculated. The smartphone and paper versions were considered equivalent at each time point if the differences (and their 95% confidence interval [CI]) between them were less than 20 points for the VAS-100 and 2.1 for NRS-11., Results: The two versions of the VAS-100 correlated strongly after emergence (Pearson's r = 0.93; P < 0.001) and upon meeting discharge criteria (r = 0.94; P < 0.001); the mean (standard deviation [SD]) Panda score after emergence was 35 (27) compared with the paper score of 37 (26) (mean difference, - 2; 95% CI, - 22 to 19). The mean (SD) VAS-100 Panda score upon meeting discharge criteria was 21 (20) compared with the paper score of 23 (21) (mean difference, - 2; 95% CI, - 17 to 13). For the NRS-11, Panda again correlated strongly with the original tool scores after emergence (r = 0.93; P < 0.001) and upon meeting discharge criteria (r = 0.96; P < 0.001); the mean (SD) Panda and paper scores after emergence were both 4 (3) (mean difference, 0.05; 95% CI, - 1.87 to 1.96). The mean (SD) NRS-11 Panda and paper scores upon meeting PACU discharge criteria were both 3 (2) (mean difference, - 0.08; 95% CI, - 1.41 to 1.26)., Conclusion: Following emergence from anesthesia in adult patients, the digital Panda version of the NRS-11, but not the VAS-100, is equivalent to the validated paper version. In those who are ready for discharge from the PACU, the digital Panda versions of both the VAS-100 and NRS-11 agreed adequately and can be used in place of the original paper versions.

A number of symmetric and asymmetric 5'-phosphate esters of the potent anti-varicella-zoster virus (VZV) agent 1-(beta-D-arabinofuranosyl)-5-prop-1-ynyluracil (882C; netivudine) were prepared as potential lipophilic, membrane-soluble prodrugs of the bio-active phosphate forms. The compounds were prepared by the base-catalysed coupling of various phosphorochloridates with the free nucleoside analogue. Compounds were fully characterized by a range of spectroscopic and analytical methods and were studied for their inhibition of several viruses in tissue culture. All of the phosphate esters were inactive against human cytomegalovirus, herpes simplex virus type 2, VZV, human immunodeficiency virus type 1 and influenza A virus (EC50 > 100 microM) except the 5'-(4-nitrophenyl phenyl) phosphate, which inhibited influenza A virus. The relative rate of esterase-mediated hydrolysis of one of the lead target structures was measured in order to rationalize the poor antiviral action, and data were collected on possible metabolites in support of this analysis. Cell-specific esterases are implicated as key determinants of the antiviral potency of prodrugs of this type.

Lipophilic masked aryloxyaminoacylphosphoramidate derivatives of 2',3'-dideoxynucleoside (ddN) analogues with potent anti-HIV activity (i.e., stavudine [d4T], azidothymidine [AZT], dideoxycytidine [ddC], 3'thio-2',3'-dideoxy cytidine [3TC], dideoxyadenosine [ddA], and 2',3'-didehydro-2',3'-dideoxyadenosine [d4A]) activity were evaluated for their activity against visna virus (VV) in sheep choroid plexus (SCP) cells. The activity of several prodrug derivatives against VV proved markedly superior to that of the corresponding free ddN analogues. In particular, the d4A and ddA prodrug derivatives were exquisitely inhibitory in this model system (50% effective concentration [EC50], < or = 0.003 microM), and their anti-VV potency exceeded by at least 200-fold the antiviral potency of the corresponding free nucleosides. Marked differences were noted in the anti-VV potencies of several of the test compounds depending on the nature of the amino acid linked to the 5'-phosphate moiety, the nature of the nucleoside, or both. In view of the stability of the prodrugs in lamb serum, the VV infection model in lambs may be considered highly useful for investigating the in vivo antiretroviral efficacy of these type of drugs, particularly the d4T, ddA, and d4A prodrug derivatives.