Novel predictors of response to therapy with terlipressin and albumin in hepatorenal syndrome-acute kidney injury.

Background: A combination of terlipressin and albumin is the first-line pharmacologic treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI). We assessed the response rates to terlipressin-albumin therapy in patients with HRS-AKI and determined early predictors of treatment response and survival. Methods: A total of 84 patients with HRS-AKI (International Club of Ascites definition 2015) treated with terlipressin-albumin were included. Predictors of HRS reversal were identified by logistic regression analysis. Survival analysis was performed using the Kaplan-Meier method, and Cox regression models were used to determine independent predictors of mortality. Results: Complete response to therapy was observed in 54.8%, partial response in 14.3%, and no response in 31% of patients. The factors associated with complete treatment response were the presence of systemic inflammatory response syndrome (SIRS), baseline serum creatinine, a rise in mean arterial pressure by day 3, and a reduction in the renal resistive index (ΔRRI) by day 3 of treatment. Independent predictors of HRS reversal were the presence of SIRS at baseline (P=0.022; odds ratio [OR] 15.74, 95% confidence interval [CI] 1.47-167.82) and ΔRRI ≥5% by day 3 of treatment (P=0.048; OR 6.67, 95%CI 1.021-43.62). Mean transplant-free survival at 6 months was significantly better in treatment responders (148 vs. 90 days, P<0.001). Independent predictors of 6-month mortality were response to treatment (P=0.004) and model for end-stage liver disease-sodium >23 (P=0.018). Conclusions: SIRS and ΔRRI are simple parameters to predict treatment response in HRS-AKI. Non-responders have higher mortality and should be identified early to expedite liver transplantation.

A case-cohort study of left ventricular diastolic dysfunction in patients with cirrhosis: the liver-heart axis.

Background: Left ventricular diastolic dysfunction (LVDD) is an early manifestation of cirrhotic cardiomyopathy. Few studies have addressed its clinical significance in cirrhosis. We assessed the association of LVDD with the factors affecting cirrhosis patients' severity, complications, and survival. Methods: A total of 203 cirrhosis patients were enrolled and underwent investigations, including 2-dimensional echocardiography with tissue Doppler imaging, and 139 patients with LVDD (cases) were compared with 64 patients without LVDD (controls). Logistic regression and Kaplan-Meier analysis were applied. Results: Mean age was 52.76±10 years. Among LVDD patients, 56% had grade-1, and 44% had grade-2 LVDD. Cirrhosis related to NASH had a more significant association with LVDD (P<0.001) than other etiologies. LVDD was significantly associated with a greater incidence of Child-Turcotte-Pugh (CTP) class C (P<0.001), higher model for end-stage liver disease scores (P=0.001), duration of cirrhosis >2 years since diagnosis (P=0.028), ascites (P<0.001), hepatic encephalopathy (P<0.010), hepatorenal syndrome (P<0.001), and a history of obesity (P=0.004). Multivariate analysis showed that higher CTP score, ascitic fluid protein and prolonged QTc interval were independently associated with LVDD (P=0.009; P=0.018; P=0.016, respectively). Kaplan-Meier survival analysis showed significantly poorer survival status in patients with higher grades of LVDD (P<0.001). The area under the receiver operating characteristic curve (0.78) was greatest for ascitic fluid protein in predicting LVDD, with a cutoff of >1 g/dL. Conclusions: Higher CTP score, prolonged QTc, higher ascitic fluid protein levels, and poor survival are significantly associated with LVDD. Ascitic fluid protein >1 g/dL could be an indicator for evaluating LVDD.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

5-HT6 Receptor Agonist and Antagonist Against ß-Amyloid-Peptide-Induced Neurotoxicity in PC-12 Cells.

Beta-amyloid peptide (Aß) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer's disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against Aß-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The Aß25-35 (50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented Aß25-35-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aß25-35-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aß25-35 induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD.

Preparation and characterization of chiral oxazaborolidine complex immobilized SBA-15 and its application in the asymmetric reduction of prochiral ketones.

The immobilization of chiral oxazaborolidine complex in the well-ordered mesochannels of SBA-15 is demonstrated by a postsynthetic approach using 3-aminopropyltriethoxysilane as a reactive surface modifier. The immobilized catalysts are characterized by various techniques, such as XRD, nitrogen adsorption, HRSEM, UV/Vis diffuse reflectance spectroscopy, and FTIR spectroscopy. The catalysts are used for the enantioselective reduction of aromatic prochiral ketones. The activity of the chiral oxazaborolidine complex immobilized SBA-15 catalysts is also compared with that of the pure chiral oxazaborolidine complex, which is a homogeneous catalyst. It is found that the activity of the chiral complex immobilized SBA-15 heterogeneous catalyst is comparable with that of the homogeneous catalyst.

Optically active metallo-supramolecular polymers derived from chiral bis-terpyridines.

The optically active metallo-supramolecular polymers were successfully synthesized via complexation of Fe(II) ions with new bis-terpyridines containing chiral tetra-ethylene glycol units at the ortho-position of the peripheral pyridine rings. In addition, we also revealed solvent and temperature effects toward assembly and dis-assembly behavior of polymers.

Effect of PEG-PLLA diblock copolymer on macroporous PLLA scaffolds by thermally induced phase separation.

A regular and highly interconnected macroporous poly(L-lactic acid) (PLLA) scaffold was fabricated from a PLLA-dioxane-water ternary system with added polyethylene glycol (PEG)-PLLA diblock using thermally induced phase separation (TIPS). The morphology of the scaffold was investigated in detail by controlling the following TIPS parameters: quenching temperature, aging time, polymer concentration, molecular structure, and diblock concentration. The phase diagram was assessed visually on the basis of the turbidity. The cloud-point curve shifted to higher temperatures with increasing PEG content in the additives (PEG-PLLA diblocks), due to a stronger interaction between PEG and water in solution. The addition of diblock series (0.5 wt% in solution) stabilized interconnections of pores at a later stage without segregation or sedimentation. The pore size of the scaffold could be easily controlled in the range 50-300 microm. A macroporous PLLA scaffold was used to study an MC3T3-E1 cell (an osteoblast-like cell) culture. The cells successfully proliferated in the PLLA scaffold in the presence of added PEG-PLLA diblock for 4 weeks.