Theophylline treatment may adversely affect the anoxia-induced erythropoietic response without suppressing erythropoietin production

Objective To investigate the influence of theophylline on erythropoiesis in chronic obstructive pulmonary disease (COPD) and explore the potential underlying mechanisms.Methods We evaluated the haematological parameters and erythropoietin (EPO) values in 38 COPD patients, 18 of which had been treated with theophylline (8 mg/kg daily) for at least 1 year, and the other 20 had never received this drug; 38 sex- and age-matched healthy volunteers served as controls. We further studied the development of BFU-E (bursts forming units of erythrocyte precursors) -derived colonies in semisolid methylcellulose cultures in blood samples from 7 patients randomly selected from both groups. In addition, we studied the effects of theophylline on the erythroid cell development by adding this agent to erythroid cell cultures from 6 healthy volunteers at various concentrations.Results Haemoglobin values were found to be significantly lower in COPD patients treated with theophylline than in those untreated (P<0.05). Both groups of patients exhibited significantly higher haemoglobin values than normal subjects (P<0.01 and P<0.001 for treated and untreated patients, respectively). Serum EPO levels did not differ among the three studied groups. Unlike untreated patients and controls, the serum of the theophylline-treated patients produced a significant growth inhibition of erythroid bursts (P<0.05); the in vitro use of theophylline showed a concentration-dependent inhibition (P<0.001).Conclusion Our findings confirm the decrease of red cell production, which occurs following administration of theophylline, exclude the possibility of decreased EPO synthesis and suggest a direct inhibitory action of theophylline on erythropoiesis.     

紫外分光光度法测定血浆茶碱浓度的改进

作者报道一种改进的血浆茶碱浓度紫外分光光度测定法,并与高效液相色谱法比较,二者相关性良好(r=0.9591,n=9,P<0.001)。本法快速、简便、可靠,其精密度及专一性均可满足临床要求,适用于茶碱血药浓度监测。     

The effect of domperidone on theophylline disposition in the rat

The effect of domperidone (2 mg kg-1) on the pharmacokinetics of a single oral dose of theophylline (25 mg kg-1) was studied in the rat. Theophylline concentrations were measured serially for 12 h using an HPLC technique. Domperidone did not have any significant effect on any of the four parameters studied: peak plasma levels (Cpmax), the time these were attained (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC). Our data preliminarily suggests that domperidone may be safely coadministered with theophylline but clearly further studies in patients or relevant animal models of gastric motility disturbances are needed to reliably rule out any potential interaction between these agents.     

Importance of drug type, tablet shape and added diluents on drug release kinetics from hydroxypropylmethylcellulose matrix tablets

The dissolution of 7 drugs from hydroxypropylmethylcellulose (HPMC) matrices have been examined to determine the time exponent (tⁿ) required to produce linear dissolution profiles. A value of n = ˜ 0.67 was obtained for time-dependent release for soluble drugs, the precise values being 0.71, 0.65, 0.67 and 0.64 for promethazine hydrochloride, aminophylline, propranolol hydrochloride and theophylline, respectively. The insoluble drugs, indomethacin and diazepam, displayed values of n = 0.90 and 0.82 indicating a near zero-order release. Matrices containing tetracycline hydrochloride, however, showed a value of n = 0.45 and displayed complex release patterns and lower release rates than anticipated on the basis of solubility. Replacement of HPMC by calcium phosphate or lactose increased the dissolution rates of promethazine hydrochloride although the values of n were unchanged. Differences in release rates between lactose and calcium phosphate replacement occurred only when matrices contained high levels of the diluents. A straight line relationship existed between release rates and tablet surface area for HPMC tablets containing promethazine hydrochloride.     

Bronchodilating Plasma Concentrations of Enprofylline and Theophylline have Minor Cardiovascular Effects in Man

Abstract: The cardiovascular effects with bronchodilating plasma concentration of theophylline (3.8–12.6 mg/l) and enprofylline (0.8–3.0 mg/l) were studied in six healthy male subjects by means of non-invasive procedures. With these plasma concentrations only minor effects were noted with regard to heart rate, blood pressure and systolic time intervals. However, both xanthines seem to have a vasodilating ability and a weak positive inotropic effect on the heart.     

Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy

The pro-convulsant actions of theophylline and caffeine have been investigated using the hippocampal slice preparation and rats administered kainic acid or Metrazol. Both theophylline and caffeine induced the generation of epileptiform activity in the CA3 region of the hippocampal slice with convulsive dose50 (CD50) values of 3 microM respectively. Kainic acid-induced bursting in hippocampal slices was enhanced by theophylline (0.3-30 microM) and caffeine (1-100 microM). Theophylline induced burst firing in response to electrical stimulation in hippocampal area CA3 but not area CA1. Theophylline (50 mg/kg) strongly potentiated the effect of the limbic convulsant kainic acid in vivo whilst a dose of 200 mg/kg was necessary to significantly lower the threshold dose of Metrazol required to induce generalized convulsions. We conclude that alkylxanthines, probably by antagonizing the effect of endogenous adenosine, exert a pro-convulsant action in the hippocampus which preferentially promotes limbic seizures.     

酮替芬、西咪替丁及红霉素对茶硷药动学影响的实验研究

研究酮替芬、西咪替丁及红霉素对家兔体内茶碱代谢的影响,结果表明:酮替芬可加快茶碱代谢,使茶碱的血清半衰期t1/2由2.74±0.75h缩短至2.33±0.56h,缩短14.96%;消除速率常数Ke由0.27±0.075/h增至0.32±0.066/h,增加20%.清除率由0.15±0.036增至0.18±0.047L/kg·h~(-1)。西咪替丁可抑制茶碱的代谢,使茶碱t1/2由2.06±0.33h延长至2.61±0.45h,延长26.69%,Ke由0.34±0.04/h减小至0.27±0.04/h下降20.59％,Cl由0.21±0.03降低至0.16±0.03L/kg·h~(-1),下降23.81%。红霉素亦可减慢茶碱代谢速率,使茶碱的t1/2由2.39±0.43h延长至3.54±0.89h,延长48.12%;Ke由0.30±0.06/h减小至0.21±0.07/h.降低30%,Cl由0.15±0.03下降至0.12±0.03L/kg·h~(-1),降低20%。     

695例茶碱血药浓度监测分析

目的：了解影响茶碱血药浓度的因素以指导临床用药。方法：本文对接受茶碱维持量疗法的695例患者的茶碱血药浓度监测结果进行了回顾性分析。结果：35.1%的病例茶碱血药浓度在有效血药浓度范围内（10-20μg/ml),35.8%的病例茶碱血药浓度低于10μg/ml,29.1%的病例茶碱血药浓度高于20μg/ml；环丙沙星，氟罗沙星，沙丁胺醇提高茶碱血药浓度；特布他林、利福平、速尿降低茶碱血药浓度；合并肝功能异常，肺心病患者茶碱血药浓度偏高；嗜烟患者茶碱血药浓度偏低。结论：茶碱血药浓度个体差异大，药物因素。疾病因素，嗜好等影响茶碱血药浓度，茶碱血药浓度监测对提高其使用的安全性和有效性具有重要的意义。     

步长稳心颗粒与茶碱缓释片联用治疗老年窦性心动过缓疗效观察

目的:观察步长稳心颗粒与茶碱缓释片联用治疗窦性心动过缓的临床疗效。方法:132例窦性心动过缓患者随机分为治疗组和对照组,治疗组68例给予步长稳心颗粒,9g/次,每天3次,并联用茶碱缓释片口服,0.1g/次,每天2次;对照组64例给予茶碱缓释片0.1g/次,每天2次。两组疗程均为1个月。观察用药前后常规心电图,动态心电图变化及症状缓解情况,副作用观察。结果:治疗组显效38例,有效20例,总有效率85.2%;对照组显效20例,有效22例,总有效率65.6%。两组疗效比较差异有显著性(P<0.05)。结论:步长稳心颗粒与茶碱缓释片联用治疗老年窦性心动过缓安全有效,副作用少,值得推广。     

Evidence that cyclic GMP may regulate cyclic AMP metabolism in the isolated frog ventricle

Both acetylcholine and 8-bromo cyclic GMP depress the contractile response of the isolated frog ventricle. An investigation has been made of the effects of both substances on the metabolism of endogenous 3,5 cyclic nucleotides. The levels of adenosine 3′, 5′ cyclic monophosphate (cyclic AMP) and guanosine 3′, 5′ cyclic monophosphate (cyclic GMP) were measured after superfusing preparations with varying concentrations (10^?10 to 10^?4m) of acetylcholine and 8-bromo cyclic GMP. The decline in contractile force was found to be accompanied by a progressive fall in intracellular cyclic AMP and a rise in cyclic GMP levels. Both the decline in contractility and the reduction in endogenous cyclic AMP are attenuated by 10^?4 theophylline. The decline in isometric twitch tension was paralleled, under all conditions, by a quantitatively equivalent reduction in the ratio cyclic AMP: cyclic GMP. The possibility that endogenous cyclic GMP may accelerate the conversion of cyclic AMP to 5 AMP, by stimulating a cyclic GMP-sensitive form of cyclic AMP phosphodiesterase, is discussed.