Acid sphingomyelinase: No potential as a biomarker for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) lacks reliable biomarkers that reflect disease activity. Recent evidence suggests that an altered sphingolipid metabolism is associated with MS pathogenesis. OBJECTIVE: To explore acid sphingomyelinase (ASM) activity and altered sphingolipid metabolism as potential biomarkers in serum of MS patients, to predict active and progressive disease, and response to disease modifying therapy (DMT). METHODS: Levels of serum ASM activity were longitudinally analyzed in 40 clinically isolated syndrome, 64 relapsing remitting (RR) and 10 primary progressive MS patients, and 22 healthy controls (HC). ASM activity and sphingolipid levels were measured in a different sample of 61 RRMS patients using DMT. RESULTS: A significant difference in ASM activity levels was observed between MS patients and HC (p < 0.001). There was no correlation between ASM activity levels and disease activity, progression or response to DMT. Ceramide (Cer)-C16:0 , Cer-C24:0 and sphingomyelin (SM)-C20:0, SM-C22:0, SM-C24:0 and SM-C24:1 showed a significant increase during fingolimod use. CONCLUSION: Although higher levels in MS patients were found, ASM activity levels do not show potential as a biomarker for predicting disease activity, progression or response to DMT. Two ceramides and four types of sphingomyelin require further investigation as potential markers for treatment response.

From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II-Sensitivity to Physiological and Physicochemical Properties.

To develop a maturation function for drug glucuronidation in children, that can be used in population and physiologically based modeling approaches, the physiological and physicochemical basis of a semiphysiological glucuronidation function for children was untangled using Simcyp. The results show that using the currently available in vitro data, in vivo morphine and zidovudine clearances were under predicted by the physiologically based model in Simcyp. The maturation profile was similar to the clinically observed profile except for the first 2 weeks of life, and liver size and UGT2B7 ontogeny are the physiological drivers of the maturation of glucuronidation. Physicochemical drug parameters did not affect this maturation profile, although log P and pKa influenced the absolute value of clearance. The results suggest that the semiphysiological glucuronidation function for young children can be used to predict the developmental clearance profile of other UGT2B7 substrates, though scenarios with nonlinear kinetics and high-extraction ratios require further investigation.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e10; doi:10.1038/psp.2012.12; advance online publication 10 October 2012.