Chronopharmacology of Albuterol in Hospitalized Asthmatic Children

Eleven children (8–16 years old) hospitalized for acute bronchospasm were included in this investigation. Throughout the study, the children received the standardized course of therapy for hospitalized asthmatics with corticosteroids and albuterol nebulizations. Children receiving ipratropium were excluded from the study. Spirometric measurements, including forced expiratory volume in 1s (FEV₁), were made immediately before and 30 min after each albuterol nebuliza-tion over a 24-h period. The well-known temporal changes in FEV₁, were observed in patients suffering from nocturnal asthma (NA): basal values were maximal at midday (10 a.m. to 2 p.m.) and lowest in the evening or at night (10 p.m. to 6 a.m.). This 24-h variation in lung function was not found in children without nocturnal exacerbations of their asthma. A 24-h variation was also observed in albuterol-induced bronchodilation in patients with NA: maximal effectiveness occurred at night, and lower effect was obtained with the midday administration. The albuterol-induced increases in FEV₁, were not clinically significant in children without nocturnal asthma except when the β₂-agonist was inhaled between 10 p.m. and 2 a.m. The data suggest that patients with nonnocturnal asthma might have different drug requirements than those with nocturnal symptoms. Key Words: Albuterol—Asthma—Circadian rhythms—-Children—FEV₁.     

Growth Hormone Secretion in Growth-retarded Asthmatic Children

The serum growth hormone response to Bovril was studied in 12 growth-retarded children with severe asthma, and was found to be normal. Eight children who were receiving corticosteroids had been small for their age before starting steroid treatment. It is concluded that there is no case for treating growth-retarded asthmatic children with growth hormone.     

Day-Night Differences in Steady-State Theophylline Pharmacokinetics in Asthmatic Children

Potential day-night differences of theophylline absorption and disposition were examined in day-active asthmatic children. Theophylline was given orally as TheoDur tablets and Somophyllin-CRT capsules (random crossover) every 12 hr (0700 and 1900), and patients were studied during two consecutive dosing intervals. In addition, patients were studied during the last 24 hr of a 48-hr continuous, intravenous aminophylline infusion. Serum theophylline concentrations were essentially constant during the intravenous infusion for the day and night periods. Thus, day and night clearances were nearly identical. Following oral administration of Somophyllin-CRT or TheoDur, areas under the serum concentration-time curves were greater during the day than the night, with Somophyllin-CRT yielding greater areas than TheoDur for both dosing intervals. Theophylline was absorbed more rapidly during the day than the night, as evidenced by a time to maximum concentration that occurred earlier in the daytime dosing interval. We conclude that theophylline clearance is not characterized by a circadian rhythm and that absorption of theophylline from Somophyllin-CRT and TheoDur is more rapid and complete during the day than the night.     

Heart Rate Variability During 24 Hours in Asthmatic Children

The autonomic circadian rhythm plays an important role in asthma. In recent years it has become possible to evaluate autonomic nervous function (ANF) using analysis of heart rate variability (HRV). We analyzed the HRV in the 24h period following the state without an asthma attack in order to study the relationship between asthma and ANF. The HRV was analyzed in 94 asthmatic children (ages 5–15 years). These subjects were divided into groups according to the severity of their asthma. After recording a 24h ambulatory electrocardiograph (AECG), the HRV was analyzed by a computer. Evaluation of the HRV was carried out using time-domain and frequency-domain analyses. The ANF of asthma subjects was decreased in comparison to the normal group. The severity of asthma had a significant effect on the %RR50 (the proportion of cycles during which the difference is > 50 ms), the SD (standard deviation; mean of standard deviation of all normal RR intervals for all 5-minute periods), the low-frequency (LF) band (0.04 to 0.15 Hz), and the high-frequency (HF) band (0.15 to 0.4 Hz) (%RR50: F = 4.31, p = 0.01; SD: F=3.48, p = 0.03; LF: F=3.67, p = 0.02; HF: F=3.41, p = 0.03). These values were lowest in the severe asthma group. With regard to the therapy grouping, the index that exhibited a significant difference was the NNA (mean of normal-to-normal RR intervals over 24h) (F = 4.43, p = 0.01) In conclusion, even in the normal condition in which the patient is free of an asthma attack, the ANF of asthma sufferers differs from that of normal children. It is possible that the different ANF of asthma sufferers is related to the severity of the asthma. (Chronobiology International, 14(6), 597–606, 1997)     

Chronopharmacology of morphine in mice

Dosing-time-dependent changes in the effect and toxicity of morphine were examined in mice housed under alternating 12 h light (07:00 to 19:00 h) and dark (19:00 to 07:00 h) cycles. Morphine (0.5 mg/kg) was injected intraperitoneally (i.p.) in animals to assess its beneficial effect (i.e., protection against the kaolin-induced, bradykinin-mediated, writhing reaction) and its toxicity (i.e., alteration of the hepatic enzymes of aspartate aminotransferase [AST] alanine aminotransferase [ALT], and glutathione [GSH] in separate experiments). The magnitude of the analgesic effect of morphine depended on dosing time, with minimum effect at 02:00 h and maximum effect at 14:00 h. The serum hepatic enzyme levels of AST and ALT increased after dosing morphine (100 mg/kg) at 02:00 and 14:00 h. Time courses of these enzymes did not differ between the two trials. However, hepatic GSH, which is involved in the detoxification of chemical compounds, significantly decreased after i.p. morphine injection at 02:00 but not at 14:00 h. Overall, the results suggest that the analgesic effect of morphine is greater after dosing during the resting than during the activity phase of mice that have been induced with bradykinin-mediated pain. Drug-induced hepatic damage as inferred by GSH alteration, however, may be greater after dosing during the active phase.     

Nutritional Status of Children Hospitalized for Parapneumonic Effusion

Background & Aims

Among children hospitalized for pneumonia, those with parapneumonic effusion (PPE) are at particular risk for nutritional deterioration. This study aimed to 1) investigate the evolution of the nutritional status during hospitalization and at outpatient follow-up; 2) determine clinical risk factors for weight loss during hospitalization; 3) describe the nutritional interventions for these children.

Methods

Retrospective chart review (January ‘07 - September ‘12) of 56 children with pneumonia, complicated by PPE in two Belgian hospitals for data on body weight and height at admission (t₀) and discharge (t₁), and two weeks (t₂) and one month (t₃) after discharge. Length of hospitalization (LoS), length of stay in paediatric intensive care (LoS_PICU) and maximal in-hospital weight loss (t_max) were calculated and nutritional interventions were recorded.

Results

The median (range) age was 3.5 (1.0–14.8) years. Weight or height was lacking in five (8.9%) children at t₀ and in 28 (50%) at t₁; 21.4% was weighed only once during hospitalization. At t_max, respectively 17/44 and 5/44 children lost ≥5% and ≥10% of their weight. Median (range) LoS and LoS_PICU were 18.0 (10–41) and 4.0 (0–23) days. One-fourth received a nutritional intervention. Weight for height at admission (WFH(t₀)) significantly predicted maximal weight loss (β (95% CI) = −0.34 (−2.0–−0.1); p = 0.03). At t₂ and t₃, 13/32 and 5/22 of the children with available follow-up data did not reach WFH(t₀), whilst in 4/35 and 5/26 body weight remained ≥5% under the weight(t₀).

Conclusions

One-third of children with pneumonia complicated by PPE and monitored for weight and height, lost ≥5% of their body weight during hospitalization. One-fourth did not reach initial WFH one month after discharge. Those with a higher WFH at admission were at higher risk of weight loss. More attention for monitoring of weight loss and the nutritional policy during and after hospitalization is warranted.     

Bacteremia in Children Hospitalized with Respiratory Syncytial Virus Infection

Background

The risk of bacteremia is considered low in children with acute bronchiolitis. However the rate of occult bacteremia in infants with RSV infection is not well established. The aim was to determine the actual rate and predictive factors of bacteremia in children admitted to hospital due to confirmed RSV acute respiratory illness (ARI), using both conventional culture and molecular techniques.

Methods

A prospective multicenter study (GENDRES-network) was conducted between 2011–2013 in children under the age of two admitted to hospital because of an ARI. Among those RSV-positive, bacterial presence in blood was assessed using PCR for Meningococcus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, in addition to conventional cultures.

Results

66 children with positive RSV respiratory illness were included. In 10.6% patients, bacterial presence was detected: H. influenzae (n = 4) and S. pneumoniae (n = 2). In those patients with bacteremia, there was a previous suspicion of bacterial superinfection and had received empirical antibiotic treatment 6 out of 7 (85.7%) patients. There were significant differences in terms of severity between children with positive bacterial PCR and those with negative results: PICU admission (100% vs. 50%, P-value = 0.015); respiratory support necessity (100% vs. 18.6%, P-value < 0.001); Wood-Downes score (mean = 8.7 vs. 4.8 points, P-value < 0.001); GENVIP scale (mean = 17 vs. 10.1, P-value < 0.001); and length of hospitalization (mean = 12.1 vs. 7.5 days, P-value = 0.007).

Conclusion

Bacteremia is not frequent in infants hospitalized with RSV respiratory infection, however, it should be considered in the most severe cases.     

小儿喘息性疾病喘息反复发作的病原学及危险因素分析

摘要目的：分析小儿喘息性疾病病原学及与喘息发作有关的因素。方法：227例患儿来我院儿科住院的患儿,在有喘息发作及无喘息发作时均取分泌物进行细菌和病毒检测,并对可能与喘息发作有关的因素做统计分析。结果：喘息发作时细菌感染91例（40．1％）,病毒感染110例（48．5％）,无喘息时72例（31．7％）检出细菌感染,59例（26％）检出病毒感染,喘息发作时细菌和病毒感染检出率均显著高于无喘息时（P〈0．05）。单因素分析过敏史、细菌感染、病毒感染、被动吸烟史、家族史和季节等暴露因素在喘息次数超过和低于4次患儿之间存在差异（P〈O．05）。多因素非条件Logistic回归分析显示病毒感染（OR=2．839）、细菌感染（OR=2．434）、过敏史（OR=4．412）和家族史（OR=2．158）为喘息性疾病患儿喘息发作次数增多的主要危险因素。结论：病毒和细菌感染为小儿喘息性疾病的主要致病原,病毒和细菌感染、有过敏史与家族史是喘息反复发作的危险因素。     

喘息性支气管炎患儿急性期血小板参数的实验观察

目的:测定喘息性支气管炎惠儿急性期血小板参数并分析其可能的临床意义.方法:用血细胞分析仪测定喘息性支气管炎患儿血小板4项参数,并随机选择30例上呼吸道感染患儿为对照.结果:与对照组相比,重症组、轻症组血小板数升高,但差异无统计学意义(P＞0.05);平均血小板体积、血小板分布宽度、大血小板比率也升高,且差异均具显著性(P＜0.01).结论:喘息性支气管炎发作时,存在血小板的活化、聚集和释放,其在炎症的发生发展中起重要作用.     

Chronopharmacology of cardiovascular medications

The cardiovascular system is well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter the physiological circadian pattern in the cardiovascular system. This observation bares implications for drug treatment, e.g. regarding drug formulations and dosing time intervals. Pitfalls may arise from neglecting circadian phase-dependency in pharmacokinetics and in the concentration-dependent effect relationship. Moreover, different types of drugs may be superior to others when circadian time-related symptoms are concerned. There is sound evidence that “time-of-day” has to be included in our diagnostic and therapeutic strategies.     

Endocrine Response to Substitution of Corticotrophin for Oral Prednisolone in Asthmatic Children

The hypothalamo-pituitary-adrenal axis has been assessed in 17 asthmatic children before and after long-term prednisolone therapy was changed to daily corticotrophin. In 14 of the 17 children the plasma corticosteroid concentration exceeded 15 μg/100 ml within five days of starting corticotrophin. No exacerbation of asthmatic symptoms occurred during conversion. The plasma corticosteroid response to insulin-induced hypoglycaemia was normal in four children about six weeks after conversion to corticotrophin, took up to 36 months to become normal in nine, and remained abnormal in one child throughout the period of the trial.     

住院肺炎患儿偏肺病毒和呼吸道合胞病毒感染研究

为探讨沈阳地区肺炎患儿中偏肺病毒(hMPV)和呼吸道合胞病毒(RSV)感染情况,用反转录聚合酶链反应(RT-PCR)法对部分因肺部感染住院患儿进行了病原学研究。结果显示,hMPV感染率为9%;而RSV感染率为46%,其中A型占40%,B型占60%。研究结果表明,在婴幼儿肺炎患儿中RSV感染率高于hMPV感染率,两者所致肺炎在发病年龄、性别及临床症状上无显著区别。     

湖南省13所综合性医院住院儿童结核病的调查分析

目的:调查分析湖南省综合性医院住院病例中儿童结核病的情况.方法:回顾性调查2006年1月至2008年3月间湖南省13所综合性医院住院病人中诊断为结核病的0-14岁儿童结核病例.结果:共调查到儿童结核病(不舍潜伏结核感染病例)195例,男□女为1.67:1,农村居住与城市居住结核病人数比为2.67:1;发病比率最高的前三位依次为肺结核、结核性脑膜炎(含结核性脑膜脑炎)、淋巴结核;患病年龄以学龄期儿童(6-14岁)最多,婴儿期最少;不同年龄段结核类型有所不同,学龄期儿童以肺结核为主,其他各年龄组则多为肺外结核(淋巴结核、结核性脑膜炎);有结核病接触史者78例,有卡介苗接种史123例.其中.明确记录卡痕者62例;无卡介苗接种史或不详的患儿中结脑比率(36.1%)显著高于有卡介苗接种史患儿(28.5%);住院病例结核诊断手段多种多样,使用最多的为PPD皮试及淋巴活检.结论:我省综合医院住院儿童结核病患者并不少见,但危重结核类型比重大,其中以学龄期儿童患病人数多,卡介苗接种质量有待提高,我省儿童结核防治之路仍然任重而道远.     

Detection of Rotavirus from Hospitalized Diarrheic Children in Uttar Pradesh, India

In the present study 220 stool samples collected from diarrheic children admitted to different hospitals and nursing homes of Uttar Pradesh and Uttarakhand were screened for rotavirus. Of 220 diarrheic samples screened 46 samples were found to be positive for rotavirus by RNA PAGE. All the isolates exhibited 4-2-3-2 migration pattern suggesting group A rotavirus. Both long and short electropherotypes were prevalent in these regions. Six different electropherotypes were detected in this study period. Male diarrheic children were found to be more susceptible to rotavirus infection (22.96 %) than that of the female ones (17.64 %). Viral RNA isolated from stool samples again subjected to VP4 gene amplification by RT-PCR using con2 and con3 primer which resulted 876 bp product suggesting group A rotavirus. Besides virus isolation was successfully done using MA104 cell line.     

Chronopharmacology of Oral Nitrates in Healthy Subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5- monitrate (IS-SMN, 60 rng) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (t_max of 0.9 h) than in the evening (t_max of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5- MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.     

Chronopharmacology of Methotrexate Pharmacokinetics in Childhood Leukemia

Survival has been shown to improve when maintenance therapy for acute lymphocytic leukemia in children is given at night rather during the day. We examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In a crossover study, we determined the pharmacokinetics of intravenous methotrexate at 10:00 and 21:00 h in six children with standard or high-risk leukemia. During the study, children refrained from concomitant drugs (6-mercaptopurine and trimethoprim sulfamethoxazole). There was a significant fall in methotrexate plasma clearance at night (from 5.6 ± 3 ml/min/kg to 4.7 ± 2.3 ml/min/kg p > 0.05). Renal clearance of methotrexate tended to decrease at night and unbound renal clearance decreased significantly (from 17.5 ± 1.7 ml/min/kg to 8.5 ± 3.6 ml/min/kg p > 0.05). Creatinine clearance did not exhibit diurnal variation, when comparing two 12-h collections, but there was a significant decrease in the nonglomerular clearance of methotrexate (from 14.8 ± 5.2 to 6 ± 4 ml/min/kg). Because it is a weak organic acid, the tubular secretion of methotrexate depends on urinary pH. At night urinary pH is more acidic. This may result in more reabsorption and hence reduced renal clearance.