Non-interaction of ketotifen and theophylline in children with asthma – an acute study

Summary Six asthmatic children participated in an acute crossover randomized study. They received a single dose of aminophylline syrup 6 mg/kg after having received ketotifen syrup 1 mg b.i.d. or place-bo for 8 days. Ketotifen did not significantly affect the heart rate, pulse pressure or such pharmacokinetic parameters of theophylline as peak serum level, time to peak, half life and AUC. Thus, ketotifen had no significant effect on the disposition of theophylline.     

Pharmacokinetics of budesonide in children with asthma

Summary The pharmacokinetics of the glucocorticoid budesonide was studied in 6 children with asthma after i.v. injection of 0.5 mg and oral inhalation of 1 mg as an aerosol. Budesonide is a 1:1 mixture of the epimers 22 S and 22 R, which were assayed separately by HPLC combined with RIA. All pharmacokinetic parameters of the epimers differed except the half-life of about 1.5 h. It was significantly shorter than that reported in adults. Plasma clearance averaged 103 l · h^–1 for epimer 22 R and 74 l · h^–1 for epimer 22 S; calculated per kg body weight these values were about 50% higher than in adults. The difference was about 40% when calculated per m² of body surface area. Since budesonide is a high-clearance drug, the data indicate higher liver blood flow · kg^–1 body weight and m² of body surface area in children. The systemic availability of the aerosol was approximately 30% of nominal dose, i.e. the same as in adults. The high clearance and short half-life of budesonide in children are advantageous in reducing the risk of possible systemic side-effects of prophylactic treatment of asthma in childhood.     

A comparison of the pharmacokinetics of theophylline in asthmatic children in the acute episode and in remission

Summary The pharmacokinetics of theophylline following a single intravenous dose of aminophylline were determined in 8 asthmatic patients in each of the acute, the recovery and the remission phases. The overall results for mean plasma theophylline clearance (78.6±33.3 ml/kg/h), plasma theophylline half-life (4.14±1.36 h) and apparent volume of distribution (0.41±0.066 l/kg) are in accordance with previously published values. There was no general statistically significant difference in any of the pharmacokinetic parameters when results from the acute and remission phases were compared. However, certain patients showed reductions in plasma theophylline clearance in the acute phase of the illness such that a dosage regimen standardised during remission may cause toxicity if continued in the acute episode. It is suggested that monitoring the plasma theophylline levels is desirable in all patients in the acute episode.Abbreviations used AV_d apparent volume of distribution - t_1/2 plasma half-life - Cl plasma clearance - P₀ plasma concentration at zero time     

三种茶碱缓释剂的药动学和生物利用度研究

本实验应用均相酶免疫法和PKBP—N_1程序包对六名健康志愿者分别口服三种茶碱缓释剂后的药动学参数和相对生物利用度进行了探讨,结果表明:三者的生物利用度、吸收速率常数和波动百分率均无显著差异(P>0.05)。     

Pharmacokinetics of theophylline and enprofylline in patients requiring a high or low dose of theophylline

Summary In patients requiring a high or low dose of theophylline the pharmacokinetics of theophylline and enprofylline were studied. The low-dose group took an average daily dose of 8.91 mg/kg body wt. and the high-dose group 24.75 mg/kg body wt. The average half-life of theophylline in the former was 7.11 h and in the latter 4.72 h. The average clearances (CL) of theophylline were 2.83 and 4.58 l/h, respectively. The daily oral intake of theophylline was negatively correlated with the theophylline t_1/2 (r=–0.63). While the t_1/2 of enprofylline was similar in the two groups, CL and volume of distribution (V_c) were slightly (about 30%) but significantly higher in patients requiring a high dose of theophylline. CL of enprofylline did not correlate with CL of theophylline, nor was the V_c of the two drugs correlated. Interindividual variability in t_1/2 and CL was considerably lower for enprofylline than for theophylline.     

茶碱类药物在哮喘治疗中的应用

近年研究表明,小剂量茶碱有抗炎、免疫调节和扩张支气管等多方面的作用,与吸入糖皮质激素联用有协同抗炎、改善肺功能的作用。     

Enprofylline pharmacokinetics in children with asthma

Summary The pharmacokinetics of intravenous enprofylline has been studied in 8 children with asthma.The mean plasma half-life of enprofylline (1.0 h) was considerably shorter than that previously reported in adults. The half-life determined from log urine excretion rate data was identical to the plasma half-life, so urine excretion could be used as a noninvasive method to study the elimination rate.As in adults, urinary recovery of unchanged drug averaged 89%, and the volume of distribution, V_z, averaged 0.58 l/kg.Clearance was higher in children than in adults when calculated per kg body weight, but not when calculated per m² body surface area. The dosage of enprofylline in children would be more accurate if calculated in proportion to surface area rather than to body weight.Data agree with published information on creatinine clearance, which, adjusted for body surface area, stays constant from the age of 3 years until early adult life.     

茶碱控释片在睡眠呼吸暂停病人中的药物动力学

目的 :研究茶碱控释片 (优喘平 )在睡眠呼吸暂停 (SAS)病人中的药物动力学。方法 :采用荧光偏振免疫法 ,测定 6例SAS病人首次口服优喘平 6 0 0mg后 48h内的血清茶碱浓度。结果 :血清中茶碱浓度在 12h左右达峰 ( 7.2 5 μg·ml-1) ,消除半衰期为 11.5h ,分布容积为 44 .49L ,总体清除率为 2 .6 1L·h-1,由此计算出达到有效治疗浓度 ( 10 μg·ml-1)所需的优喘平平均日剂量为 733mg。优喘平服药 3d达稳态时的峰谷浓度波动系数为2 4.31%。结论 :优喘平在SAS病人中口服给药后的药动学特征符合控释制剂要求 ,血药浓度波动较小 ,稳态时可达有效治疗浓度 ,为SAS病人安全有效用药提供了依据。     

茶碱对哮喘气道炎症的作用(英文)

目的:研究小剂量茶碱对哮喘气道炎症的作用。方法:19名哮喘患者用茶碱缓释剂(200mg,bid,平均血浆茶碱浓度7.9mg/L)治疗4周,分别用瑞氏染色、免疫组织化学及荧光免疫法检测治疗前后高渗盐水诱导痰中嗜酸细胞(Eos)、激活的Eos(EG2~(2 )Eos)和嗜酸细胞阳离子蛋白(ECP)的变化,并观察治疗前后症状积分和肺功能的变化。结果:用茶碱治疗前,患者痰中Eos、EG~(2 )Eos和ECP比健康人明显增加;用茶碱治疗4周后,哮喘患者诱导痰中Eos百分数下降(40％±17％ vs 29％±11％,P<0.01),EG~(2 )Eos百分数显著下降(28％±9％ vs 10 ％±8％,P<0.01),痰ECP明显下降[(373±206)vs(220±132)μg/L,P<0.01];症状明显好转(7.1±1.2 vs 5.4±1.6,P<0.01);肺功能明显改善,FEV_(1.0)增加(2.2±0.6 vs 2.4±0.5,P<0.01),FEV_(1.0)％也增加(60％±13％ vs 65％±13％,P<0.01)。结论:小剂量茶碱对哮喘气道炎症有明显抑制作用,同时使患者症状和肺功能明显改善。     

The airway effects of stopping regular oral theophylline in patients with asthma

Aims We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline.
Methods Eighteen subjects with mild stable asthma were given oral theophylline 10  mg  kg⁻¹ day⁻¹ or placebo for 2 weeks in a double-blind crossover study. FEV₁ and PD₂₀ histamine were measured before and 8  h after the first dose of treatment and 8, 32 and 56  h after the final dose. PD₂₀ AMP was measured before treatment and 9  h after the final dose.
Results Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD₂₀ histamine or FEV₁ up to 8  h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV₁ (mean difference 0.15  l, 95% CI 0.03, 026) and PD₂₀ AMP compared to placebo but no difference in other end points.
Conclusions The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.     

Long-term treatment with oral nifedipine plus theophylline in the management of chronic bronchial asthma

Summary The effect on bronchial smooth muscle of slow release theophylline plus placebo and theophylline plus slow release nifedipine administered for a prolonged period to 12 asthmatic and hypertensive patients has been studied. Both combinations led to a significant improvement in respiratory function parameters when compared to baseline values. No additional improvement in pulmonary function was found on long term treatment with theophylline plus nifedipine. A reduction in the number of asthmatic attacks, in the use of inhaled beta₂-agonists and better control of arterial blood pressure resulted from use of theophylline plus nifedipine. That drug combination is safe and valuable in patients with chronic bronchial obstruction and cardiovascular disease.     

Acute effects of short-term subcutaneous terbutaline on theophylline disposition

Summary Theophylline and subcutaneous terbutaline are frequently used concurrently in the management of acute asthma. Recent evidence demonstrating a reduction in theophylline serum concentrations during concomitant oral terbutaline therapy prompted our evaluation of subcutaneous terbutaline's effect on theophylline pharmacokinetics. Using a randomized, placebo controlled, crossover design, the disposition of a single oral theophylline dose (7 mg/kg) was studied in eight healthy, adult males before and after repeated subcutaneous administration of terbutaline (0.25 mg). Two-way analysis of variance revealed no significant difference in elimination rate constant (ke), area under the concentration-time curve (AUC), or apparent oral clearance (CL/F) of theophylline following terbutaline administration. These results indicate that subcutaneous administration of terbutaline does not alter the pharmacokinetics of single, oral doses of theophylline in adults.     

Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease

Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV₁ were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUC_ss/AUC₁, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV₁ 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.     

Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease

Summary The pharmacokinetics of theophylline was investigated in five hyperthyroid, five hypothyroid, and five euthyroid patients, all with chronic obstructive pulmonary disease. Wide individual variability was found in theophylline kinetics, but the rate of elimination of theophylline was significantly higher in hyperthyroid, and lower in hypothyroid patients than in the euthyroid patients (k_el=0.155, 0.060 and 0.107 h^–1, respectively). The values for clearance and volume of distribution were not consistently changed compared with those in the euthyroid group, although all the parameters except AUC were significantly different in hyperthyroid and hypothyroid patients. There was a positive correlation between both thyroxine and triiodothyronine serum concentrations and total body clearance of theophylline (r=0.795 and r=0.791, respectively). It is concluded that in spite of the wide interindividual variability and the relatively small differences in the pharmacokinetics of theophylline in thyroid dysfunction compared with the euthyroid status, these differences have to be considered in certain clinical situations, as they may require changes in the therapeutic regimen for administration of theophylline in hyperthyroid or hypothyroid patients.     

Once-daily theophylline in the treatment of nocturnal asthma

The efficacy and side-effects of individually adjusted doses of controlled-release theophylline given once daily in the evening (average dose 650 mg) were compared with those of standard treatment with controlled-release terbutaline 7.5 mg b.d. Thirty-six asthmatics with regular morning obstruction ("morning dipping") were studied over two treatment periods each of two weeks, according to a crossover, randomized, double blind design. Morning peak expiratory flow (PEF) was slightly but significantly higher with theophylline (363 l.min-1) than terbutaline (342 l.min-1). Feelings of dyspnoea on waking in the morning were also less pronounced with theophylline. There were no other differences between the treatment periods during the day or night, with respect to dyspnoea or any the other symptoms. Side-effects were mild and were reported with similar frequencies during both treatments. It is concluded than an individually adjusted dose of once-daily theophylline administered in the evening is at least as effective as conventional therapy with controlled-release terbutaline in preventing nocturnal and early morning asthma, when both drugs are added to regular medication with inhaled sympathomimetics and steroids.     

Pharmacokinetics of theophylline in patients with COPD and its interference factors

AIM： To study the pharmacokinetics of theophylline in patients with chronic obstructive pulmonary diseases （COPD） and its interference factors. METHODS： Serum theophylline concentrations in 9 patients with COPD after oral administration of theophylline （200 mg, tid） for 5 consecutive days or combining with nifedipine （ 10 mg, tid） for 5 consecutive days were determined by high performance liquid chromatography（HPLC） with ultraviolet spectrophotometry. RESULTS： The pharmacokinetics of theophylline in COPD patients was one-compartment model after oral administration of theophylline （200 mg, tid） for 5 consecutive days. The significant difference in individual variation on pharmacokinetics of theophylline was observed in this study. The volume of distribution （ Vd ） was （0.50 ± 0.21） L/kg, the elimination half-life （ t1/2 ） was （5.4 ± 1.3） h and clearance （CL） was （0.07 ± 0.03） L·h^-1·kg^-1 in the patients with COPD. There was no significant difference in Vd, t1/2, and CL between COPD patients and healthy volunteers （ P 〉 0.05）. The values of k and C1 were faster and t 1/2 was shorter in the middleaged patients than those in old COPD patients （P 〈 0.05）.[第一段]     

Personality and theophylline pharmacokinetics

Summary Thirteen volunteers received an iv dose of theophylline followed by blood sampling for 8 h to calculate pharmacokinetic parameters. Ten patients with asthma undergoing chronic dosing with slow release aminophylline underwent 12 h of blood sampling to calculate theophylline clearance. Both groups completed an Eysenck Personality Inventory (EPI) from which was derived scores for neuroticism (N) and extroversion (E). Using multiple regression analysis no independent effect of either N or E score on theophylline clearance or half-life could be demonstrated.     

Influence of theophylline on gastro-oesophageal reflux and asthma

Summary The aim of the study was to determine whether gastro-oesophageal (GO)-reflux was increased by normal maintenance doses of theophylline, and if so, whether this was detrimental to lung function in asthmatic patients with symptoms of reflux. In 25 patients with moderate or severe bronchial asthma and a history of respiratory symptoms aggravated by reflux, two consecutive oesophageal 24-h pH recordings were made, one with and the other without their ordinary dose of slow release theophylline.The theophylline treatment caused a significant increase in total reflux time and reflux symptoms but did not worsen the asthma. Patients with subtherapeutic serum levels showed significant improvement in lung function and those with therapeutic serum levels did not.It is concluded that theophylline, in view of its potential to exacerbate GO-reflux, should be used with caution as maintenance therapy in asthmatic patients with GO-reflux.     

茶碱缓释片治疗支气管哮喘60例的临床评价

本文报告应用信谊药厂生产的茶碱缓释片治疗60例支气管哮喘患者的疗效及副作用。对哮喘的疗效,有效率为75％,显效率为28％。口服剂量200mgbid,7d为一疗程。该药具有作用持久,血药浓度稳定、服药次数少、副作用小等优点;值得临床推广应用。