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

Lymphocyte Responses to Chymotrypsin- or Trypsin V-Digested β-Lactoglobulin in Patients with Cow's Milk Allergy

<p/> <p>Chymotrypsin- or trypsin V- (a mixture of trypsin and chymotrypsin) digested β-lactoglobulin (BLG) peptides were prepared and were confirmed to have much less immunoglobulin (lg)G and lgE reactivity compared with intact BLG by IgG inhibition enzymelinked immunosorbent assay and IgE dot blotting. The lymphocyte responses to intact BLG and these peptides were examined using peripheral blood mononuclear cells (PBMCs) from 10 patients with cow's milk allergy. The PBMCs from most patients had lower lymphocyte responses to chymotrypsin- and trypsin V-digested BLG peptides than those to intact BLG. However, PBMCs from one and two patients retained significant proliferative responses to both peptides and to only the former peptide, respectively. Interferon-c production stimulated by chymotrypsin-digested peptides was still detectable in all five patients tested. Chymotrypsindigested BLG reduced lgE reactivity but still induced some lymphocyte responses.</p

Pharmacogenetics of asthma in children

Allergic diseases such as bronchial asthma and atopic dermatitis develop by a combination of genetic and environmental factors. Several candidate causative genes of asthma and atopy have been reported as the genetic factors. The clinical features of patients and causes of diseases vary. Therefore, personalized medicine (tailor-made medicine) is necessary for the improvement of quality of life (QOL) and for asthma cure. Pharmacogenetics is very important for personalized medicine. Here, we present the genetics and pharmacogenetics of asthma in children. Finally, we show the guideline for personalized medicine for asthma, particularly in childhood, including the pharmacogenetics of anti-asthmatic drugs, preliminarily produced by the authors

<Original Paper>Effect of the Application of Rice Straw and (NH_4)_2SO_4 to a Paddy Field on the Competitive Nodulation Ability of Indigenous Bradyrhizobium Strains

Competitive nodulation abilities of indigenous Bradyrhizobium strains in a paddy rice field at Osaska Prefectural Agricultural and Forestry Research Center were estimated by measuring both their nodule occupancy after inoculation of the soil suspensions to soybean and N-phenyl-1-naphthylamine (NPN) uptake activity of the isolates from the soils. Three plots (50 m^2 each) in the field had been applied annually for 18 years with (NH_4)_2SO_4 and rice straw at the following rate. Plot I : 0 and 0 kg, plot II : 100 and 0 kg, plot III : 100 and 7000 kg ha^<-1> y^<-1> , respectively. The inoculation test showed that bradyrhizobial population from the plot II had the highest competitive nodulation ability against B. japonicum strain 138 NR, and that from the plot I was the lowest. There was no significant difference in diversity of bradyrhizobial population among three plots in respect to intrinsic antibiotic resistance of the isolates of Bradyrhizobium from these plots. However, the plot II contained the highest proportion of the isolates which have large NPN uptake activity, indicating high competitive nodulation ability of the isolates. These findings were consistent with the previous results which indicated an increase in the competitive nodulation ability of a strain of B. japonicum under oligotrophic conditions

IL-12B Promoter Polymorphism Associated with Asthma and IL-12B Transcriptional Activity

Background: The interleukin-12B gene (IL-12B) encodes the p40 chain of interleukin-12 (IL-12), which promotes cell-mediated Th1 responses and the production of interferon-gamma (IFN-γ) that downregulates IgE production. Chromosome 5q31-q33 near the IL-12B locus is significantly linked to asthma, as determined by a genome-wide search in the Japanese population. Methods: We sequenced exons 1–8 including parts of the introns and promoter region of IL-12B in asthmatic patients and healthy controls. We examined plasma IL-12 concentrations, IL-12 production by Derf1-stimulated peripheral blood mononuclear cells (PBMCs) and the IL-12B transcriptional activity. Results: IL-12B promoter polymorphism existed as −2703CTCTAA/GC and −2403T/C alleles, which were linked to each other. Homozygosity for haplotype 1 (−2703CTCTAA /−2403T) was associated with asthma susceptibility in Japanese children (P < 0.001). Both plasma IL-12 concentrations and IL-12 production by Derf1-stimulated PBMCs in the subjects with homozygotes for haplotype 1 were lower than those with homozygotes for haplotype 2 (−2703GC /−2403C) (P < 0.001). The transcriptional activity of the construct with haplotype 1 was lower than that of the construct with haplotype 2, and the IL-12B transcriptional activity was influenced by the −2403T/ C allele rather than by the −2403CTCTAA/GC allele. Conclusions: Homozygosity for haplotype 1, which is associated with reduced IL-12B transcriptional activity and reduced IL-12 production, is a predisposing factor for asthma susceptibility in Japanese children

Relationship between the benefits of suplatast tosilate, a Th2 cytokine inhibitor, and gene polymorphisms in children with bronchial asthma

Although currently available antiasthmatic drugs are effective for many patients with bronchial asthma, some patients do not respond well to medications or exhibit more frequent adverse effects compared to other patients. Antiasthmatic treatment should be tailored individually according to the predispositions and pathophysiological conditions of patients. No reports have been made concerning the relationships between the effects of Th2 cytokine inhibitors and gene polymorphisms. The present study was therefore performed to investigate the relationships between gene polymorphisms known to be involved in allergy and cytokine production in peripheral blood mononuclear cells and the clinical efficacy of suplatast tosilate, a Th2 cytokine inhibitor, to clarify factors determining responses to treatment. A total of 20 children were enrolled in the study. The children were enrolled in a run-in period of 2 weeks and then received suplatast tosilate orally for 8 weeks. The children or their parents were instructed to keep an asthma diary to record changes in signs/symptoms of bronchial asthma before and after treatment. Concentrations of interferon (IFN)-γ and interleukin (IL)-4 in the supernatant were determined using ELISA methods. Using the invader assay method, the genotypes of polymorphisms of the genes were determined. Treatment with suplatast tosilate was more effective in children without the −444 A/C polymorphism of the LTC4 synthase gene and in children without the IL-13 variant R110Q. In children who responded well, production of IFN-γ was significantly increased after treatment. In this study, responses to suplatast tosilate were associated with SNPs of the LTC4 synthase and IL-13 gene as well as change in the production of IFN-γ before and after drug administration