Pharmacokinetics of Beclomethasone Dipropionate in an Hydrofluoroalkane-134a Propellant System in Japanese Children with Bronchial Asthma

ABSTRACTBackgroundHydrofluoroalkane-134a (HFA) has been shown to be a safe replacement for chlorofluorocarbons (CFCs) as a pharmaceutical propellant, with the advantage that it has no ozone-depleting potential. This is the first report of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized solution formulation using an HFA propellant system (HFA-BDP) in Japanese children with bronchial asthma.MethodsPlasma concentrations of beclomethasone 17-monopropionate (17-BMP), a major metabolite of BDP, following an inhaled dose of HFA-BDP (200 μg as four inhalations from 50 μg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters.ResultsThe area under the concentration-time curve from time zero to the last quantifiable time (AUC0-t) was 1659 ± 850 pg • h/mL (arithmetic mean ± standard deviation (SD)), the maximum concentration observed (Cmax) was 825 ± 453 pg/mL and the apparent elimination half-life (t1/2) was 2.1 ± 0.7 hours. The time to reach Cmax (Tmax) was 0.5 hours in all patients. No special relationship was observed between these parameters and age or body weight. These parameters were compared with the previously reported parameters of American children with bronchial asthma. The Japanese/American ratio of the geometric means of each parameter was 1.36 for AUC0-t, 1.04 for Cmax and 1.4 for t1/2. The median of Tmax was 0.5 hours in American patients as well as Japanese patients.ConclusionsThe pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma are reported for the first time and a similarity to those in American children is suggested

Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts

Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I), anabolic regulators of bone metabolism. Although mice lacking the IRS-2 gene (IRS-2−/− mice) developed normally, they exhibited osteopenia with decreased bone formation and increased bone resorption. Cultured IRS-2−/− osteoblasts showed reduced differentiation and matrix synthesis compared with wild-type osteoblasts. However, they showed increased receptor activator of nuclear factor κB ligand (RANKL) expression and osteoclastogenesis in the coculture with bone marrow cells, which were restored by reintroduction of IRS-2 using an adenovirus vector. Although IRS-2 was expressed and phosphorylated by insulin and IGF-I in both osteoblasts and osteoclastic cells, cultures in the absence of osteoblasts revealed that intrinsic IRS-2 signaling in osteoclastic cells was not important for their differentiation, function, or survival. It is concluded that IRS-2 deficiency in osteoblasts causes osteopenia through impaired anabolic function and enhanced supporting ability of osteoclastogenesis. We propose that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, as we previously reported; the integration of these two signalings causes a potent bone anabolic action by insulin and IGF-I

Genotypic Variation of the Ability of Root to Penetrate Hard Soil Layers among Japanese Wheat Cultivars(Crop Physiology and Ecology)

The hard soil in the field is a major constraint for the cereal production because it mechanically restricts the root expansion and water absorption. The ability of root to penetrate into the hard soil is an important factor affecting yield stability of wheat (Triticum aestivum L.) under hard soil and drought conditions. We investigated the variation in the penetrating ability of roots (PA) among Japanese wheat cultivars and its relationship with other shoot and root characters to acquire basic information to develop the cultivars with a higher PA. The evaluation was conducted by the two experiments using the two groups of cultivars : 1) 43 Hokkaido cultivars in the first experiment, 2) 38 Honsyu, including Shikoku and Kyusyu, cultivars in the second experiment. In each experiment, one seedling of each cultivar was grown in a pot with a disc made of paraffin and Vaseline mixture (PV) as a substitute for the hard soil layer. The number of roots penetrating through the PV disc per plant (NRP), the number of seminal and crown roots reached the PV disc per plant (NRR) and the penetration index (PI=NRP/NRR) of each cultivar were evaluated as the traits related to PA. NRP significantly varied with the cultivar from 4.0 to 29.7 and 3.0 to 22.0 in the first and second experiments, respectively. NRP were significantly correlated with NRR (r=0.644 in the first and r=0.477 in the second experiment) and PI (r=0.863 in the first and r=0.811 in the second experiment), but the relationships between NRR and PI were not significant (r=0.260 in the first and r=0.190 in the second experiment). NRR was significantly correlated with the degree of winter growth habit (requirement of vernalization), root dry weight (DW) above the PV disc, the number of stems and leaf DW in each population. Correlations between PI and other characters were low or not significant. These results indicate that a large genotypic variation exists among Japanese wheat cultivars in NRP, and that PI is a suitable indicator of PA. Cultivars with a high PA detected in this study will be useful genetic resources of wheat to improve the yield stability under drought and hard soil conditions

Genotypic Variation of the Ability of Root to Penetrate Hard Soil Layers among Japanese Wheat Cultivars

The hard soil in the field is a major constraint for the cereal production because it mechanically restricts the root expansion and water absorption. The ability of root to penetrate into the hard soil is an important factor affecting yield stability of wheat (Triticum aestivum L.) under hard soil and drought conditions. We investigated the variation in the penetrating ability of roots (PA) among Japanese wheat cultivars and its relationship with other shoot and root characters to acquire basic information to develop the cultivars with a higher PA. The evaluation was conducted by the two experiments using the two groups of cultivars: 1) 43 Hokkaido cultivars in the first experiment, 2) 38 Honsyu, including Shikoku and Kyusyu, cultivars in the second experiment. In each experiment, one seedling of each cultivar was grown in a pot with a disc made of paraffin and Vaseline mixture (PV) as a substitute for the hard soil layer. The number of roots penetrating through the PV disc per plant (NRP), the number of seminal and crown roots reached the PV disc per plant (NRR) and the penetration index (PI = NRP/NRR) of each cultivar were evaluated as the traits related to PA. NRP significantly varied with the cultivar from 4.0 to 29.7 and 3.0 to 22.0 in the first and second experiments, respectively. NRP were significantly correlated with NRR (r=0.644** in the first and r=0.477** in the second experiment) and PI (r=0.863** in the first and r=0.811** in the second experiment), but the relationships between NRR and PI were not significant (r=0.260 in the first and r=0.190 in the second experiment). NRR was significantly correlated with the degree of winter growth habit (requirement of vernalization), root dry weight (DW) above the PV disc, the number of stems and leaf DW in each population. Correlations between PI and other characters were low or not significant. These results indicate that a large genotypic variation exists among Japanese wheat cultivars in NRP, and that PI is a suitable indicator of PA. Cultivars with a high PA detected in this study will be useful genetic resources of wheat to improve the yield stability under drought and hard soil conditions