In vivo evaluation of drug dialyzability in a rat model of hemodialysis.

It is important to calculate the drug removal by hemodialysis (HD) for drug dosing regimens in HD patients. However, there are limited and inconsistent information about the dialyzability of drugs by HD. Therefore, the aim of our study is to evaluate drug removal by utilizing a rat model of HD (HD rat) and to extrapolate this result to the drug removal rate in HD patients. HD rats received bilateral nephrectomy and HD for 2 h. The dialysis removal of 6 drugs was evaluated in HD rats. Dialysis efficiency, plasma protein binding rate (PBR) and distribution volume (Vd) of drugs were also measured. Furthermore, we examined the correlation between the dialyzability of drug in HD rats and humans and constructed the prediction formula of the drug dialyzability in HD patients. The clearance of urea and creatinine and normalized dialysis dose in HD rats were 0.83 ± 0.07 mL/min, 0.70 ± 0.08 mL/min, and 0.13 ± 0.06, respectively. The drug dialyzability in HD rats was similar to reported clinical data except for doripenem. A higher correlation was observed between drug dialyzability in reported clinical data and HD rats which were adjusted for PBR (r2 = 0.936; p < 0.001) compared to unadjusted (r2 = 0.812; p = 0.009). Therefore, we constructed the prediction formula of the drug dialyzability in HD patients by utilizing the HD rat model and PBR. This study is useful for evaluating the dialyzability of high-risk drugs in a clinical setting and might provide appropriate preclinical dialyzability data for new drug.

Remarkable stimulation of emission quenching on a clay surface.

Tetra-cationic pyrene derivative (Py(4+)) and tris(bipyridine)ruthenium(II) (Ru(2+)) were hybridized onto the surface of a synthesized clay. We observed the remarkable stimulation of excited Py(4+) emission quenching on the clay surface, with a very large apparent quenching rate constant (kq = 7.4 ± 0.7 × 10(15) L mol(-1) s(-1)).

Reference values for Japanese children's respiratory resistance using the LMS method.

BACKGROUND: The forced oscillation technique (FOT) is useful for studying pulmonary function in children, as well as in school children with asthma. However, the standard values for respiratory resistance (Rrs) in Asian school children remain unknown. We evaluated the standard Rrs using a type of FOT, impulse oscillometry (IOS), in healthy Japanese children at elementary and junior high schools. METHODS: A total of 795 children (age range: 6-15 years; mean age ± SD: 11.1 ± 2.4 years; 404 boys, 391 girls) at elementary and junior high schools participated in the study. Of the 795 children, we evaluated the Rrs of 537 children aged 6-15 years (mean ± SD: 10.8 ± 2.4 years) using IOS. RESULTS: Regression analyses with three IOS parameters, Rrs at 5Hz (R5), Rrs at 20Hz (R20), and Rrs difference between 5Hz and 20Hz (R5-R20), for age, height, weight, and degree of obesity as independent variables demonstrated the strongest correlation between each parameter and children's height. All parameters decreased with increasing height. Using the lambda-mu-sigma (LMS) method, we created standard curves for the Rrs values based on height. CONCLUSIONS: Our standard curves could be useful for diagnosis and control evaluation of childhood asthma.

Relationship between bronchial hyperresponsiveness and lung function in children age 5 and 6 with and without asthma.

BACKGROUND AND OBJECTIVE: It is unknown whether wheezy children have bronchial hyperresponsiveness (BHR) or which lung function parameters are correlated with BHR in children. We evaluated the relationship between BHR parameters and the lung functions by minimizing the effects of age and height in asthmatic, non-asthmatic wheezers and healthy children. METHODS: The subjects comprised of 154 children aged 5 and 6 years (78 males, 76 females), who were divided into three groups: asthmatics, non-asthmatic wheezers and healthy controls. Spirometry and a methacholine inhalation challenge by the oscillation method were performed. RESULTS: The age of the study cohort was 5.9 ± 0.2 years (mean ± standard deviation), and the height was 114.4 ± 5.3 cm. No significant differences in height, weight, body mass index or lung function were observed in the three groups. The minimal dose of methacholine to start bronchoconstriction, a parameter of bronchial sensitivity, was lower in asthmatics and non-asthmatic wheezers than that in controls. The speed of bronchoconstriction in response to methacholine, a parameter of bronchial reactivity, was strongly correlated with baseline respiratory resistance (Rrs cont) in all three groups. CONCLUSIONS: Our data suggest that it not possible to distinguish preschool children with asthma from non-asthmatic wheezers based on their bronchial sensitivity and that the baseline Rrs has a strong effect on the bronchial reactivity in children.

Relationship between exhaled nitric oxide and small airway lung function in normal and asthmatic children.

BACKGROUND: In children, exhaled nitric oxide (eNO) is usually confounded by factors such as age and height. We evaluated the relationship between eNO and lung function by minimizing the effects of aging and height. METHODS: In Study 1, the subjects comprised 738 elementary school children and junior high school children (aged 6 to 15 years, 366 males and 372 females). They were divided into two groups according to age (6-10 years and 11-15 years). A height range was determined by a histogram of height in each group. In Study 2, lung function, respiratory resistance and eNO level were measured in age- and height-limited groups. RESULTS: In Study 1, total of 148 younger children ranging in height from 120 to 130 cm and 180 older children ranging in height from 148 to 158 cm participated in Study 2. The level of eNO among asthmatic children was higher than that of normal children in both the younger and the older groups. The decrease in forced expiratory volume in 1 second (FEV(1)) and other parameters of central airway resistance did not correlate with the eNO level. However, the small airway parameters of MMEF and V(25)/HT in older asthmatic children, and V(25)/HT and R(5)-R(20) in younger asthmatic children inversely correlated with eNO. CONCLUSIONS: Our data suggest that eNO level inversely correlates with small airway narrowing, and airway inflammation has a significant effect on small airway lung function in asthmatic school children.

Consistently high levels of exhaled nitric oxide in children with asthma.

BACKGROUND: Exhaled nitric oxide (eNO) levels in children are unstable because they are regulated by many potent factors. The purpose of the current study was to evaluate the reliability of eNO levels between a long interval and other lung functions in normal and asthmatic children. METHODS: Eighty-three elementary school children (aged 11-12 years; male : female, 39 : 44) participated in this study. Lung function, airway resistance and eNO levels were measured twice: the first measurement was in autumn 2007, and the second was one year later. RESULTS: There were 62 non-asthmatic control children (male : female, 31 : 31) and 21 asthmatic children (male : female, 8 : 13). In both the first and the second examination, the levels of eNO in children with asthma were higher than those in children without asthma. The parameters of lung function and the respiratory resistance in children without asthma showed a good correlation between the results of the first and second examinations. The eNO level in non-asthmatic children showed a good correlation between the two. On the other hand, the peripheral airway parameters of lung function and the respiratory resistance in children with asthma were not correlated between the first and the second examinations. The eNO level in these patients was well correlated between the two examinations. CONCLUSIONS: These data suggest that the eNO level showed good reproducibility in children with and without asthma. The eNO level is therefore considered to be a useful marker for reproducibly evaluating a subject's airway condition.

Changes in the highest frequency of breath sounds without wheezing during methacholine inhalation challenge in children.

BACKGROUND AND OBJECTIVE: It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. METHODS: Thirty-six children (8.2 +/- 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre-HFI and pre-HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post-HFI and post-HFE). RESULTS: Breath sounds increased during methacholine-induced bronchoconstriction. Max HFI was significantly greater than pre-HFI (P < 0.001), and decreased to the basal level after bronchodilator inhalation. Post-HFI was significantly lower than max HFI (P < 0.001). HFI and HFE were also significantly changed (P < 0.001). The percentage change in HFI showed a significant correlation with the speed of bronchoconstriction in response to methacholine (P = 0.007). CONCLUSIONS: Methacholine-induced bronchoconstriction significantly increased HFI, and the increase in HFI was correlated with bronchial reactivity.

Relationship between bronchial hyperreactivity and asthma remission during adolescence.

BACKGROUND: Many children with asthma outgrow this disease after the onset of puberty. However, the precise mechanism of outgrowing asthma in children is still unclear. OBJECTIVE: To evaluate the characteristics of respiratory physiology during adolescence. METHODS: The results of the lung function test and methacholine inhalation challenge were prospectively evaluated in adolescent patients with asthma with and without symptoms. One hundred sixty children with asthma participated. Twenty-eight children had symptom-free adolescent asthma (i.e., remission asthma) (boy to girl ratio, 16:12; mean age, 14.6 years), 25 had intermittent adolescent asthma (boy to girl ratio, 16:9; mean age, 14.9 years), and 47 had symptomatic adolescent asthma (boy to girl ratio, 27:20; mean age, 12.7 years). For comparison purposes, 60 younger children with symptomatic asthma participated. The parameters of bronchial hyperresponsiveness, baseline respiratory resistance, threshold of methacholine (Dmin) (bronchial sensitivity), and speed of bronchial constriction (Sm) (bronchial reactivity) were measured by methacholine inhalation challenge using the continuous oscillation method. RESULTS: There was no significant difference in lung function results, such as forced vital capacity and forced expiratory volume in 1 second, between the intermittent asthma and the remission asthma groups. Also, there was no significant difference in baseline respiratory resistance and Dmin between the 2 groups. However, the value of Sm of the remission asthma group was significantly lower than that of the intermittent asthma group (P = .02) and the symptomatic asthma group (P = .02). CONCLUSIONS: These data show that the adolescents with asthma remission showed a significant decrease of Sm, whereas Dmin was not changed. These results suggest one of the mechanisms by which asthma is outgrown in children and explain the common clinical aspects of adolescent asthma, such as symptom-free but bronchial hyperresponsive asthma.

Effect of bronchoconstriction on exhaled nitric oxide levels in healthy and asthmatic children.

BACKGROUND: Exhaled nitric oxide (eNO) has recently been proposed to be a noninvasive marker of airway inflammation in asthma. OBJECTIVE: To evaluate the effect of bronchoconstriction by means of methacholine inhalation challenge on levels of eNO in children. METHODS: Spirometry, impulse oscillometry, and eNO measurements were performed before and after methacholine inhalation challenge (bronchoconstriction phase) and after beta2-agonist inhalation (bronchodilation phase) in 92 children (62 children with asthma, 13 wheezy children, and 17 healthy children). RESULTS: A significant decrease occurred in the eNO level after methacholine inhalation challenge (P < .01). This decrease did not correlate with the percentage decrease in forced expiratory volume in 1 second or with the change in large airway resistance (R20), but it did correlate with the percentage decline in maximal expiratory flow at 50% vital capacity and with the change in small airway resistance (R5-R20). The eNO decrease lasted for 15 minutes after beta2-agonist inhalation in the group with a high percentage decrease in R5-R20 (>200%). On the other hand, in the group with a low percentage decrease in R5-R20 (< or =200%), eNO recovered to the previous level immediately after beta2-agonist inhalation. CONCLUSIONS: The eNO level significantly decreases after methacholine inhalation challenge. This decrease primarily depends on bronchoconstriction of the small airways.

A flow- and pressure-controlled offline method of exhaled nitric oxide measurement in children.

BACKGROUND: Exhaled nitric oxide (eNO) is a noninvasive marker of airway inflammation. However, previous studies show that the offline value is lower than the online value. OBJECTIVE: To compare a standard offline eNO measurement apparatus with a modified apparatus that can monitor flow volume and respiratory pressure. METHODS: We studied 73 cooperative individuals aged 5 to 28 years (32 children: mean age, 8.3 years; 41 adults: mean age, 21.5 years). We modified the standard device by including a flow meter with a manometer and attaching a plastic tube connected to a 3-way valve to control the resistance. The online and offline (measured using the modified device and the standard device) eNO determinations were compared in a single session and were analyzed using a nitric oxide analyzer. RESULTS: There was a good relationship between the online and modified offline eNO measurements in children. The modified offline method showed a stronger correlation with the online method (r = .97 vs. r = .92), and the modified offline eNO value was more similar to the online eNO value than to the standard offline value. The mean difference between the online and standard offline eNO values was 52%, whereas the mean difference between the online and modified offline eNO values was only 10%. CONCLUSIONS: Using the offline method, we can easily control the resistance and flow volume to reach the same value measured by the online method in childhood respiratory diseases.