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The measurement of tissue lipid and glycogen contents and the establishment of normal levels of variability are important when assessing changes caused by pathology or treatment. We measured hepatic and skeletal muscle lipid and glycogen levels using 1H and 13C MRS at 3 T in groups of subjects with and without type 2 diabetes. Within-visit reproducibility, due to repositioning and instrument errors was determined from repeat measurements made over 1 h. Natural variability was assessed from separate measurements made on three occasions over 1 month. Hepatic lipid content was greater in subjects with diabetes relative to healthy subjects ( p = 0.03), whereas levels of hepatic and skeletal muscle glycogen, and of intra- and extra-myocellular lipid, were similar. The single-session reproducibility values (coefficient of variation, CV) for hepatic lipid content were 12% and 7% in groups of subjects with and without diabetes, respectively. The variability of hepatic lipid content over 1 month was greater than the reproducibility, with CV = 22% ( p = 0.08) and CV = 44% ( p = 0.004) in subjects with and without diabetes, respectively. Similarly, levels of variation in basal hepatic glycogen concentrations (subjects with diabetes, CV = 38%; healthy volunteers, CV = 35%) were significantly larger than single-session reproducibility values (CV = 17%, p = 0.02 and CV = 13%, p = 0.05, respectively), indicating substantial biological changes in basal concentrations over 1 month. There was a decreasing correlation in measurements of both hepatic lipid and glycogen content with increasing time between scans. Levels of variability in intra- and extra-myocellular lipid in the soleus muscle, and glycogen concentrations in the gastrocnemius muscle, tended to be larger than expected from single-session reproducibility, although these did not reach significance. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article discusses research done on the impact of the Src kinase inhibitor saracatinib on bone turnover in healthy men. Src is a nonreceptor tyrosine kinase that has a significance to osteoclast function and bone resorption. Study subjects consisted of 59 men whose mean age was 34.6 years old and who were divided into five groups. It found that there were no significant changes in bone turnover compared to placebo after initial dose of saracatinib.

The primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed. Twelve healthy volunteer subjects (age range 22–48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full ‘cocktail’ as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUClast (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events Overall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67–1.10), midazolam, 0.96 (0.74–1.24), tolbutamide, 0.86 (0.72–1.03), debrisoquine 1.04 (0.97–1.12) and chlorzoxazone, 0.95 (0.86–1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone. The five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically important drug–drug interactions during drug development. [ABSTRACT FROM AUTHOR]

A correction to the article "Effects of the Src Kinase Inhibitor Saracatinib (AZD0530) on Bone Turnover in Healthy Men: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending-Dose Phase I Trial" that was published in a 2010 issue is presented.

Aims: To determine whether there is a pharmacokinetic interaction between the antiepileptic drugs remacemide and phenobarbitone., Methods: In a group of 12 healthy adult male volunteers, the single dose and steady-state kinetics of remacemide were each determined twice, once in the absence and once in the presence of phenobarbitone. The effect of 7 days remacemide intake on initial steady-state plasma phenobarbitone concentrations was also investigated., Results: Apparent remacemide clearance (CL/F) and elimination half-life values were unchanged after 7 days intake of the drug in the absence of phenobarbitone (1.25 +/- 0.32 vs 1.18 +/- 0.22 l kg(-1) h(-1) and 3.29 +/- 0.68 vs 3.62 +/- 0.85 h, respectively). Concomitant administration of remacemide with phenobarbitone resulted in an increase in the estimated CL/F of remacemide (1.25 +/- 0.32 vs 2.09 +/-0.53 l kg-1 h-1), and a decreased remacemide half-life (3.29 +/- 0.68 vs 2.69 +/- 0.33 h). The elimination of the desglycinyl metabolite of remacemide also appeared to be increased after the phenobarbitone intake (half-life 14.72 +/- 2.82 vs 9.61 +/- 5.51 h, AUC 1532 +/- 258 vs 533 +/- 281 ng ml(-1) h). Mean plasma phenobarbitone concentrations rose after 7 days of continuing remacemide intake (12.67 +/- 1.31 vs 13.86 +/- 1.81 microgram ml(-1))., Conclusions: Phenobarbitone induced the metabolism of remacemide and that of its desglycinyl metabolite. Remacemide did not induce its own metabolism, but had a modest inhibitory effect on the clearance of phenobarbitone.