Reliability and Validity of the Adapted Nepali Version of the AO Spine Patient Reported Outcome Spine Trauma.

BACKGROUND: The AO Spine Patient Reported Outcome Spine Trauma has been validated in English and Dutch language, however, there is an absence of a translated and validated version in Nepali language. The purpose of this study was to translate the AO Spine Patient Reported Outcome Spine Trauma into Nepali and adapt cross-culturally as outlined by established guidelines, as well as test its psychometric properties among Nepali speaking spine trauma patients. METHODS: Patients were recruited from two Nepali centers as a cross-sectional multicenter validation study. The English version of AO Spine Patient Reported Outcome Spine Trauma was translated and cross-culturally adapted into Nepali language following international guidelines. Next to AO Spine Patient Reported Outcome Spine Trauma also the EQ-5D-3L was filled out by the patients for concurrent validity. Descriptive statistics were used to analyze the patient characteristics. Assessment of measurement properties included content validity (floor and ceiling effects), internal consistency (Cronbach's ? and item total-correlation coefficients) and test-retest reliability by the Bland-Altman plot and Intraclass Correlation Coefficients. Spearman correlation tests were performed within the items and in correlation to EQ-5D-3L. RESULTS: Sixty two spine trauma patients completed the instrument with a mean time of 6.8 minutes. The translated version showed good content validity with no floor and ceiling effects. The internal consistency was excellent with a Cronbach's ? of 0.95. The Spearman correlations within the AO Spine Patient Reported Outcome Spine Trauma items were 0.07 - 0.65 and the test-retest analysis showed excellent results with an Intraclass Correlation Coefficients value of 0.95 (CI 0.93 - 0.97). Inverse correlation was observed between Nepali AO Spine PROST with EQ-5D-3L components. CONCLUSIONS: The Nepali version of AO Spine Patient Reported Outcome Spine Trauma demonstrated excellent validity and reliability results for measuring patient-reported outcomes of spine trauma patients.

Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy.

Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.

Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E(2) synthase-1 inhibitors.

mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE2. Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs (28, 48, 49) were identified with <10nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE2 biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib.

Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR and pharmacokinetic evaluation.

The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed.