Intersubject variability in plasma theophylline levels after oral and intravenous administration in Jordanian patients with chronic obstructive pulmonary disease

Plasma theophylline concentrations were determined in 151 Jordanian patients with chronic obstructive pulmonary disease. Mean plasma levels after oral administration were below the therapeutic range and significantly lower than after intravenous administration. Plasma levels in patients with congestive heart failure (CHF) were higher than in patients with no CHF. Trough plasma theophylline concentrations after intravenous administration in patients less than 18 years of age were significantly lower than in those aged 18-60 years. The overall results are in agreement with observations made in other ethnic groups.     

Prediction of optimum oral theophylline dose in patients with obstructive airways disease.

The hypothesis that a logarithmic correlation exists between the plasma theophylline concentrations 6 h after a test dose C(6) and the maintenance dose calculated to achieve a desired drug concentration during chronic oral administration (DM,CALC) was tested. A nomogram based on this relationship was evaluated as a means of predicting the optimum dose of theophylline in 14 patients with obstructive airways disease (DM,PRED). Each patient was given 5 mg/kg theophylline intravenously (i.v.) and plasma theophylline concentrations were measured for 12 h thereafter including one exactly 6 h after commencing the i.v. infusion C(6). Pharmacokinetic parameters derived from the plasma concentration-time curve were used to establish DM,CALC for a concentration of 10 micrograms/ml. DM,PRED was obtained from the nomogram using both the optimum and the actual values for C(6). Subsequently oral sustained-release theophylline was administered and the dose adjusted to establish a trough concentration of approximately 10 micrograms/ml. This dose was then corrected arithmetically, assuming a linear relationship between dose and plasma level, to represent that required to achieve a plasma concentration of exactly 10 micrograms/ml (DM,ACT). The correlation between C(6) and log DM,CALC was confirmed (r = 0.97 P less than 0.001), validating the hypothesis. DM,ACT was found to correlate significantly with DM,PRED (r = 0.90, P less than 0.01) substantiating the value of the nomogram. In nine of the 14 patients, DM,ACT corresponded satisfactorily to DM,PRED. In the remaining five, for whom DM,ACT lay outside the 95% confidence limits for the predicted dose, DM,PRED in general underestimated DM,ACT, an advantage in a drug with a low therapeutic index. The predictive error for DM,PRED was lower than that for DM,CALC, and the bias using either method was not significant. The results suggest that a single plasma theophylline assay following a test dose, and the nomogram may be useful in simplifying optimal theophylline administration.     

Impairment of theophylline clearance by a hypocaloric low-protein diet in chronic obstructive pulmonary disease

The effect of a hypocaloric, low protein diet on theophylline kinetics was studied in a 70-year-old man with chronic obstructive pulmonary disease who lost 6.2 kg of weight. Total systemic clearance, unbound clearance, and intrinsic hepatic clearance fell dramatically. Theophylline elimination half-life rose from 8.4 to 17.1 h. Therefore, a diet deficient in both calories and protein can significantly impair theophylline clearance and prolong theophylline elimination half-life.     

茶碱对慢性阻塞性肺疾病稳定期诱导痰白细胞介素-8及肺功能的影响

目的探讨茶碱对慢性阻塞性肺疾病稳定期诱导痰白细胞介素-8及肺功能的影响。方法将40例稳定期COPD患者随机分为试验组和对照组,试验组给予茶碱口服,对照组给予安慰剂口服,共8周,观察治疗前后诱导痰白细胞介素8(IL-8)及肺功能的变化。结果试验组患者治疗8周后诱导痰IL-8浓度较治疗前显著降低(P<0.05),肺功能显著改善(P<0.05),而对照组诱导痰IL-8浓度及肺功能治疗前后差异无统计学意义。结论茶碱可减轻COPD患者气道炎症,改善COPD稳定期肺功能。     

茶碱在老年慢性阻塞性肺疾病患者中的群体药动学

目的：建立茶碱在老年慢性阻塞性肺疾病患者中的群体药动学（PPK）模型,并获取药动学参数,为临床制定个体化给药方案提供参考。方法：收集2014年4—12月某院诊断为慢性阻塞性肺疾病应用茶碱治疗的68例老年患者的血药浓度监测数据及临床资料,运用非线性混合效应模型法（NONMEN）定量分析性别、年龄、体质量及肝肾功能等因素对药动学参数的影响,最终建立PPK模型。采用拟合优度、自举法和可视化检验对最终模型的性能进行内部验证。结果：茶碱的药动学符合一室模型,最终模型公式为：CL=θ_CL×（WT/63）^θWT×exp（η_CL）,V=θ_V×exp（η_V）,其中的协变量为体质量,模型CL和V的群体典型值分别为0.849 L·h^-1,13.7 L。拟合优度、自举法和可视化检验的评价结果表明最终模型稳定,预测结果可靠。结论：建立的PPK模型能较好地描述茶碱在老年慢性阻塞性肺疾病患者中的药动学特点,患者体质量对参数CL有显著性影响。     

Early use of oral theophylline in hospitalized chronic obstructive pulmonary disease patients: cost-containment through medical education

This study measured the impact of an education program conducted by a clinical pharmacist on early conversion from intravenous to oral theophylline in hospitalized chronic obstructive pulmonary disease patients. Two separate two-month audit periods were conducted on the pulmonary medicine service (PMS) of a teaching hospital. During the first audit period (pre-ed), no education was provided. Prior to each month of the second two-month audit period (post-ed), an education program and handout outlining the rationale for early conversion from intravenous to oral theophylline was presented to medicine residents rotating onto the PMS. The results of this preliminary study suggest that the education program was responsible for a statistically significant decrease in intravenous aminophylline therapy from three days (pre-ed) to one day (post-ed). As a result of the reduction in length of intravenous therapy, both drug costs and patient charges were reduced by a statistically significant amount.     

Plasma theophylline level and ventilatory function in chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate

Summary Plasma levels of theophylline and broncholytic activity have been studied in 12 patients with chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate, administered as a press-coated tablet (Brondaxin^R). The plasma levels determined immediately before and 80 minutes after each dose showed very good agreement with those calculated on the basis of data from a previous single dose study. The plasma concentration and improvement in ventilatory function were closely correlated throughout the 48 hours of the study. A tendency towards further reduction of bronchial obstruction was observed during the second day, despite essentially unchanged plasma levels of theophylline. The results provide a rational basis for determination of an optimal dose schedule for oral treatment with choline theophyllinate to reduce the symptoms of obstructive bronchial disease.     

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.     

Lack of an effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline during concurrent administration in patients with chronic obstructive pulmonary disease.

The effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline was evaluated in a multiple-dose, randomized placebo-controlled, double-blind two-period crossover study in 13 patients who were undergoing theophylline therapy for chronic obstructive pulmonary disease. Two treatments were administered, each for 7 days: theophylline + 200 mg nefazodone twice daily (every 12h) and theophylline+matching nefazodone placebo capsule twice daily (every 12h). Mean peak and trough plasma concentrations of theophylline ranged from 13.1 to 14.5 micrograms ml-1 and 11.6 to 14.2 micrograms ml-1, respectively, at steady-state when theophylline was administered with or without concurrent dosing of nefazodone. Similarly, the mean area under the curve for theophylline ranged from 93.5 to 103 micrograms ml-1 h. When nefazodone and theophylline were co-administered, theophylline pharmacokinetic parameters did not significantly differ from those obtained when theophylline was administered with placebo. Forced expiratory volume in one second (FEV1) measurements taken when nefazodone or placebo were administered with theophylline did not differ from those obtained at baseline. The plasma concentration-time profiles for nefazodone and its metabolites were similar to those in other studies where nefazodone was administered alone. Since nefazodone did not affect the pharmacokinetics or the pharmacodynamics of theophylline, no change in theophylline dose should be needed as a consequence of nefazodone co-administration.     

慢性阻塞性肺疾病患者肺泡液体清除作用机制研究

目的本研究旨在探讨慢性阻塞性肺疾病(COPD)患者离体肺段肺泡液体清除率(AFC)的改变及其与环磷酸鸟苷(cGMP)依赖性蛋白激酶2(PKG2)的关系。方法应用临床外科手术肺切除患者的肺段标本,将药物通过插管注入远端肺组织。应用考马斯亮兰法测定肺泡液体内小牛血清白蛋白浓度的方法测定人离体肺段AFC。应用相关酶联免疫试剂盒检测PKG2。结果 COPD患者肺组织AFC增加,PKG2明显高于对照组。结论 COPD患者气道黏液分泌增多肺脏液体清除作用增强,其机制可能与上皮钠通道功能增强有关。     

舒利迭联合茶碱对慢性阻塞性肺疾病稳定期患者肺动脉压及右心功能的观察

目的：观察联合使用舒利迭及茶碱后,慢性阻塞性肺疾病（chronic obstructive pulmonarydisease,COPD）稳定期患者肺动脉压及右心功能的变化。方法：选择2010年9月-2012年6月期间在我院住院出院后进行长期门诊管理的COPD稳定期患者128人,进行回顾性分析,在吸入舒利迭一年后,比较右心几何参数及多普勒参数。结果：不同肺动脉压力基线水平病人在治疗前后心脏彩超各项指标表现各异,肺动脉压正常组多项参数指标无统计学意义（P〉o．05）;轻中度肺动脉高压组,患者具有较明显的肺动脉收缩压（40．19±5．82）mmHg、右室Tei指数（0．42±0．03）下降（P〈0．05）;重度肺动脉高压组,右心室Tei指数（0．50±0．06）、右房横径[RA（39．13±1．68）mm]、右室前后径[RV（38．97±2．13）mm]均有改变,差异具有统计学意义。结论：舒利迭联合使用茶碱,对于稳定期COPD患者,能部分改善右心功能。     

Prediction of maintenance oral theophylline dosage using single oral doses in patients with obstructive airways disease

This study was designed to test whether single oral doses of theophylline, rather than the specified single intravenous infusions, could be used with a nomogram designed to predict the maintenance oral dose necessary to establish plasma theophylline concentrations of 10 micrograms ml (Koup et al., 1979) in patients with obstructive airways disease. A test dose of theophylline (5 mg kg) was administered on two separate occasions as an oral elixir and as an intravenous infusion. Exactly 6 h after each test dose, plasma theophylline concentration was measured, and the result used to predict daily maintenance dose requirements. During subsequent oral administration, a sustained-release preparation was given in equally divided 12-hourly doses, and 'steady-state' concentrations were measured at trough. Nineteen patients completed the study, and on doses ranging from 4.2 to 21.1 mg kg-1 day-1, trough concentrations of 5.4 to 15.8 micrograms ml (mean 10.0 +/- 0.7 micrograms ml) were achieved. No significant differences were noted between the dose predictions made following either the oral or the intravenous test doses, and the predictive accuracy using the oral route was not compromised. This would suggest that the test dose of theophylline may be administered orally, instead of intravenously, with this nomogram without reducing its efficiency.     

Decrease in theophylline clearance after the administration of erythromycin to a patient with obstructive lung disease

It has been demonstrated previously that erythromycin can inhibit the total body clearance of theophylline, resulting in elevated serum theophylline concentrations. The overall incidence of this interaction and the population at risk have not been elucidated fully. Recent investigations have suggested that such an interaction is doubtful and that patients in whom this occurrence was suspect developed alterations in theophylline disposition secondary to worsening pulmonary function, not from erythromycin therapy alone. This case report shows that the interaction between theophylline and erythromycin can be clinically significant, producing as much as a 50-percent reduction in the total body clearance of the bronchodilator. The magnitude and time course of this interaction in patients with congestive heart failure and chronic obstructive pulmonary disease may differ considerably from that reported in healthy volunteers.     

口服不同疗程小剂量阿奇霉素对稳定期慢性阻塞性肺疾病患者临床疗效和安全性的研究

目的:研究不同用药疗程小剂量(0.25 g?d-1)阿奇霉素口服对稳定期慢性阻塞性肺疾病(chronic obstructive pulmo-nary disease,COPD)患者临床疗效和安全性的影响.方法:将165例稳定期COPD患者随机分为3组:用药3个月(A组)、用药6个月(B组)和用药12个月(C组),每组...     

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of ??3860G?>?A, ??163C?>?A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h)?=?4.530?×?(FFM/56.1)^0.75 ×?0.713^CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.     

司帕沙星对老年慢性阻塞性肺病患者茶碱缓释片药动学的影响

目的:研究司帕沙星对老年慢性阻塞性肺病(COPD)患者茶碱缓释片药动学的影响.方法:采用荧光偏振免疫法检测18例老年COPD患者联用司帕沙星前后茶碱各时点的血药浓度,用PKBP-N1程序求得药动学参数,并作统计学分析.结果:联用司帕沙星(200mg,qd)5 d后血药浓度较联用前均有升高(P＜0.01),药动学参数曲线下面积(AUC)及最大峰浓度(Cmax)差异有极显著性(P＜0.01).结论:司帕沙星以200 mg,qd给药对茶碱的药动学有显著性影响,临床联用时应监测茶碱血药浓度,防止茶碱因代谢减慢而引起中毒.     

影响慢性阻塞性肺疾病患者正确使用定量型气雾剂的因素分析及对策

目的 探讨慢性阻塞性肺疾病（COPD）患者正确使用定量型气雾剂的必要性和可行性. 方法 对120例COPD患者使用定量型气雾剂,按使用的7个步骤进行初试记录.出院前复试,出院后2周再次复试.比较患者在初、复试中的正确使用率. 结果 初始时,120例COPD患者中能正确使用定量型气雾剂者18例（15%）,常见的错误为：先按压后吸气（90例次）、连喷几次后再吸气（30例次）、吸气后无屏气（28例次）、吸人激素后无漱口（20例次）、使用前无摇匀（18例次）、先吸入糖皮质激素后再吸入β2受体激动剂（80例次）.出院前复试时总的正确使用率增至88例（73%）.出院2周第二次复试时总的正确使用率降至56%（68例）. 结论 定量型气雾剂在COPD患者中使用的正确率低影响疗效.建立规范化的指导和定期培训才能保证使用的正确性和有效性.     

临床药师对稳定期慢性阻塞性肺疾病患者的用药指导

目的探讨临床药师在慢性阻塞性肺疾病(COPD)稳定期用药治疗中的作用。方法将我院2010年1月至2013年1月出院的COPD患者124例,完全随机分为对照组和干预组,于出院后1、3、6个月,应用BODE指数评价效果。结果第1个月,两组BODE指数比较差异无统计学意义(P>0.05);第3个月,干预组患者的BMI、FEV1%pred%等较对照组增加(P<0.05);第6个月,干预组的m MRC、6MWD较对照组降低(P<0.05)。结论临床药师参与稳定期COPD患者的药物指导,有利于提高患者的生活质量。