Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody, in healthy Japanese male subjects.

Interleukin 5 (IL-5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti-IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single-blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750 mg) or placebo. Subjects were observed for up to 151 days postdose, depending on the dose administered. Blood samples were collected to measure mepolizumab concentrations, blood eosinophils, IL-5, and antibodies to mepolizumab. Mepolizumab exhibited dose-proportional pharmacokinetics. The terminal phase half-life was 19.7-34.6 days, independent of dose. Higher mepolizumab plasma concentrations were associated with lower blood eosinophil counts. Mepolizumab 75-750 mg reduced blood eosinophils for ≥3 months postdose. Mepolizumab demonstrated a favorable safety profile: of 41 reported adverse events, most were mild in severity and none were serious. No neutralizing antibodies to mepolizumab were detected. Sustained reduction in blood eosinophils after single intravenous mepolizumab doses ≥ 75 mg, along with mepolizumab pharmacokinetics and a favorable tolerability profile in healthy Japanese subjects, provides a solid foundation for future studies with mepolizumab in Japanese patients with asthma.

Effects of surface pre-reacted glass-ionomer fillers on mineral induction by phosphoprotein.

OBJECTIVES: The aim of this study was to evaluate the mineralizing potential of ions released from surface pre-reacted glass-ionomer (S-PRG) fillers on mineral induction by phosphoprotein in vitro. METHODS: Phosvitin was used as a model of dentin phosphoprotein in this study. Phosvitin was immobilized on agarose beads with divinyl sulfone. Five aliquots of phosvitin-immobilized agarose beads were incubated in control or experimental mineralizing solution. The experimental mineralizing solutions were made from eluates of resin filled with S-PRG fillers. The beads were incubated at 37°C in a shaking water bath, and aliquots were taken at several time points during the incubation. Then the beads were analyzed for calcium by atomic absorption spectrometry. RESULTS: Phosvitin-immobilized agarose beads induced mineral formation after incubation for 5.3h in the metastable solution without ions eluted from S-PRG fillers. Undiluted eluates significantly reduced mineral induction time. SEM observation and X-ray diffraction revealed larger apatite crystals on the beads incubated with eluates of S-PRG fillers than with the control. CONCLUSIONS: S-PRG fillers may play a role in mineral induction.

Water sorption/solubility of self-etching dentin bonding agents.

OBJECTIVES: The purpose of this study was to compare the water sorption/solubility, percent conversion and microtensile bond strength of three single-step self-etching adhesives with those of a two-step self-etching primer adhesive system. METHODS: Solvent evaporation from the adhesives was determined gravimetrically. After removal of volatile solvents, the resins were cast into disks and polymerized. One-half of the disks were incubated in water while the other half were incubated in hexadecane. Repeated measurements of water sorption were made for 10 days followed by drying for 2.5 days to a constant weight. Percent conversion was done using FTIR spectroscopy. Microtensile bond strengths were measured 24h after bonding. RESULTS: All of the adhesives lost 20-30% of their weight after 4 min of forced air except for Fluorobond II which lost no weight. All resins stored in water exhibited a time-dependent increase in water sorption and solubility. The resins stored in hexadecane showed very low sorption and solubility. Water sorption was highest for Absolute 2 (20.7%), intermediate for Fluorobond Shake One (10.2%) and lowest for Clearfil (3)S (8.9%) and Fluorobond II (7.5%). Percent conversions ranged from a low of 68.3% for Absolute 2 to a high of 87.4% for Clearfil (3)S. The two-step self-etching primer adhesive (Fluorobond II) gave the lowest water sorption and lowest solubility of any of the tested adhesives. SEM observations of resin disks incubated in hexadecane looked similar to unincubated controls. Incubating resin disks in artificial saliva covered the surfaces of the resins with mineral crystallites. SIGNIFICANCE: Single bottle self-etching adhesives show higher water sorption/solubilities than two-step self-etching adhesives. The former products would not be expected to function as well as the latter products.

In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists.

Novel isoxazolopyridone derivatives that are metabotropic glutamate receptor (mGluR) 7 antagonists were discovered and pharmacologically characterized. 5-Methyl-3,6-diphenylisoxazolo[4,5-c]pyridin-4(5H)-one (MDIP) was identified by random screening, and 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) was produced by chemical modification of MDIP. MDIP and MMPIP inhibited L-(+)-2-amino-4-phosphonobutyric acid (L-AP4)-induced intracellular Ca2+ mobilization in Chinese hamster ovary (CHO) cells coexpressing rat mGluR7 with Galpha(15) (IC50 = 20 and 26 nM). The maximal response in agonist concentration-response curves was reduced in the presence of MMPIP, and its antagonism is reversible. MMPIP did not displace [3H](2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) bound to mGluR7. These results suggested that these isoxazolopyridone derivatives are allosteric antagonists. In CHO cells expressing rat mGluR7, MDIP and MMPIP inhibited l-AP4-induced inhibition of forskolin-stimulated cAMP accumulation (IC50 = 99 and 220 nM). In CHO cells coexpressing human mGluR7 with Galpha(15), MDIP and MMPIP also inhibited the l-AP4-induced cAMP response. The maximal degree of inhibition by MMPIP was higher than that by MDIP in a cAMP assay. MMPIP was able to antagonize an allosteric agonist, the N,N'-dibenzhydryl-ethane-1,2-diamine dihydrochloride (AMN082)-induced inhibition of cAMP accumulation. In the absence of these agonists, MMPIP caused a further increase in forskolin-stimulated cAMP levels in CHO cells expressing mGluR7, whereas a competitive antagonist, LY341495, did not. This result indicates that MMPIP has an inverse agonistic activity. The intrinsic activity of MMPIP was pertussis toxin-sensitive and mGluR7-dependent. MMPIP at concentrations of at least 1 microM had no significant effect on mGluR1, mGluR2, mGluR3, mGluR4, mGluR5, and mGluR8. MMPIP is the first allosteric mGluR7-selective antagonist that could potentially be useful as a pharmacological tool for elucidating the roles of mGluR7 on central nervous system functions.