Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children

We set out to evaluate lung deposition, systemic availability, and basic pharmacokinetic parameters of beclomethasone dipropionate (BDP) in children with chronic asthma. Plasma levels of BDP, 17 and 21 beclomethasone monopropionate (17-BMP and 21-BMP), and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A) 100 microg HFA-BDP, B) 200 microg HFA-BDP, C) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal (GI) absorption of drug, and D) 400 microg CFC-BDP. A breath-actuated pMDI (Autohaler) was used for HFA inhalations, and a pMDI with a large volume spacer (Volumatic) for CFC inhalations. Treatments A-D were given in a randomized, cross-over design. Fourteen patients aged 10-14 years completed all 5 study days. The mean systemic bioavailabilities in percent of dose leaving the canister valve (ex-valve) were 70% (100 HFA), 74% (200 HFA), 60% (200 HFA + charcoal), and 27% (400 microg CFC). After HFA treatment, 82% of the systemically available dose was absorbed through the lungs, and 18% from the gastrointestinal tract. The estimated bioavailability of BDP from the GI tract was 68%. BDP was metabolized to 17-BMP within minutes. Mean steady-state volume of distribution of 17-BMP was 84 L, and the mean terminal half-life (T((1/2))) after the four inhalations was 2.7 hr (range, 2.2-3.7 hr). Mean T((1/2)) and clearance after i.v. administration were 1.7 hr and 0.9 L/min, respectively. The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer.     

儿童幽门螺杆菌iceA1、babA2基因分布及其细胞免疫功能研究

目的探讨儿童幽门螺杆菌(Helicobacterpylori,Hp)iceA1、babA2基因分布特征及其细胞免疫功能。方法对152例有消化道症状患儿行胃镜检查,并在胃窦部取粘膜作Hp的分离培养,利用聚合酶链反应技术(PCR)测定分离培养出的Hp菌株的iceA1、babA2基因,并采用生物素-链霉亲和素(biotin-sreptavidin,BSA)系统检测患者外周血T细胞亚型,ELISA法检测其细胞因子。结果152例中,检出Hp菌株98例,其中iceA1阳性菌株65例,轻度胃炎、中至重度胃炎iceA1阳性率分别为43.59%(17/39)、79.25%(42/53),差异有统计学意义(P<0.01);babA2阳性菌株71例,轻度胃炎、中重度胃炎babA2阳性率分别为48.72%(19/39)、86.79%(46/53),差异有统计学意义(P<0.05);6例活动性胃炎均为iceA1、babA2阳性;iceA1 、babA2 患儿的CD3 、CD4 、CD4 /CD8 和IL-2下降,IL-6、IL-8水平升高(P均<0.001)。结论儿童Hp感染多为iceA1 、babA2 菌株。iceA1 、babA2 Hp菌株为高毒力菌株,易引起较严重的慢性胃炎,使患者细胞免疫功能下降,引起以Th1细胞为主的炎症浸润反应。     

Granulopoietic studies in acute lymphocytic leukemia of children

Summary Studies have been carried out on the levels of serum and urine colony stimulating activity (CSA) and peripheral blood and bone marrow colony forming cell numbers in children with acute lymphocytic leukemia (ALL) during various phases of their disease. These studies have suggested that serum and urine levels of colony stimulating factor are reduced during the initial or relapse phase of the disease compared to levels found during remission. It has also been found that the number of bone marrow colony forming cells is reduced in relapse or before treatment and elevated during remission while the number of peripheral blood colony forming cells is increased during relapse or before treatment and normal during remission. It has also been shown that mixing of serum or leukemic cells with normal human bone marrow cells inhibits colony formation.Supported by grants from the National Institutes of Health, National Cancer Institute (1R01CA11305-5 and CA05058-10), American Cancer Society, Colorado Division, Maytag Memorial Grant and Public Health Service Research Grant CA12247 from the National Cancer Institute.     

Safety of inhaled corticosteroids in children

Inhaled corticosteroids (ICS) are now first-line therapy for persistent asthma in children. The major safety concerns of long-term ICS therapy for childhood asthma are potential effects on adrenal function, growth, and bone mass. Dosage, type of inhaler device, and individual drug characteristics influence systemic effects of ICS. Sensitive measures of basal adrenal function can show statistically significant changes during ICS therapy, but these do not accurately predict clinically meaningful adrenal axis suppression. Adrenal insufficiency is rare and confined to children receiving high doses of ICS. Dose-related inhibition of growth has been seen in some short- and intermediate-term studies, but long-term studies have found no detrimental effect on final height. ICS therapy has not been associated with significant changes in measurements of bone and bone biomarkers, but more studies of high doses and of therapy in adolescents are needed. Overall, although ICS are the most effective anti-inflammatory treatment available for asthma, high doses of ICS in children are still of concern. The risk of high doses is compounded in children with concomitant allergic conditions that require multiple forms of topical corticosteroids. Benefits of ICS clearly outweigh potential adverse effects and risks associated with poorly controlled asthma. Risk can be minimized by using the lowest effective ICS dose, limiting systemic availability of the drug through proper technique to minimize swallowed drug, and selection of agents with efficient first-path hepatic inactivation of swallowed drug. Adjuvant treatments can reduce the dose of ICS required for asthma control, allowing a reduction in overall systemic exposure for most children with mild-to-moderate persistent asthma. Therefore, these agents should be added to, but should not replace, ICS therapy.     

Schistosoma mansoni-related morbidity on Ukerewe Island, Tanzania: clinical, ultrasonographical and biochemical parameters

One thousand six hundred and ninety-five inhabitants of 3 rural villages on Ukerewe Island, Lake Victoria, Tanzania, were examined by clinical, parasitological, ultrasonographic and—in part—serological means to evaluate Schistosoma (S.) mansoni-related morbidity on a community level. Villagers frequently complained of typical colitis symptoms (abdominal pain 80.1%, bloody stools 43.1%, diarrhoea 35.1%); haematemesis, on the other hand, was rare (and reports doubtful in most cases). 16.9% of the population had been given praziquantel previously. Overall S. mansoni prevalence was 86.3%, with a median egg output of 176 eggs per gram (e.p.g.) and a maximum output of 17 984 e.p.g. Children and adolescents were infected more severely than adults, men more severely than women. Pretreated individuals excreted significantly fewer ova (median 124 vs 192e.p.g., P<0.001). Hepatomegaly (determined by ultrasonography) was present in 35%, splenomegaly in 80%. Organomegaly was significantly related to egg output. Pretreated persons had lower rates of splenomegaly and left lobe hepatomegaly. Low-degree periportal fibrosis was common, while severe grades of fibrosis (MANAGIL score II and III) were present in about 6%. About 10% had other abnormalities on liver sonography (irregular parenchymal texture and/or shape); these persons passed significantly more S. mansoni ova than others. Clear sonographic signs of portal hypertension were seen in 2.1%. Serum procollagen-IV-peptide and γ-glutamyl-transferase levels were increased in persons with severe periportal fibrosis, irregular liver texture or portofugal collateral vessels. Thus, S. mansoni infection in the western part of Ukerewe Island is frequent and often severe, leading to a high prevalence of gastrointestinal symptoms. Hepatosplenic involvement does occur, although symptomatic cases of portal hypertension were not identified beyond doubt. The overall level of schistosomal morbidity is thus considered intermediate. Serum procollagen-IV-peptide may be a promising marker of schistosomal liver disease. Our data suggest that S. mansoni infection may also be related to diffuse liver parenchyma alterations in this area.     

Nasal airflow and resistance measured by active anterior rhinomanometry in healthy children and adolescents

Rhinomanometry allows objective assessment of nasal patency in pediatric patients with nasal and other respiratory problems. However, no reliable reference values are available in the pediatric age group. We measured nasal inspiratory airflow and nasal inspiratory resistance of the right and left nostrils (V'nar, V'nal, Rnar, and Rnal) and total nasal inspiratory flow and resistance (V'na and Rna) at a transnasal pressure of 150 Pa during quiet breathing in healthy children with a closed mouth by using active anterior rhinomanometry. Cross-sectional measurements were done in 192 healthy Caucasian children and adolescents free of nasal or other respiratory diseases (age, 2-19 years; body height, 94-190 cm; 95 boys and 97 girls). The values of V'na, V'nar, and V'nal increased significantly with an increase of body height or age (P<0.0001). Rna, Rnar, and Rnal significantly decreased with an increase of body height and age (P<0.0001). No significant statistical differences were found between boys and girls (P=0.11) or between right and left nostrils (P=0.07). V'nar and Rnar comprised 50.1%, and V'nal and Rnal 49.9%, of total V'na and Rna, respectively. Best-fit regression equations relating rhinomanometric parameters and body height or age were power functions. We obtained reference regression equations with upper and lower limits, and prepared tables listing reference (normal) values of rhinomanometric parameters in healthy pediatric Caucasian patients, against which patients with nasal obstruction can be compared.     

An increased level of antibodies to β-ltoglobulin is a risk determinant for early-onset Type 1 (insulin-dependent) diabetes mellitus independent of islet cell antibodies and early introduction of cow's milk

Summary Using a case-control design we have studied whether antibodies to cow's milk proteins are risk determinants for childhood-onset Type 1 (insulin-dependent) diabetes mellitus independent of early exposure to cow's milk formula and islet cell antibodies. Sera from 116 recentonset diabetic children and 112 age- and sex- matched control children were analysed for cow's milk protein IgA, IgG and IgM antibodies, -lactoglobulin IgA and IgM antibodies and islet cell antibodies. The titres were compared to questionnaire data on duration of breast-feeding and introduction of formula feeding. Most antibody levels tended to be increased among diabetic compared to control children. This was statistically significant for cow's milk protein IgA antibodies (p <0.001) and -ltoglobulin IgA antibodies (p <0.01) as well as for islet cell antibody-positivity which was found among 92% of the diabetic and 3% of control children. The differences in cow's milk protein antibodies as well as -lactoglobulin antibodies were more pronounced among children with an early onset of Type 1 diabetes. Breast-feeding duration was significantly inversely related to the log of -Mactoglobulin IgG (r = –0.16, p = 0.04) and the log of cow's milk protein IgA antibodies (r = –0.17, p<0.001). A positive correlation was found between formula feeding and the logarithm of -lactoglobulin IgG antibodies (r = 0.22, p = 0.01) and the log of cow's milk protein IgA antibodies (r = 0.16, p = 0.04). In a multiple logistic regression analysis it was found that IgA antibodies to -lactoglobulin and cow's milk protein were significantly related to the risk of Type 1 diabetes independent of islet cell antibodies. When introducing formula feeding before the age of 4 months as a variable in the regression it was shown that islet cell antibodies and -lactoglobulin IgA antibodies were still significantly and independently related to an increased risk of diabetes whereas cow's milk protein IgA antibodies did not add further to the regression. It is concluded that -lactoglobulin IgA antibodies are significantly associated with an increased risk of diabetes at a young age independent of islet cell antibody-status and of an early weaning to cow's milk formula. In genetically susceptible children early exposure to -actoglobulin might be one trigger in the autoimmune process leading to development of Type 1 diabetes.     

Intestinal helminth infestation is associated with increased bronchial responsiveness in children

Non-atopic asthma is the predominant phenotype in non-affluent parts of Latin America. We recently reported that infestation with Ascaris lumbricoides increased the risk of non-atopic asthma in less affluent areas of Brazil but the mechanism is unclear. The present study was conducted to determine whether helminth infestation is associated with heightened bronchial responsiveness (BHR), a common finding in asthma. A random sample of 50 asthmatic and 50 non-asthmatic controls (mean age 10.1 years) were selected from a larger cohort (n = 1,011) without knowledge of their helminth infestation status. Three stool samples were collected from each child on different days and each sample was analyzed by the Kato-Katz method for quantitative determination of helminth eggs. Bronchial provocation tests were performed with inhaled 4.5% hypertonic saline using the ISAAC Phase II standardized protocol. There was no difference between the prevalence of positive BHR in the asthmatics (20.4%) compared with the controls (14.6%) (P = 1.0). Helminth infestation was detected in 24.0% of children, with A. lumbricoides being the most common. Children with high load infestation (>or=100 eggs/g) were five times more likely to have BHR than children with low load or no infestation. Despite the small sample size the results of the present study suggest that the link between high load helminth infestation and non-atopic asthma may be mediated via heightened bronchial responsiveness, possibly due to an inflammatory response to the pulmonary phase of the helminth life cycle.     

Expanding indications for the treatment of pulmonary artery stenosis in children by using cutting balloon angioplasty.

OBJECTIVES: To evaluate the role of cutting balloon angioplasty in children with pulmonary artery stenosis. BACKGROUND: Pulmonary artery stenoses can be either congenital or secondary to postoperative scar formation. Isolated multiple small-vessel pulmonary artery stenoses are very rare. No surgical procedures for their treatment are currently available. METHODS: We report on four patients in whom standard and high-pressure balloon angioplasty had failed. Three of the four (2.5-, 3-, and 3.5-years-old; two girls) had isolated multiple peripheral pulmonary artery stenosis. The fourth patient was an 11-month-old girl (8 kg) with tetralogy of Fallot and hypoplastic pulmonary artery branches treated with the implantation of two stents in the pulmonary arteries. During the follow-up this patient developed severe intrastent restenosis and showed severely hypoplasic distal left pulmonary artery. RESULTS: We treated 11 vessels. The mean vessel diameter increased by 81% (P<0.0001) and RV/LV pressure ratio decreased from 1.15 to 0.75 (P=0.05). Patient treated for intrastent restenosis underwent successful complete tetralogy of Fallot repair. None of the patients suffered procedure-related complications. At a median follow-up of 18 months, results were stable and no late complications had occurred. CONCLUSIONS: Cutting balloon angioplasty is a promising technique for the treatment of highly challenging pathologies such as small vessel pulmonary artery stenoses and intrastent restenosis.