Xenografted Tumors Share Comparable Fraction Unbound and Can Be Surrogated by Mouse Lung Tissue.

Free (unbound) drug concentration at the site of action is the key determinant of biologic activity since only unbound drugs can exert pharmacological and toxicological effects. Unbound drug concentration in tumors for solid cancers is needed to understand/explain/predict pharmacokinetics, pharmacodynamics, and efficacy relations. Fraction unbound (fu ) in tumors is usually determined across several xenografted tumors derived from various cell lines in the drug discovery stage, which is time consuming and a resource burden. In this study, we determined the fu values for a set of diverse compounds (comprising acid, base, neutral, zwitterion, and covalent drugs) across five different xenografted tumors and five commercially available mouse tissues to explore the correlation of fu between tumors and the possibility of surrogate tissue(s) for tumor fu (fu,tumor) determination. The crosstumor comparison showed that fu,tumor values across tumors are largely comparable, and systematic tissue versus tumor comparison demonstrated that only lung tissue had comparable fu to all five tumors (fu values within twofold change for >80% compounds in both comparisons). These results indicated that mouse lung tissue can be used as a surrogate matrix for a fu,tumor assay. This study will increase efficiency in fu,tumor assessment and reduce animal use (adapting the replace, reduce, and refine principle) in drug discovery. SIGNIFICANCE STATEMENT: The free drug concept is a well accepted principle in drug discovery research. Currently, tumor fraction unbound (fu,tumor) is determined in several tumors derived from different cell lines to estimate free drug concentrations of a compound. The results from this study indicated that fu,tumor across xenografted tumors is comparable, and fu,tumor can be estimated using a surrogate tissue, mouse lung. The results will increase efficiency in fu,tumor assessment and reduce animal use in drug discovery.

Reliability of Extensor Pollicis Brevis (EPB) Entrapment Test in Identifying a Separate Compartment for EPB in Patients with de Quervain Disease.

Background: The presence of a separate compartment for the extensor pollicis brevis tendon (EPB) has an implication in the treatment outcome for de Quervain disease. The EPB entrapment test, proposed by Alexander and colleagues, claims to correlate with the presence of a separate compartment for EPB. The purpose of our study is to evaluate the reliability of the EPB entrapment test in predicting a separate compartment for EPB in patients with de Quervain disease. Methods: This was a prospective observational study involving 50 consecutive patients who underwent de Quervain release by a single surgeon. Preoperatively, EPB entrapment test was performed by the operating surgeon. The outcome of the test was recorded and the presence of a separate compartment for the EPB was determined during surgery. Sensitivity, specificity, positive predictive value and negative predictive value of the EPB entrapment test was determined. Results: EPB entrapment test was positive in 28 of 50 patients. In 21 of them, a separate compartment for the EPB was noted. The positive predictive value of the test was found to be 75.8%. The test had a false positive rate of 26.9%, a false negative rate of 12.5%, sensitivity of 87.5% and specificity of 73%. There is a significant association between a positive EPB entrapment test and the presence of a separate compartment for the EPB (p value <0.001). The sensitivity of the test increases to 95.8% if pain on both extension and abduction of the thumb is considered a positive response. Conclusions: The EPB entrapment test is a reliable clinical test to look for the presence of a separate compartment for EPB. Considering the response of pain on both extension and abduction of the thumb further improves the sensitivity of the test. Hence, we suggest including this response also as a positive test. Level of Evidence: Level II (Diagnostic).

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis.

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

An Uncommon Cause of Hypertensive Urgency in Young Adolescent: Case Report.

Mid aortic syndrome is rare cause of hypertensive urgency in children with poor outcome if left untreated, high index of suspicion with prompt management is the key to survival with good outcome. A 12-year-old boy was presented with fever, puffiness of face, and breathing difficulty. Clinically, he had hypertension with differential pulsation and BP in upper and lower limbs. He had peak systolic gradient of 80 mm Hg between upper and lower limb. His echocardiography and CT angiography was suggestive of significant isolated 80% narrowing of abdominal aorta without involvement any other large vessels. Percutaneous balloon dilatation of aorta was done considering multiple parameters. Post procedure, there was significant improvement in BP and we could wean his multiple anti-hypertensive drugs to keep his blood pressures below 95th centile. His BP remained control with minimum upper and lower limb gradient on follow up of almost 1 year. HOW TO CITE THIS ARTICLE: Dekate PS, Reddy S, Prasad VSV, Boda S, Saini L, Patil P. An Uncommon Cause of Hypertensive Urgency in Young Adolescent: Case Report. Indian J Crit Care Med 2019;23(7):339-341. KEY MESSAGE: Mid aortic syndrome is most uncommon amongst them. With prompt diagnosis and proper selection of therapeutic options like balloon dilatation or surgical correction, it has good prognosis. Aortic narrowing because of different diseases is an uncommon cause of HT urgency in children.

Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist.

A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4a-d and 5a-c respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30 µM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC50 of 4a (SB70) has been determined as 6 µM which is in the same range of current benchmarks for PAR2 antagonists.

Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia.

Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.

Rational design, synthesis, and structure-activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.

Effect of organic versus inorganic fluoride on enamel microhardness: An in vitro study.

INTRODUCTION: Dental caries is one of the most prevalent infectious diseases affecting the human dentition. Fluorides are effective anti-carious agents and have been widely used for caries prevention in the form of systemic and topical fluorides. Neutral sodium fluoride (NaF) is commonly used as a topical fluoride agent. A special category of topical fluorides are organic fluorides in the form of amine fluorides (AmF). Researchers have reported that AmF is superior to inorganic fluorides in improving the caries resistance of enamel due to the significant anti-enzyme effect of the organic fragment. AIM: The aim of the present study was to compare the enamel surface micro hardness after topical application of NaF and AmF solutions. MATERIALS AND METHODS: Twenty fresh samples of sound human enamel were treated with demineralizing solution for 72 h and divided into Group A (treated with NaF) and Group B (treated with AmF) solutions for 3 min twice daily for 7 days. In between treatment, the samples were stored in artificial saliva. The enamel surface hardness was measured with Vickers hardness test at baseline, post-demineralization and post-treatment with two different fluoride solutions (NaF and AmF) and a comparative analysis was made. RESULTS: The increase in mean micro hardness of human enamel after treatment with AmF application was found to be statistically significant (P < 0.01) when compared to the mean micro hardness after treatment with NaF. CONCLUSION: Fluoride enhances the remineralization process by accelerating the growth of enamel crystals that have been demineralized. It can be concluded from the present study that AmF compounds result in a marked increase in enamel micro hardness when compared to NaF.

Comparison of shear bond strength of aesthetic restorative materials.

AIM: The present study was conducted to determine and compare the shear bond strengths of Conventional glass ionomer; Resin-modified glass ionomer; Polyacid-modified composite and Composite Resin, and to assess and determine the mode of failure (adhesive, cohesive, mixed). MATERIALS AND METHODS: Occlusal dentin of 40 extracted human teeth were randomly divided into four groups of ten teeth, each based on the restorative materials tested as follows: Group I: Conventional Glass Ionomer Cement (Control); Group II: Resin-modified Glass Ionomer Cement; Group III: Polyacid-modified Composite Resin; Group IV: Hybrid Composite Resin. The bonded materials were subjected to shear bond strength (SBS) testing in a Instron Universal Testing Machine (UTM) at a crosshead speed of 0.5 mm/min. The bond failure location was examined by the use of a stereomicroscope at 10× magnification. The mean SBS of Groups I-IV obtained was 3.81, 9.71, 11.96 and 18.16 MPa, respectively. Comparison of mean shear bond strengths of all groups was done by one way ANOVA test and comparison of means in between groups by the Student's t test. CONCLUSION: It is concluded that the compomer restorative materials show higher shear bond strength than conventional glass-ionomer and resin-modified glass-ionomer, but less than composite resin.

Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability.