Operational definitions improve reliability of the age-related white matter changes scale.

BACKGROUND AND PURPOSE: Although the age-related white matter changes (ARWMC) scale has been advocated to be applicable to both MRI and CT for assessing the severity of WMC, its inter-rater reliability on CT is only fair. We aimed to operationalize the ARWMC scale and investigate the effect of this operationalization on the reliability and validity on MRI and CT. METHODS: Operational definitions of the ARWMC scale were derived from Erkinjuntti research criteria for subcortical vascular dementia and Scheltens scale. Using original and operationalized ARWMC scale, eight observers recorded the time for rating per MRI and per CT. We investigated the inter-rater and intrarater reliability as well as validity against volume using data from 97 stroke patients. RESULTS: Inter-rater reliability of the operationalized scale on CT (0.874, 95% confidence interval [0.780-0.934]) was better than the original scale (0.569, 95% confidence interval [0.247-0.775]). Its intrarater reliability on CT (0.869) and reliability on MRI (inter-rater: 0.860; intrarater: 0.838) was comparable with the original scale (CT intrarater: 0.750 and on MRI inter-rater: 0.845; intrarater: 0.853). The time required to administer the operationalized scale (4'2″ for MRI and 1'18″ for CT) was similar to that of the original scale (3'56″ for MRI and 1'16″ for CT). The original scale and operationalized scale also significantly correlated with WMC volume (operationalized scale ρ = 0.613, P < 0.001, original scale ρ = 0.638, P < 0.001). CONCLUSION: Operational definitions improve the inter-rater reliability of ARWMC scale on CT, and it correlates with volumetric measurement.

Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.

AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.