多索茶碱与莫西沙星在大鼠体内药动学的相互作用

 目的考察多索茶碱和莫西沙星在大鼠体内的药动学特性及合用时的相互作用。方法采用高效液相色谱法测定大鼠给药后不同时间的多索茶碱和莫西沙星的血浆浓度。血浆浓度 时间数据用非线性程序WINNONLIN拟合，求得药动学参数。结果两药合用与单独用药时的药-时曲线基本一致,多索茶碱呈一级吸收一级开放式模型，莫西沙星呈一级吸收二室开放式模型，药动学参数无统计学差异。但多索茶碱与莫西沙星合用时，多索茶碱的代谢产物之一茶碱的AUC约是单用多索茶碱时的2倍。结论两药合用药动学上无明显的相互作用, 但莫西沙星有减慢多索茶碱的代谢产物茶碱代谢的趋势，两药可以同时服用，但应注意监测茶碱的血药浓度。     

高效毛细管电泳测定茶碱血浓度方法的研究

 目的：建立用高效毛细管电泳測定茶碱血葯浓度的方法。方法：血浆样品用三氯醋酸沉淀蛋白，緩沖液为50 mmol/L SDS加25 mmol/L磷酸盐缓冲液，pH = 8. 0,紫外λ 203 nm检測。结果：线性范围为5. 0-30. 0 μg/ml,平 均回收率为101. 75%,日内和日间误差分別低于3%和4%。经与HPLC比较，表明其測定结果与HPLC无显著性 差异（P>0.05)。结论：此方法分析速度快，分离效果好，适用于临床病人血葯浓度的监測     

硝苯地平对慢性阻塞性肺病患者茶碱药物动力学的影响

 目的：研究慢性阻塞性肺病（COPD）患者合用硝苯地平前后茶碱稳态血药浓度及药物动力学的变化。方法：高效液相色谱（HPLC）法测定9名COPD患者po茶碱片（200 mg,tid）5 d后及加服硝苯地平（10 mg，tid)5 d后茶碱血药浓度，以PKBP-N₁计算机程序拟合药物动力学参数。结果：COPD患者合用硝苯地平5 d后，茶城稳态平均血药浓度下降1.77士2.04 mg/L，c_max和AUC_0～8均较用硝苯地平前降低，分别为12.3士6.5和9.9士4.9 mg/L，82.4士52.1和62.5士38.8（mg?h)/L(P<0.05)。其它药物动力学参数无明显改变（P>0.05)。结论：COPD患者合并使用硝苯地平，无需改变氨茶碱的治疗剂量，两药可以合用。     

Medication compliance in children with asthma

A questionnaire to assess compliance with prescribed therapy was completed by 200 children with asthma. The validity of the questionnaire was assessed objectively by measuring plasma theophylline concentrations in 37 subjects and by weighing metered dose aerosol canisters before and after use in 19 subjects. The average compliance was 67.9%. The close agreement between answers to the questionnaire and the objective measurements of compliance indicated that most participants recalled the drug regimens accurately. Good compliance was related to whether Australia was the parents' country of origin, to knowledge of the disorder and to comprehension of medication but was not related to perception of the severity of the illness. This study demonstrates that compliance is relatively poor even in a clinic population which attends regularly and appears well-motivated.     

Differences in caffeine and paraxanthine metabolism between human and murine CYP1A2

For the characterisation of murine models of CYP1A2 mediated metabolism in humans we compared the metabolism of caffeine and paraxanthine in human liver microsomes (LM) (two samples) and in LM from CYP1A2-null and wild-type mice. Inhibition experiments were carried out with the quinolones norfloxacin and pefloxacin and the substrate, caffeine. Additionally, in vivo pharmacokinetics of paraxanthine was determined in CYP1A2-null and wild-type mice. All LM produced the primary metabolites of caffeine and paraxanthine. In human LM, the main metabolite of caffeine was paraxanthine (K(M) 0.4 and 0.5 mmol L(-1)). In wild-type and CYP1A2-null mice LM, the main caffeine metabolite was 1,3,7-trimethylurate, but formation was not saturable. Apparent K(M) for paraxanthine formation from caffeine in wild-type and CYP1A2-null murine LM were 0.2 and 4.9 mmol L(-1), respectively. The main metabolite of paraxanthine was 1-methylxanthine in human (K(M) 0.13 and 0.2 mmol L(-1)) and in wild-type mice LM (K(M) 0.53 mmol L(-1)). In CYP1A2-null murine LM, the main paraxanthine metabolite was 7-methylxanthine. The quinolones competitively inhibited caffeine metabolism in human but not in wild-type or CYP1A2-null murine LM. No obvious differences were seen for blood pharmacokinetics and urinary metabolite excretion of paraxanthine between CYP1A2-null and wild-type mice. Thus, for paraxanthine, norfloxacin and pefloxacin interaction with CYP1A2 there were clear differences between mice and man. Our results suggest that an interspecies comparison is required for the metabolism of individual xenobiotics interacting with CYP1A2 prior to the use of mice models to predict its toxicity and/or pharmacological activity in man.     

Ignoring Pharmacokinetics May Lead to Isoboles Misinterpretation: Illustration with the Norfloxacin-Theophylline Convulsant Interaction in Rats

Purpose. To investigate the norfloxacin-theophylline convulsant interaction in vivo, with an experimental approach distinguishing between pharmacodynamics and pharmacokinetics contributions to the observed effect. Methods. Male Sprague Dawley rats (n = 38) were infused each compound separately or in different combination ratios. Infusion was maintained until the onset of maximal seizures. Cerebrospinal fluid and plasma samples were collected for high performance liquid chromatography drug determination. The nature and intensity of the pharmacodynamics interaction between drugs was quantified with an isobolographic approach. Results. Isobolograms suggested a relatively marked antagonism between norfloxacin and theophylline at the cerebrospinal fluid (previously shown to be part of the biophase) and dose levels, but not at the plasma (free and total concentrations) levels. These apparent discrepancies could be explained by nonlinear distribution or/and distribution desequilibrium phenomenon. Conclusions. These findings showed that the quantitative isobolographic approach is appropriate to assess the nature and intensity of the pharmacodynamic interaction between two drugs when data are collected within the biophase, but that data interpretation outside the biophase can be risky due to further pharmacokinetic complexities, in particular slow or/and nonlinear diffusion into the biophase.     

Clinical Observation of Irbesartan in Treatment of Vasovagal Syncope

Vasovagal syncope (VVS), a clinical problem with highmorbidity, seriously affects patients' life style, therefore ap-propriate prophylaxis and treatment of VVS are imperative.Though β-blockers, theophylline, and scopolamine have sh-own curative effects on WS, their use are limited due to sideeffects. We hypothesize that irbesartan, an angiotensin Ⅱ rece-ptor antagonist, can be used to treat VVS with no limitationespecially in small dosage.     

吸入激素联合缓释茶碱与β_2-受体激动剂治疗儿童哮喘比较

目的比较吸入糖皮质激素(ICS)联合缓释茶碱(SRT)与ICS联合长效β2-受体激动剂(LABA)治疗中、重度儿童哮喘的疗效和安全性。方法141例4—14岁中、重度哮喘患者随机分成两组。A组73例,吸入丙酸氟替卡松气雾剂(FP),同时口服茶碱缓释片舒弗美。B组68例,沙美特罗/丙酸氟替卡松(SM／FP)干粉剂吸入治疗,疗程12周。比较A、B两组的临床疗效及安全性。结果治疗后两组患者晨间最大呼气峰流速(PEFam)与第1秒时间肺活量(FEV1)占预计值的百分比明显升高(P<0．01),两组间比较无显著性差异(P>0．05)。日、夜间症状评分较治疗前均显著降低(P<0．01),两组间比较无显著性差异(P> 0．05)。两组患者使用快速缓解药物(沙丁胺醇气雾剂)的揿数较治疗前均明湿减少(P<0．01),两组间比较无显著性差异(P>0．05)。结论ICS联合SRT治疗中、重度儿童哮喘,其疗效相似于ICS联合LABA,无严重不良反应。     

Antimitotic and Cytotoxic Effects of Theophylline in MDA-MB-231 Human Breast Cancer Cells

A variety of cancer cell lines, including MDA-MB-231 human breast cancer cells, exhibit mitotic inhibition by cAMP. In earlier work, we found that the phosphodiesterase inhibitor, theophylline, reduced the number of cells and altered cellular morphology. In the current study, we evaluated the effects of theophylline on macromolecule synthesis and indices of cell viability. Theophylline evoked a concentration- and time-dependent decrease in DNA synthesis. However, the net decrease in cell number was greater than that predicted solely from mitotic arrest. Assessment of protein synthesis indicated a second effect of theophylline separable from that on DNA synthesis. This was confirmed by decreased cell viability and adhesion. Exposure of the cells to the phosphodiesterase inhibitor, IBMX, in concentrations that produced inhibition of DNA synthesis equivalent to that seen with theophylline, elicited a smaller reduction in cell number. Theophylline also evoked specific changes in the expression or function of membrane-bound adenylyl cyclase activity, effects that are likely to contribute to sustained reactivity of these cells to other cAMP-related inhibitors of cell proliferation, such as isoproterenol. The multiple pharmacologic properties of theophylline, producing mitotic inhibition, cytotoxicity and altered signaling in MDA-MB-231 cells, may provide insight into novel therapeutic strategies.