A new chondrogenic differentiation initiator with the ability to up-regulate SOX trio expression.

During random screening for chondrogenic differentiation inducers, we found that Compound-1, 4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]benzene-1,3-diol, initiated chondrogenic differentiation of the chondroprogenitor cell line ATDC5. Compound-1 initiated chondrogenic differentiation of the mesenchymal stem cell line C3H10T1/2 in regions where cell aggregates formed and simultaneously inhibited adipogenic differentiation. In C3H10T1/2 cells, Compound-1 increased the expression of Sry-related high-mobility-group box transcription factors L-SOX5, SOX6, and SOX9 (SOX trio) more strongly than bone morphogenic protein (BMP)-2. cAMP-dependent protein kinase (PKA) inhibitors suppressed Compound-1-dependent L-SOX5 and SOX6 up-regulation. PKA inhibitors also suppressed the up-regulation of aggrecan mRNA induced by Compound-1, indicating that increases in L-SOX5 and SOX6 mRNA, in which the PKA pathway participates, are involved in the mechanisms behind the action of Compound-1. On the other hand, the SOX6 and aggrecan gene expression, which were up-regulated by BMP-2, were not affected by the PKA inhibitor. Compound-1 induced chondrogenic differentiation of bone marrow stromal cells and recovered cartilage matrix production by primary chondrocytes, which had been decreased by interleukin-1beta. These results show the potential of Compound-1 to be a new cartilage repair agent for inducing chondrogenic differentiation via SOX trio up-regulation.

Pharmacokinetic and pharmacodynamic evaluations of novel oral morphine sustained release granules.

Pharmacokinetics and pharmacodynamics of novel oral sustained-release granules based on swelling polymer incorporation layer system (SPILA granules) containing morphine hydrochloride was evaluated. SPILA granules were designed to release morphine faster in neutral environment than in acidic one to keep higher plasma levels over a protracted period, especially after 12 h post dose. SPILA granules were orally administered to beagle dogs to compare the pharmacokinetics with commercially available twice-a-day dosage form, MS Contin. T(max) and AUC(0-24 h) values of SPILA granules were 6 h and 191 microg.h/ml, respectively. T(max) and AUC(0-24 h) values of MS Contin were 2 h and 146 microg.h/ml, respectively. Relative bioavailability following SPILA granules administration to twice-a-day MS Contin (30 mg) administration was 131%. In rats, analgesic effect was evaluated over 24 h. SPILA granules and aqueous solutions were administered to rats to compare the analgesic effect. AUC(0-24 h) value for SPILA granules was 8.88 microg.h/ml, which was a little lower than that for the aqueous solution (10.1 microg.h/ml), whereas the analgesic effect after SPILA granules once-a-day administration expressed as AURC (1701% Analgesia.h) was similar to that after the aqueous solution 4 times-a-day administration (1603% Analgesia.h). These results indicate that SPILA granules based on the pH-dependent release regulating polymer system can be a good candidate for an oral once-a-day sustained-release dosage form.