The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis. ß

The AUC of mycophenolic acid is predictive of the likelihood of allograft rejection after renal transplantation in patients receiving mycophenolate mofetil.

A randomized, crossover study of 12 healthy volunteers was conducted with single, 1.5-g doses of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), after oral and intravenous administration. During the intravenous infusion, phase systemic plasma clearance of MMF was approximately 10 L/min and the half-life (t1/2) was a few minutes. After oral administration, however, plasma MMF was below quantitation limits at all times. The plasma MPA profile of oral MMF showed a sharp peak at approximately 1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t1/2 of MPA was similar for both routes (approximately 17 hours). The area under the concentration-time curve (AUC) from time 0 to 24 hours was statistically higher for intravenous than for oral administration, but total AUC showed statistical equivalence (80-120 rule), with mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route. Total plasma AUC of mycophenolic acid glucuronide (MPAG), the sole metabolite of MPA, was four- to five-fold higher than MPA. Total 48-hour MPAG recovery in urine was statistically equivalent for the two routes and represented a mean of 70% of administered drug; corresponding MPA recovery was less than 1%. Renal clearance (ClR) values required transport mechanisms for MPAG, but not for MPA. The ClR of MPAG was statistically higher after intravenous administration than oral administration. MMF administered orally undergoes rapid, complete absorption and essentially complete presystemic deesterification. There was presystemic removal of MPA, but enterohepatic circulation compensated for the first pass loss. Renal metabolism of MPA also may have occurred.

No abstract

Colour evolution and colour changes were analysed from surface images of small specimens of three thermally-modified timber species using the CIEL*a*b* colour space. Upon heat exposure, the wood substance became orange and then approached grey irrespective of species; this was accompanied by a steady reduction in lightness. Colour changes were similar in the three woods at any given level of heat-induced weight loss (WL), whilst changes in the three coordinates of the CIEL*a*b* space in function of WL were different regardless of the wood species. For DL*, the profile was curvilinear and monotonous, while Da* and Db* bear a complex, non-linear profile. In turn, DE* was found to be highly influenced by the behaviour of DL*. It is proposed that DE* in thermally modified wood originates from chemical changes in the main wood polymers, more so in lignin than in polysaccharides, due to the darkening of the lignin itself. This was associated with the generation of chromophoric groups, mainly the increase in carbonyl groups appearing in the Fourier transform infrared spectra of lignin between 1710 and 1600 cm -1 , particularly the emergence of quinone species.Digital images (3550=450 pixels) of TMW surfaces (radial plane) were recorded on an Epson Perfection 4990 flatbed scanner on conditioned specimens without further preparation. Ten specimens per treatment (a combination time-temperature) were scanned for each species; only the after-treatment colour was measured. The before-treatment colour used for each modified