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。     

司帕沙星及洛美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　研究司帕沙星及洛美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　36例老年COPD患者口服茶碱缓释片10 0mg ,q8h×9d ,d 4起Ⅰ组18例合用司帕沙星片2 0 0mg ,qd ;Ⅱ组18例合用洛美沙星胶囊4 0 0mg ,q12h。于d 4、10采集血样,采用荧光偏振免疫法检测茶碱的血药浓度,用PKBP N1程序求得药动学参数。结果　合用司帕沙星后茶碱血药浓度较合用前明显升高(P <0 .0 1) ,AUC及cmax差异有高度统计学意义(P <0 .0 1) ;而合用洛美沙星后其血药浓度较合用前稍有升高(P >0 .0 5 ) ,药动学参数除tmax有统计学意义(P <0 .0 5 )外,其余的变化均无统计学意义。结论　司帕沙星对茶碱的药动学有显著性影响,而洛美沙星对茶碱的药动学情况基本上无明显的影响。     

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.     

Pharmacokinetics of an ultralong sustained-release theophylline formulation when given twice daily in elderly patients with chronic obstructive pulmonary disease: monitoring implications

The steady-state pharmacokinetics of an ultralong sustained release formulation of theophylline (Unilong) twice daily (bid) in elderly hospitalized patients suffering from chronic obstructive pulmonary disease (COPD) have been studied in order to establish guidelines for monitoring. The study was carried out in 37 patients (33 men), aged 60-87 years. Samples were collected from 0 to 12 h after the morning dose on day 9 of treatment with 250 mg bid (n=25) or 375 mg bid (n=12). Considerable variability in apparent clearance (range 0.33-1.49 ml/min per kg of ideal body weight), Css(min)/D (range 0.28-1.86), Css(max)/D (range 0.65-2.33) and (Css(max)-Css(min))/Css(avg) (range 0.18-0.80) was observed. There was no significant correlation between the patient's age and apparent clearance within this elderly population. The concentration-to-dose ratio and the relationship between the steady-state plasma concentration at different times during the dosage interval and Css(avg) are described. It is concluded that the interpatient variability in peak-trough fluctuation of this formulation was higher than that described in healthy volunteers by other investigators, and that the apparent clearance did not decrease with age within this elderly population with COPD. The importance of theophylline monitoring is emphasized and rules to estimate Css(avg) and Css(5h) from Css(0h) when only a single sample obtained before the morning dose is available are given.     

Pharmacokinetics of theophylline in patients following short-term intravenous infusion

Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin^® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, V_d=0.451 (0.258–0.789) l/kg ideal body weight, and t_1/2(el)=7.1 (2.6–19.1) h.     

Effect of cimetidine and ranitidine on plasma theophylline in patients with chronic obstructive airways disease treated with theophylline and corticosteroids

Summary Thirty adults with chronic obstructive airways disease, who were stabilised on theophylline and corticosteroids, took part in a single blind study of the effects of cimetidine and ranitidine on plasma theophylline concentrations. The patients were randomised to receive either 150 mg ranitidine b. d. or 400 mg cimetidine b. d. for one week and serial plasma theophylline measurements were made over a 12-hour period on two consecutive days before, during and after treatment with the H₂-antagonist.There was a significant increase in plasma theophylline during treatment with cimetidine; two patients had levels > 20 mg·1^–1. The average increase in the theophylline concentration due to cimetidine was 32%. There was no significant change in plasma theophylline during ranitidine administration. No adverse effect occurred in any patient during the study.     

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]     

Dipyridamole treatment in chronic obstructive airways disease: Effect on platelet regeneration time

Summary The platelet regeneration time (PRT) determined in a group of hypoxaemic patients with chronic obstructive airways disease (COAD), before and after treatment with dipyridamole 150 mg tid, was compared with a group of control subjects. The PRT was computed by a modified non-radioisotope technique and was expressed as t_1/2 in days. The patient group showed a significantly shortened PRT as compared to controls of the same age and sex (2.10±0.16 vs 3.65±0.26 days;p<0.001). One month of dipyridamole administration resulted in prolongation of the PRT in COAD patients (2.10±0.16 days pre-treatment vs 2.75±0.20 post-treatment;p<0.01), without affecting the platelet cyclo-oxygenase system. This study indicates that dipyridamole may be beneficial in pathological conditions, which are characterized by increased platelet turnover, possibly leading to frequent thromboembolic complications.     

茶碱在慢性阻塞性肺病患者血药浓度的动态分析

目的监测慢性阻塞性肺病(COPD)治疗中茶碱的合理血药谷浓度。方法用回顾性分析方法,收集本院近11年来的90例COPD病例,给予小剂量氨茶碱0.125g,静脉滴注,1日2次。在治疗中做过5次以上(平均每人12.5次)茶碱血药谷浓度动态监测。结果90例患者的950次血药浓度结果中,有74.3%分布在3～10μg·mL-1;有85.7%症状得到控制,有6.6%病情好转。大部分患者的茶碱血药谷浓度在3～10μg·mL-1波动。结论用茶碱治疗COPD时,推荐血药谷浓度调控在3～10μg·mL-1。     

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.     

Effect of verapamil in obstructive airways disease

Summary Lung resistance and the ECG were studied before and after i.v. injection of verapamil in six healthy subjects and in nine patients with obstructive airways disease. No systematic effect on lung resistance was found in any of the groups. There was prolongation of atrio-ventricular conduction time in those healthy subjects who received a larger dose of verapamil. Inhalation of isoprenaline caused a significant decrease of lung resistance in patients with obstructive airways disease. It is concluded that verapamil is not contraindicated in the latter disease. The results support the hypothesis that verapamil causes quantitatively different effects on the same type of tissue at different sites.     

Disposition and clinical pharmacokinetics of microcrystalline theophylline

Summary Variation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair®) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19±9 min (mean±SD). Maximal serum concentrations reached after 100±30 min were found to be in a rather narrow range: 9.8±2.5 mg · 1^–1. The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7±10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.     

茶碱葡萄糖注射液治疗慢性阻塞性肺疾病急性加重的疗效

目的 :观察茶碱葡萄糖注射液治疗慢性阻塞性肺疾病 (COPD)急性加重伴喘息症状的疗效和安全性。方法 :COPD急性加重伴喘息的病人 6 0例 ,随机分成治疗组 34例和对照组 2 6例 ,分别予茶碱葡萄糖注射液 0 .2g ,iv ,gtt,或氨茶碱注射液0 .2 5 g 加入 5 %葡萄糖注射液 10 0mL ,iv ,gtt ,均注射 1次。记录用药前、治疗后即刻及结束后 6 0 ,180 ,36 0min的症状、肺功能、心电图、茶碱血药浓度及不良反应。结果 :治疗组iv ,gtt结束时 ,病人通气功能改善 ,喘息症状缓解 ,36 0min时 ,肺功能好转率为 71% ,喘息缓解有效率为 5 9%。与对照组比较无统计学差异 (P >0 .0 5 )。不良反应少。结论 :茶碱葡萄糖注射液适用于治疗COPD急性加重的喘息症状。     

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.     

Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment

Chronic obstructive pulmonary disease represents a major global health care burden for both primary and secondary care providers and is the most common respiratory condition necessitating hospital admission. Short-acting bronchodilators play a vital role in immediate relief of symptoms, while inhaled long-acting bronchodilators and inhaled corticosteroids are advocated for regular use in individuals with persistent symptoms and exacerbations. Theophylline is a nonspecific phosphodiesterase inhibitor and is usually reserved for patients with ongoing symptoms despite optimum inhaled bronchodilator treatment or when difficulty is encountered with inhaler devices. However, it is often not widely used mainly due to frequency of dose-related adverse effects, numerous drug interactions and narrow therapeutic index. This in turn has lead to the development of more selective phosphodiesterase inhibitors in an attempt to create a drug which patients can use with beneficial effects but without the problems associated with theophylline. Current data do indicate that phosphodiesterase 4 inhibitors confer some benefits in chronic obstructive pulmonary disease when compared to placebo in terms of lung function, quality of life and exacerbations. They are also generally well tolerated. Further studies are required to determine fully their long-term beneficial and adverse effect profiles and ultimately where they might comfortably sit in management algorithms.     

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。     

康复治疗在慢性阻塞性肺疾病缓解期患者中的作用

目的观察康复治疗对慢性阻塞性肺疾病（COPD）缓解期患者肺功能、6min步行距离膈肌移动范围的影响。方法COPD缓解期患者共50例,随机分为对照组25例和康复治疗组25例,前者给一般内科治疗,后者在一般内科治疗基础上根据患者病情制订康复治疗方案,交代患者和家属参照执行,并留患者的联系方式以监督实施和随访。结果康复治疗组与对照组比较,康复治疗对缓解期COPD患者的肺功能、6min步行距离、膈肌移动范围改善显著,急性发作次数明显少于对照组。结论康复治疗在改善患者生存质量、减少住院和就诊次数等方面具备综合效果。     

高血糖对慢性阻塞性肺疾病患者预后的影响

目的住院期间血糖升高对慢性阻塞性疾病急性发作期(COPD-AE)患者近期预后的影响。方法对131例COPD-AE患者入院3d内进行空腹血糖测定。根据空腹血糖把患者分为血糖异常组(空腹血糖≥6.1mmol/L),血糖正常组(空腹血糖<6.1mmol/L)。结果82例(62.6%)COPD-AE患者空腹血糖≥6.1mmol/L,其中确诊糖尿病患者36例(27.5%),血糖升高组多为高龄患者,住院期间病死率明显高于血糖正常组(P<0.05)。结论住院期间血糖升高是影响COPD-AE患者预后的一个重要的危险因素,对血糖升高的患者应给予积极的治疗。     

The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease

Summary We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances.Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml·h^–1·kg^–1 respectively.Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml·h^–1·kg^–1 respectively.There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance.It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.