Pharmacokinetics of intravenously administered piperacillin in preadolescent children

We studied the pharmacokinetics of piperacillin in 37 preadolescent children (mean age 52 months, range 1 month to 11 years) after 50 mg/kg IV doses. Pharmacokinetic parameters were determined after the initial dose in 18 instances and after subsequent doses in 32 instances. There were no significant differences between the initial doses and the subsequent doses in the plasma piperacillin concentrations at comparable times, the elimination rate constants, the elimination-phase plasma half-lives, the total body clearances, the apparent volumes of distribution, or the areas under the concentration curves. At the end of a 30-minute infusion of the drug, the plasma concentration was 166.2 +/- 42.2 mg/L (mean +/- SD) and ranged from 91.6 to 268.3 mg/L. The mean half-life was 31.0 +/- 9.4 minutes. The half-life of piperacillin in children 1 to 6 months of age (47.2 minutes) was significantly longer than in older children (28.8 minutes) (P less than 0.05). Likewise, the total body clearance of the drug in the younger age group (71.7 ml/min/m2) was significantly lower than in the older children (130.8 ml/min/m2) (P less than 0.05). The mean renal clearance of the drug was only 63% (range 39% to 85%) of the total body clearance, suggesting a variable but substantial nonrenal route of elimination. The intravenous administration of 50 mg/kg piperacillin every four hours results in adequate plasma concentrations for the treatment of most infections caused by gram-negative and gram-positive organisms.     

Dose-response relationships of intravenously administered terbutaline in children with asthma

The bronchodilator effect of three successive stable plasma terbutaline levels was studied in 10 children with asthma. Each terbutaline plateau was achieved by giving a rapid intravenous infusion of terbutaline, 0.9 microgram/kg, followed by a continuous infusion for 2 hours. Mean plasma terbutaline concentrations (18, 36, and 53 nmol/L at the three plateaus) were found to correlate linearly with the maintenance dose of terbutaline (2.4, 4.5, and 6.3 micrograms/kg/hr, respectively). Mean forced expiratory volume in 1 second increased from 65% to 96%, and mean forced mid-expiratory flow from 32% to 71% of the predicted normal value during the study (p less than 0.01); maximum bronchodilation was obtained at mean terbutaline levels of about 30 nmol/L (range 20 to 60). Effective plasma terbutaline levels were associated with side effects such as headache and tremor in all patients. In addition, heart rate increased from 84 to 116 beats/min, systolic blood pressure rose from 115 to 129 mm Hg, and diastolic blood pressure dropped from 72 to 61 mm Hg during the study. We conclude that a loading dose of 2 micrograms terbutaline per kilogram of body weight over 5 minutes, followed by a continuous infusion of 4.5 micrograms terbutaline per kilogram per hour, is suitable for treatment of severe bronchoconstriction in children. Because of interindividual variations in drug metabolism and clinical effect, dose adjustment should be evaluated at regular intervals.     

Pharmacokinetics of desmopressin administered as tablet and oral lyophilisate formulation in children with monosymptomatic nocturnal enuresis

Desmopressin 120 μg oral lyophilisate and 200 μg tablet are considered bioequivalent, based on extrapolation of studies in a limited number of adults and on one dose-finding study of desmopressin oral lyophilisate in children. However, no comparative pharmacokinetic study in children was executed confirming this statement. No data are available on the influence of food intake on the bioavailability of desmopressin tablet in a pediatric setting, although studies in adults have documented that food intake results in a significantly lower desmopressin plasma concentration. In this study, we analyzed plasma concentrations of desmopressin oral lyophilisate and tablet with concomitant food intake. Twenty-three children with monosymptomatic nocturnal enuresis (mean age, 12.7 years) were recruited. Two tests were performed on two separate days in identical conditions with a standardized food and fluid intake. Desmopressin was administered as desmopressin tablet or desmopressin oral lyophilisate immediately after a meal. Desmopressin plasma concentration was measured at 1 h, 2 h, and 6 h postdosing. No significant difference in plasma concentration of 120 μg desmopressin oral lyophilisate and 200 μg tablet was demonstrated, even with concomitant food intake. A significant difference in variability was found, identifying a smaller variance for desmopressin oral lyophilisate plasma concentrations at all time points. This study demonstrates comparable plasma levels for desmopressin oral lyophilisate, despite the lower dose. The dosage for desmopressin oral lyophilisate is more predictable due to the significantly smaller variance. Therefore, desmopressin oral lyophilisate seems more suitable, especially in the younger age group for which time interval between dinner and drug administration is limited.     

Pharmacokinetics of intravenously administered azithromycin in pediatric patients

BACKGROUND: The objective of this study was to characterize the pharmacokinetics and tolerance of a single intravenous (IV) azithromycin dose in children. METHODS: Subjects were stratified into 4 age groups: 0.5-2 years; >2-<6 years; 6-<12 years; and 12-<16 years. Each subject received a single 10 mg/kg dose (500 mg maximum) infused in 1 hour. Serial venous blood samples were obtained for a 168-hour period, and laboratory safety evaluations were performed immediately preceding azithromycin administration and at the conclusion of the study. Serum azithromycin concentrations were quantified with a validated high performance liquid chromatography method with mass spectrometric detection. Pharmacokinetic indices were calculated for each subject by noncompartmental techniques. RESULTS: Thirty-two subjects (6.7 +/- 5.0 years, 11 boys) participated. Mean serum concentration-time data were comparable for the 4 age groups. For all subjects with evaluable data, the mean area under the curve from 0 to 72 hours (AUC0-72) was 8.2 microg . h/mL (n = 26), the maximum concentration (Cmax) was 2.4 microg/mL and the elimination half-life (t1/2) was 65.2 hours (n = 25). The AUC0-72 and Cmax were not associated with age. The dose was well-tolerated with no serious adverse events. CONCLUSION: The disposition of azithromycin after a single 10-mg/kg IV dose (maximum labeled adult dose of 500 mg) is comparable in pediatric patients between 0.5 and 16 years of age. These pharmacokinetic data can be used to guide dose selection for future therapeutic trials of IV azithromycin in pediatric patients.     

Glomerular filtration rate in healthy Nigerian children and in children with sickle cell anaemia in a steady state.

In a prospective study, the glomerular filtration rate (GFR) of 365 Nigerian children aged 4-14 years was determined at the University of Nigeria Teaching Hospital, Enugu. The subjects were made up of 305 healthy children and 60 children with sickle cell anaemia in a steady state. For the healthy children who served as controls, the mean (SD) GFR was 112 (35)ml/min/1.73m2, there being no sex difference. The peak GFR was recorded in boys at 9 years and girls at 13 years. In the children with sickle cell anaemia in a steady state, the mean (SD) GFR was 111 (36), a figure similar to that of normal controls.     

Bioavailability of sodium valproate suppositories during repeated administration at steady state in epileptic children

Oral administration of antiepileptic drugs can temporarily be impossible under certain conditions, such as altered states of consciousness, spike-wave stupour, gastrointestinal disturbances with nausea and vomiting, prior to or during surgery or certain diagnostic procedures, and because of drug refusal in patients with mental retardation or psychiatric problems. Although rectal administration of sodium valproate (NaVPA) has been shown to be a possible alternative route, little is known about the bioavailability and local effects during repeated administration of NaVPA suppositories. These aspects were investigated in 13 epileptic children and adolescents on chronic NaVPA therapy. Eight patients were treated with the oral solution (Group A, mean age 10.6 years) and five patients with enteric coated tablets (Group B, mean age 16.4 years). In every patient five serum levels of VPA over a 24 h period were measured under steady-state conditions. Thereafter, suppositories were administered for 2–7 days and serum levels were again determined (identical dosing and sampling times). Bioavailability of NaVPA was calculated on the basis of the area under the concentration vs. time curve over 24 h. The average bioavailability for suppositories compared with the oral form was 112.4% in Group A and 99.5% in Group B. Fluctuations of serum VPA levels were very similar with suppositories and oral solution, and more pronounced than with the enteric coated tablets. Stool frequency was not increased by repeated administration of suppositories, except for a three-fold increase in one patient. There was no objective or subjective evidence of local irritation from the suppositories. In conclusion, NaVPA suppositories have the same bioavailability under steady-state conditions as oral preparations and they are well tolerated. NaVPA suppositories thus represent a useful alternative when oral administration is temporarily impossible, and no adjustment in dose is necessary.Abbreviations NaVPA sodium valproate - VAP valproate     

Wheeze detection as a measure of bronchial challenge in young children with cough-variant asthma and with classic asthma

AIM: Tracheal and chest auscultation for wheeze and transcutaneous oximetry have both been suggested as outcome measures of bronchial provocation tests in young children. The aims of this study were to compare the sensitivity of these two techniques as endpoints for methacholine challenge in young children with cough-variant asthma (CVA) and with classic asthma (CA), and to investigate whether oxygen saturation levels at the presence of wheezing differ in these two groups. METHODS: We performed a retrospective analysis of methacholine challenge test data from 4- to 6-year-old children with CVA (n = 41) and from those with CA (n = 53). The challenges used a modified auscultation method that set wheeze detection and/or oxygen desaturation for determining the endpoint. RESULTS: The frequency of wheeze detection at the endpoint was significantly lower than that of oxygen desaturation (46.3% vs. 78.0%) in the CVA group, which contrasted with findings (75.5% vs. 50.9%) in the CA group. Oxygen saturation levels at the presence of wheezing were significantly lower in the CVA group than in the CA group (94.5 +/- 1.5% vs. 95.9 +/- 1.8%, p = 0.006). CONCLUSION: Wheeze detection is a less sensitive outcome measure than oxygen desaturation and is associated with a lower oxygen saturation level in young children with CVA, compared to those with CA.     

硫酸沙丁胺醇在治疗儿童支气管哮喘中的临床疗效分析

目的评估高选择性β2受体激动剂硫酸沙丁胺醇在儿童支气管哮喘轻中度急性发作治疗中的临床疗效与安全性。方法门诊诊断为哮喘轻中度急性发作的5～13岁患儿104例,随机分为硫酸沙丁胺醇缓释胶囊组(A组,52例)和丙卡特罗组(B组,52例)。观察2周,记录患儿哮喘日间及夜间症状评分及清晨峰流速值占正常预计值的百分比(PEFam%),在治疗前及治疗第7、14天检查肺功能,记录1 s用力呼气量占正常预计值的百分比(FEV1%),评估临床疗效评分及有效率,记录不良反应。结果 A组在治疗后第7、14天的哮喘日间症状、夜间症状、FEV1%、PEFam%与治疗前比较,均有明显改善,差异有统计学意义(P均<0.001);与B组比较,差异均无统计学意义(P>0.05)。A组临床总有效率、不良反应事件发生率与B组相比差异均无统计学意义(χ2=3.041、0.343,P均>0.05)。结论硫酸沙丁胺醇缓释胶囊在治疗哮喘轻中度急性发作中能较好改善患儿的临床症状及肺功能,缓解喘息,维持症状稳定,有较好的安全性。[临床儿科杂志,2011,29(10):967-970]     

半胱氨酰白三烯拮抗剂治疗儿童哮喘(英文)

哮喘是一种梗阻性肺疾病,以支气管收缩、持续性气道炎症和气道重塑为特征。临床上常用吸入皮质激素和β2受体拮抗剂辅佐治疗儿童哮喘,但这些药物疗法的治疗效果不是很理想,而且不适当的大剂量皮质激素会导致骨质疏松,生长迟缓和青光眼等严重副作用。口服抗白三烯剂是一种治疗儿童哮喘的新方法。白三烯是由花生四烯酸通过5 脂肪氧化酶途径由肥大细胞、嗜酸粒细胞和肺泡巨噬细胞合成的脂质。它通过与气道平滑肌上的CysLT1受体结合参与哮喘的炎症反应而引起支气管收缩。最近的研究表明,半胱氨酰白三烯可以介导上皮下胶原沉着和平滑肌肥大增生,从而导致不可逆的气道重塑和气道阻塞。实验研究和初步的临床研究显示,白三烯拮抗剂孟鲁司特辅助治疗儿童哮喘,可以减少皮质激素和β2拮抗剂的用量,预防气道重塑、减轻哮喘症状。然而,抗白三烯药物的疗效还需通过随机、双盲和多中心的临床研究得到进一步证实。     

High-versus low-dose, frequently administered, nebulized albuterol in children with severe, acute asthma

Thirty-two 5- to 17-year-old children who had severe, acute asthma were randomly assigned to receive either high doses (0.15 mg/kg of body weight per dose) or low doses (0.05 mg/kg of body weight per dose) of nebulized albuterol every 20 minutes for six doses. Compared with the low-dose regimen, the high-dose regimen resulted in significantly greater improvement in forced expiratory volume in 1 second, forced vital capacity, and wheeze score and a lower hospitalization rate. The changes in heart rate, respiratory rate, blood pressure, white blood cell count, and serum potassium concentration did not differ significantly between the groups. The incidence of side effects, which included tremor, hyperactivity, and vomiting, was not significantly different in the two populations. Serum albuterol levels varied widely, but there was no correlation between the levels and the increase in heart rate or other side effects. high-dose, frequently administered, nebulized albuterol appears both safe and effective in treating severe, acute asthma in children.     

Pharmacokinetics of high-dose etoposide administered in combination with fractionated total-body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Etoposide (VP-16) is one of the most widely used antitumor agents in pediatric oncology as well as chemotherapeutic agents used in conditioning regimen prior to allo-HSCT for childhood ALL. This study included 21 children with ALL who underwent allo-HSCT after conditioning with FTBI and high-dose of VP-16 (60 mg/kg) given intravenously as single four-h infusion on day -3 (n=2) or day -4 (n=19) prior to allo-HSCT. Blood samples were collected at defined time intervals until 120 h elapsed from the end of infusion. VP-16 plasma concentrations were determined using validated HPLC method. Three-compartment model was assumed for assessing PK parameters of VP-16. The median value of VP-16 C(max) measured at the end of infusion was 188.0 μg/mL (range 148.0-407.0 μg/mL). Out of 21 studied children, VP-16 was still detectable in 17 patients 72 h (median concentration 0.31 μg/mL) and in eight patients 96 h (median concentration 0.31 μg/mL) after the end of infusion. VP-16 concentration 96 h after the end of infusion was positively correlated with VP-16 AUC and negatively correlated with VP-16 CL normalized to body weight.     

A single dose of intramuscularly administered dexamethasone acetate is as effective as oral prednisone to treat asthma exacerbations in young children

OBJECTIVE: To evaluate whether a single dose of intramuscularly administered dexamethasone acetate (IM Dex) was as safe and effective as a 5-day course of oral prednisone (PO Pred) in the treatment of young children with mild-moderate exacerbations of asthma. STUDY DESIGN: A prospective, randomized, investigator-blinded study was done in a tertiary care medical center in children (6 months to 7 years of age) who required corticosteroids to treat mild-moderate asthma exacerbations as outpatients. Patients were randomized to receive either a single dose of IM Dex ( approximately 1.7 mg/kg) or PO Pred ( approximately 2 mg/kg/d for 5 days). Clinical asthma score, behavioral changes, albuterol use, and tolerance of the medication were recorded in a home diary for 7 days. Cortisol/creatinine ratios on first morning void urine samples were obtained on day 14. The primary outcome measures were changes in clinical asthma score through day 5 and tolerance of the medication. RESULTS: Fifteen patients in the IM Dex group (mean age 37 months) and 17 in the PO Pred group (mean age 36 months) completed the study. Clinical asthma score improved significantly in both groups during the first 5 days of therapy, and no significant difference was seen in the rate of improvement between the 2 groups. Three children refused more than 75% of their prednisone doses, and another 4 missed 30% to 50% of the doses despite their parents' best efforts. The intramuscular injection caused no complications, and approximately 70% of parents in both groups stated that they would choose IM Dex to treat their child's next asthma exacerbation. CONCLUSION: In this group of children a single intramuscular injection of dexamethasone acetate was as effective as a 5-day course of PO Pred for the management of mild-moderate outpatient asthma exacerbations.