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

An Arabidopsis SBP-domain fragment with a disrupted C-terminal zinc-binding site retains its tertiary structure

AbstractSQUAMOSA promoter-binding proteins (SBPs) form a major family of plant-specific transcription factors, mainly related to flower development. SBPs share a highly conserved DNA-binding domain of ∼80 amino acids (SBP domain), which contains two non-interleaved zinc-binding sites formed by eight conserved Cys or His residues. In the present study, an Arabidopsis SPL12 SBP-domain fragment that lacks a Cys residue involved in the C-terminal zinc-binding pocket was found to retain a folded structure, even though only a single Zn2+ ion binds to the fragment. Solution structure of this fragment determined by NMR is very similar to the previously determined structures of the full SBP domains of Arabidopsis SPL4 and SPL7. Considering the previous observations that chelating all the Zn2+ ions of SBPs resulted in the complete unfolding of the structure and that a mutation of the Cys residue equivalent to that described above impaired the DNA-binding activity, we propose that the Zn2+ ion at the N-terminal site is necessary to maintain the overall tertiary structure, while the Zn2+ ion at the C-terminal site is necessary for the DNA binding, mainly by guiding the basic C-terminal loop to correctly fit into the DNA groove

GABA-A and GABA-B Receptors in Filial Imprinting Linked With Opening and Closing of the Sensitive Period in Domestic Chicks (Gallus gallus domesticus)

Filial imprinting of domestic chicks has a well-defined sensitive (critical) period lasting in the laboratory from hatching to day 3. It is a typical model to investigate the molecular mechanisms underlying memory formation in early learning. We recently found that thyroid hormone 3,5,3′-triiodothyronine (T3) is a determinant of the sensitive period. Rapid increases in cerebral T3 levels are induced by imprinting training, rendering chicks imprintable. Furthermore, the administration of exogenous T3 makes chicks imprintable on days 4 or 6 even after the sensitive period has ended. However, how T3 affects neural transmission to enable imprinting remains mostly unknown. In this study, we demonstrate opposing roles for gamma-aminobutyric acid (GABA)-A and GABA-B receptors in imprinting downstream of T3. Quantitative reverse transcription polymerase chain reaction and immunoblotting showed that the GABA-A receptor expression increases gradually from days 1 to 5, whereas the GABA-B receptor expression gradually decreases. We examined whether neurons in the intermediate medial mesopallium (IMM), the brain region responsible for imprinting, express both types of GABA receptors. Immunostaining showed that morphologically identified putative projection neurons express both GABA-A and GABA-B receptors, suggesting that those GABA receptors interact with each other in these cells to modulate the IMM outputs. The roles of GABA-A and GABA-B receptors were investigated using various agonists and antagonists. Our results show that GABA-B receptor antagonists suppressed imprinting on day 1, while its agonists made day 4 chicks imprintable without administration of exogenous T3. By contrast, GABA-A receptor agonists suppressed imprinting on day 1, while its antagonists induced imprintability on day 4 without exogenous T3. Furthermore, both GABA-A receptor agonists and GABA-B receptor antagonists suppressed T3-induced imprintability on day 4 after the sensitive period has ended. Our data from these pharmacological experiments indicate that GABA-B receptors facilitate imprinting downstream of T3 by initiating the sensitive period, while the GABA-A receptor contributes to the termination of the sensitive period. In conclusion, we propose that opposing roles of GABA-A and GABA-B receptors in the brain during development determine the induction and termination of the sensitive period

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

Inspired by nature: Fiber networks functionalized with tannic acid and condensed tannin-rich extracts of Norway spruce bark show antimicrobial efficacy

This study demonstrated the antibacterial and antiviral potential of condensed tannins and tannic acid when incorporated into fiber networks tested for functional material purposes. Condensed tannins were extracted from industrial bark of Norway spruce by using pressurized hot water extraction (PHWE), followed by purification of extracts by using XADHP7 treatment to obtain sugar-free extract. The chemical composition of the extracts was analyzed by using HPLC, GC‒MS and UHPLC after thiolytic degradation. The test matrices, i.e., lignocellulosic handsheets, were produced and impregnated with tannin-rich extracts, and tannic acid was used as a commercial reference. The antibacterial and antiviral efficacy of the handsheets were analyzed by using bioluminescent bacterial strains (Staphylococcus aureus RN4220+pAT19 and Escherichia coli K12+pCGLS11) and Enterovirus coxsackievirus B3. Potential bonding of the tannin-rich extract and tannic acid within the fiber matrices was studied by using FTIR-ATR spectroscopy. The deposition characteristics (distribution and accumulation patterns) of tannin compounds and extracts within fiber networks were measured and visualized by direct chemical mapping using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and digital microscopy. Our results demonstrated for the first time, how tannin-rich extracts obtained from spruce bark side streams with green chemistry possess antiviral and antibacterial properties when immobilized into fiber matrices to create substitutes for plastic hygienic products, personal protection materials such as surgical face masks, or food packaging materials to prolong the shelf life of foodstuffs and prevent the spread of infections. However, more research is needed to further develop this proof-of-concept to ensure stable chemical bonding in product prototypes with specific chemistry