Clinical and bacteriological evaluation of the efficacy of piperacillin in children with pneumonia.

We aimed to prospectively evaluate the clinical and bacteriological effects of piperacillin in children with pneumonia. Twenty-eight patients (6 months to 5 years of age) with pneumonia were treated with piperacillin. In the same period, 95 strains of Haemophilus influenzae and 41 strains of Streptococcus pneumoniae were isolated in our department and the minimum inhibitory concentration (MIC) of piperacillin was determined. The clinical efficacy of piperacillin was excellent in 4 cases, good in 23, and fair in 1; the response rate was 96.4% (27/28). Among the isolates from our department, there were 4 strains (9.8%) of penicillin-susceptible S. pneumoniae (PSSP), 32 strains (78.0%) of penicillin-intermediate-resistant S. pneumoniae (PISP), and 5 strains (12.2%) of penicillin-resistant S. pneumoniae (PRSP). Against S. pneumoniae, the MIC50 and MIC90 for piperacillin were 0.5 microg/ml and 2 microg/ml, respectively. Panipenem showed the best results, followed by piperacillin, ampicillin, and flomoxef. Among the isolates from our department, there were 51 strains (53.7%) of beta-lactamase-negative ampicillin-susceptible H. influenzae, 42 strains (44.2%) of beta-lactamase-negative ampicillin-resistant H. influenzae, 1 strain (1.1%) of beta-lactamase-positive ampicillin-resistant H. influenzae, and 1 strain (1.1%) of beta-lactamase-positive amoxicillin-clavulanic acid-resistant H. influenzae. The MIC50 and MIC90 for piperacillin against H. influenzae were 0.0625 microg/ml and 0.125 microg/ml, respectively. Tazobactam/piperacillin and piperacillin showed the best results, followed by panipenem, ampicillin, and flomoxef. Piperacillin proved to be very useful for the treatment of pneumonia in children.

Pharmacokinetics of beclomethasone dipropionate in an hydrofluoroalkane-134a propellant system in Japanese children with bronchial asthma.

BACKGROUND: Hydrofluoroalkane-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. METHODS: Plasma concentrations of beclomethasone 17-monopropionate (17-BMP),a major metabolite of BDP, following an inhaled dose of HFA-BDP (200 microg as four inhalations from 50 microg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters. RESULTS: The area under the concentration-time curve from time zero to the last quantifiable time (AUC(0-t)) was 1659 +/- 850 pg x h/mL (arithmetic mean +/- standard deviation (SD)), the maximum concentration observed (C(max)) was 825 +/- 453 pg/mL and the apparent elimination half-life (t(1/2)) 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 AUC(0-t), 1.04 for Cmax and 1.4 for t(1/2). The median of Tmax was 0.5 hours in American patients as well as Japanese patients. CONCLUSIONS: The 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.

Neuroradiologic findings in Sotos syndrome.

Sotos syndrome is a well-known anomaly syndrome characterized by overgrowth, characteristic facial gestalt, and developmental delay, and haploinsufficiency of the NSD1 gene has been revealed as one of the major genetic causes. However, there have been only a few reports on neuroradiologic findings by computed tomography (CT) or magnetic resonance imaging (MRI), and functional examination of the brain has not been reported. We examined three cases with typical Sotos syndrome, which also were confirmed by genetic analysis with a specific probe for the NSD1 gene. The results of MRI showed the characteristic features that have been reported previously. The findings obtained by using single-photon emission computed tomography and magnetic resonance spectroscopy suggested an association between mental delay and behavioral tendency in Sotos syndrome and immaturity in frontal brain function.

Suppression of IFN-gamma production in atopic group at the acute phase of RSV infection.

Several studies have suggested that respiratory syncytial virus (RSV) bronchiolitis induced the change of cytokine production profile in childhood. We sought to determine whether the RSV-induced cytokine production was affected by the patient's atopic background. We quantified interferon-gamma (IFN-gamma) and interleukin (IL)-4 in the supernatant of peripheral blood mononuclear cells (PBMCs) cultured for 24 h and in the presence of phytohemaglutinin (PHA), IL-12, or IL-18, from 14 infants who were divided into two groups, those who are non-atopic and an atopic group. In RSV-infected infants with atopic diseases, IFN-gamma production from IL-12- or especially IL-18-stimulated PBMCs was subtotally suppressed in the acute phase, whereas in RSV-infected infants without atopic diseases IFN-gamma production was not suppressed on acute phase. The IFN-gamma suppression observed in the atopic group is not caused by the immaturity of an infant's immune system since reduced IFN-gamma production to RSV is not observed in the infants of non-atopic group. IFN-gamma suppression in regard to RSV infection might be caused by some genetic factor involved in the development of atopic disease such as IL-18 signal cascade.

A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases.

Cysteinyl leukotrienes (cysLTs) play important roles in bronchial asthma, and can mediate bronchial smooth muscle constriction and increase mucous secretion, vascular permeability and cellular infiltration. We identified a novel heterozygous single-nucleotide substitution 10G>A (Glu 4 Lys) in the first exon of the leukotriene C4 synthase gene (LTC4S). This substitution was detected in 5 of 141 allergic patients, but not in 110 nonallergic subjects. There was a difference in the Glu 4 Lys frequency between the allergic patients and nonallergic subjects (Fisher's exact test, p=0.0460). The five patients with Glu 4 Lys had allergic diseases such as bronchial asthma and/or allergic dermatitis. Furthermore, a familial analysis of Glu 4 Lys revealed a link with allergic diseases. Thus, our results suggest that Glu 4 Lys in the LTC4S might be associated with allergic diseases.

A novel single-nucleotide substitution, Leu 467 Pro, in the interferon-gamma receptor 1 gene associated with allergic diseases.

We identified a novel heterozygous single-nucleotide substitution 1400 T right curved arrow C (Leu 467 Pro) in the seventh exon of the interferon-gamma receptor 1 (IFNGR1) gene. This substitution was detected in 6 of the 89 allergic patients but not in the 72 non-allergic subjects. There was a difference in the L467P frequency between the allergic patients and the non-allergic subjects (Fisher's exact test: p=0.033). The 6 patients with L467P have allergic diseases such as bronchial asthma and/or allergic rhinitis. Furthermore, a familial analysis for L467P revealed a linkage between allergic diseases and L467P. Serum IgE levels of the patients with L467P were higher than those of the non-allergic subjects (p=0.001). Our previous studies have been shown that interferon-gamma (IFN-gamma) production by PBMCs in the allergic patients was lower than that in the non-allergic subjects. In this study, although IFN-gamma production in the allergic patients with L467P was equivalent to that in the non-allergic subjects, their serum IgE levels were high and they had allergic diseases. Our results suggest that some allergic patients have IFNGR dysfunction, and that L467P in the IFNGR1 gene is one of candidate susceptibility genes for allergic diseases.

[Evaluation before and after pranlukast administration with the QOL questionnaire (revised version 2001) for pediatric patients with bronchial asthma and their parents or caregivers].

We conducted a longitudinal investigation with the QOL questionnaire (revised version 2001) before and after the 4-week-administration of a leukotriene receptor antagonist pranlukast. A significant improvement in the < 4 yrs group was observed at week 1, and that in > or = 4 yrs group at week 2. Under these conditions, the overall QOL score, physical domains and mental domains, significantly improved in both the < 4 yrs group and the > or = 4 yrs group. Overall, a slight correlation was observed between ratio changes in QOL scores and differences in symptom scores. However, no correlation was found in part of patients, suggesting that the QOL questionnaire allows measurement of mental changes in the patients themselves and their parents or caregivers for therapeutic effects which cannot be determined with ordinary physical findings only. In "event present" group, a significant difference in physical and mental domains was revealed by the comparison of QOL scores before and after administration. And furthermore in "event absence" group, the p-value for physical domain and mental domain was 0.0505 and 0.0912 in the < 4 yrs group, respectively, 0.0101 and 0.0446 in the > or = 4 yrs group, respectively. The above results led us to consider the QOL questionnaire (revised version 2001) useful for routine medical care. Furthermore, pranlukast was considered useful for improvement not only of physical symptoms of bronchial asthma but also of the patient's QOL, although the placebo effects in this open trial must be considered.

Predominant expression of 950delCAG of IL-18R alpha chain cDNA is associated with reduced IFN-gamma production and high serum IgE levels in atopic Japanese children.

BACKGROUND: We previously reported that serum IgE levels were negatively correlated with the amount of IFN-gamma produced by phytohemagglutinin-stimulated or IL-12-stimulated PBMCs and that one of the mechanisms of the pathogenesis of atopy was the reduced IFN-gamma production, which led to upregulated IgE production. OBJECTIVE: IL-18 is also known to be a strong inducer of IFN-gamma production. However, it has not yet been determined whether IL-18 is associated with atopic disease. METHODS: We investigated the response to IL-18 or IL-12 stimulation and the sequence of IL-18 receptor (IL-18R) alpha chain cDNA in 41 nonatopic controls and 39 atopic patients. RESULTS: Serum IgE level was negatively correlated with IFN-gamma production by PBMCs stimulated with IL-18. The IL-18R alpha chain cDNA of atopic patients was sequenced. We identified a 3-base deletion of the IL-18R alpha chain cDNA (950delCAG ), which was generated by alternative splicing, as determined on the basis of genomic sequence data for the IL-18R alpha chain gene. PBMCs with the predominant expression of 950delCAG significantly showed the reduced IFN-gamma production after IL-18 stimulation. There was a significant difference in the expression pattern of the IL-18R alpha chain transcript between the atopic patients and the nonatopic controls. CONCLUSION: According to these results, the dominant expression of the 950delCAG transcript of IL-18R alpha chain cDNA, which was associated with reduced IFN-gamma production by IL-18 stimulation and high serum IgE levels, is predisposition to some atopic diseases.