茶碱经微处理机程序输注迅速达到期望兔血浆稳态水平

自制二室模型药物程序输液泵。向控制器输入兔茶碱药物动力学参数，期望血浆稳态浓度，体重及时间。输注速率（Ｋ）＝ＣｐｓｓＫ１０Ｖｃｗｔ｛１＋［（Ｋ２１－β）／β］ＥＸＰ（－Ｋ２１ｔ）｝，血药浓度预报式为Ｃ（ｔ）＝Ｃｐｓｓ（１－ｅ＾ａｔ），依据显示配药液，自动输注，比色法测定血药浓度，９６％的执行百分误小于±３０％，其绝对值的中位数为８．３％。虽然Ｔ１２β＝６．０８ｈ，但输注后３０ｍｉｎ，血药浓度达期望     

茶碱指数衰减滴注及程序输注的研究

用紫外分光光度计法测定兔血浆茶碱浓度.应用群体兔药代动力学参数进行恒速静脉滴注、指数衰减滴注及程序输注。结果:虽茶碱T_(1/2β)=6.08h,但指数衰减滴注及程序输注仅需30min即可达到预期血药稳态浓度。程序输注及指数衰减滴注的执行百分误的中位数分别为7.8％.14％。     

丙戊酸恒速给药在小鼠体内时间药物动力学及进食条件的影响(英文)

目的:研究丙戊酸(VA)药物动力学昼夜节律变化及进食条件对节律的影响.方法:对自由进食及限定进食的ICR小鼠分别以渗透压微泵技术(1.062 mg·h~(-1))及iv(50 mg·kg~(-1))给予丙戊酸钠,并测定VA动力学的时间依赖性变化.结果:血浆VA浓度及清除率在稳态时呈昼夜节律性变化(P<0.01),限定进食时间影响VA动力学的节律,使峰值位相移动约12h.结论:用药时间是影响VA药动学的重要因素.进食条件是VA药动学节律的同步因子之一.     

迅速达到稳态水平的三次相继输注法的实验研究

我们曾推导出迅速达到并维持在稳态水平的三次相继恒速输注法的有关公式。该方法先用快速负荷输注,继以慢速负荷,血药浓度逐步下降,最后用维持输注.使血药浓度持续在期望的稳态水平。本文首先根据家兔静注槐果碱求得的动力学参数,再设计达到期望稳态水平10μg/ml和5μg/ml时,所需的三种相继恒速输注速率和输注时间。结果表明,数学理论模拟血药一时间曲线和实验数据有良好的契合。其超逾浓度较之Wagner提出的二次相继输注法要小。     

用蒿甲醚和吡喹酮早期治疗兔的血吸虫感染(英文)

兔于感染血吸虫尾蚴后d 7或d 21分别开始ig 1次蒿甲醚(Art)10mg·kg~(-1)和吡喹酮(Pra)40mg·kg~(-1),然后每隔1wk ig 1次相同剂量的Art或Pra连给3—4次,减♀虫率达98％以上,且部分兔无♀虫,上述兔经Art或Pra早期治疗后,其肝脏与正常兔相仿,或仅有轻度变化,一些与急性血吸虫病有关的指标测定亦为阴性。     

蒿甲醚或吡喹酮早期治疗感染血吸虫尾蚴兔和犬的肝脏显微镜检查(英文)

目的:观察感染血吸虫尾蚴后早期用蒿甲醚(Art)或吡喹酮(Pra)治疗,对宿主肝组织的影响。方法:犬感染198-202条尾蚴后d7ig Art 10 mg·kg~(-1),Art胶囊(ArtC)15mg·kg~(-1)或感染后d 21ig Pra 30-40 mg·kg~(-1),1—2 wk重复给药1次,共2—4次;兔每隔日感染48—52条尾蚴,共5次,并于第1次感染后d7或d 21 ig上述剂量的Art和Pra,停药后4—5wk剖杀取肝作切片观察。结果:犬与兔经Art或Pra早期治疗后,减♀虫率达92.1％—100％,肝切片中的总虫卵肉芽肿数分别减少70.9％—97.3％和76.5％—97.4％,肝叶结构和肝索排列正常。结论:2种药物早期治疗对宿主肝脏有保护作用。     

固定或改变目标浓度的普鲁泊福目标控制输注的性能

目的　评价国人应用固定或改变目标血药浓度的普鲁泊福 (异丙酚 )目标控制输注 (TCI)系统的性能。方法　自行编制以药代动力学模型为基础的控制程序 ,使用Marsh的普鲁泊福参数 ,通过佳士比 3 40 0注射泵控制普鲁泊福的静脉给药速度。 2 3例择期手术病人 ,分为A、B两组 ,A组给药过程中固定目标血药浓度 ;B组给药过程中改变目标浓度4次。间断采动脉血 ,HPLC荧光法测定血药浓度。结果　313个血标本的执行误差的中位数 (MDPE) =2 6 % ,执行误差绝对值的中位数 (MDAPE) =2 2 3 % ,分散度 (divergence)= - 1 5 0 %·h-1,摆动度 (wobble) =2 2 5 %。A、B两组间MDPE差异有显著性 (P <0 0 5 )。进一步分析去除血药浓度调高后 5min内的数据 ,则两组MDPE差异无显著性 (P>0 0 5 )。结论　使用Marsh的参数进行普鲁泊福TCI麻醉 ,系统的总体性能较好。给药方案与采血时点对性能分析结果产生影响     

电子轰击离子化气相质谱法测定人类血浆中的丙卡特罗(英文)

目的:建立一种简便灵敏的气相质谱法用于测定丙卡特罗的血药浓度。方法:采用电子轰击离子化气相质谱法,以丙咪嗪做内标,样品采用液-液萃取、衍生化处理,分离柱为毛细管柱,进样器和接口温度分别为280℃和250℃,载气(氦气)流速为0.8 mL·min~(-1),进样口选择脉冲不分流模式,离子源和四极杆的温度分别为230℃和150℃。结果:测定方法的检测限为5 ng·L~(-1);线性范围为10-10000 ng·L~(-1);日内(n=5)和日间(n=5)变异系数均小于10％,平均回收率为99.1％±1.3％。结论:本方法灵敏、简便,可用于丙卡特罗的药代动力学研究。     

基因重组人粒细胞集落刺激因子在兔和小鼠中的药物动力学(英文)

目的：研究家兔和小鼠中重组人粒细胞集落刺激因子的药物动力学．方法：用Ｉｏｄｏｇｅｎ法制备１２５ＩｒｈＧＣＳＦ．用分子筛ＨＰＬＣ测定浓度．结果：ｉｖ后浓度时间曲线符合二房室模型．初期和末端Ｔ１／２分别为０２５－０３３ｈ和３２－４６ｈ．ＡＵＣ和剂量接近正比．ｓｃ达峰时间０５９±０２５ｈ，生物利用度为１０．药物主要以原型从尿排泄．给药后泌尿系统放射性最高，胆胃肠道次之，骨髓和脾脏略低或接近血浆．结论：家兔和小鼠ｒｈＧＣＳＦ药物动力学数据为临床试验提供有用参考．     

苯甲脒类BACE1抑制剂的设计和合成(英文)

本文通过对已有小分子库进行虚拟筛选, 得到了可与BACE1活性中心Asp228、Asp32形成氢键作用的苯甲脒片段, 并在其基础上, 设计出了3-苯乙基苯甲脒类BACE1抑制剂。虽然活性测试结果显示这些化合物对BACE1的抑制活性较弱, 但是可以通过进一步的结构优化3-苯乙基苯甲脒类化合物来提高对BACE1的抑制活性。     

Falsely raised plasma theophylline concentrations in renal failure

Summary We studied the validity of plasma theophylline measurements in renal failure. Patients with increased serum creatinine receiving theophylline had drug measurements by four methods: high pressure liquid chromatography (HPLC) fluorescence polarization immunoassay (FPIA), enzyme immunoassay (EIA) and dipstick immunoassay (DI). The mean±SD (µmol/l) for plasma theophylline in the 18 patients with renal impairment was: HPLC 63.4±36.7; EIA 64.4±35.9; FPIA 70±3.43; DI 122±65.9.A significant correlation (r=0.94, p<0.01) was obtained between serum creatinine and the difference in theophylline concentrations between HPLC and DI. Plasma theophylline results should be interpreted with caution in patients with renal failure.     

Lack of effect of ponsinomycin on the plasma pharmacokinetics of theophylline

Summary The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline.The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.     

中空纤维离心超滤法检测人血浆中氨茶碱的游离药物浓度

目的:建立一个准确、简单、快速的分析人血浆中游离氨茶碱浓度的方法,并应用于临床治疗药物监测。方法:0.5 ml血浆样品经过中空纤维离心超滤(HFCF-UF)处理,以甲醇-10 mmol·L^-1乙酸铵缓冲溶液(15/85, V/V)为流动相,采用Diamonsil C₁₈色谱柱分离,流速为1.0 ml·min^-1,检测波长为275 nm,进样量为20 μl。结果:血浆中游离氨茶碱浓度在0.25~25 μg·ml^-1范围内线性关系良好,最低定量限0.1 μg·ml^-1,日内、日间RSD分别小于1.1%和1.3%。结论:该方法简单、准确、重现性好,特别适合基层开展临床游离药物浓度的监测。该方法成功的应用于临床游离氨茶碱浓度的监测,为临床游离氨茶碱治疗药物监测提供了一个可靠的分析平台和进一步阐述游离药物浓度与药物疗效或毒性之间的关系奠定了基础。     

Spiramycin has no effect on serum theophylline in asthmatic patients

Summary Fifteen asthmatic patients receiving a sustained-release theophylline preparation were also treated with spiramycin for at least 5 days. The macrolide antibiotic had no significant effect on the steady-state theophylline concentration, unlike erythromycin and troleandomycin, which belong to the same class of antibiotics. The latter two drugs have different chemical structures and decrease theophylline clearance. Accordingly, spiramycin comedication does not require special serum level drug monitoring or adjustment of the dose of theophylline.     

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.     

氨茶碱对人体心电图和定量脑电图的影响及其与唾液氨茶碱含量的关系

目的 评价氨茶碱对人体心电图和定量脑电图的影响及其与唾液氨茶碱含量的关系。方法 采用双盲安慰剂对照，研究了氨茶碱对１０例健康人心电图和定量脑电图的影响。结果 顿服氨茶碱０．４ｇ，２ ｈ后心电图 Ｒ波振幅从 ９、９± ２．８ ｍ增高到 １２．０± ３．６ ｍ（Ｐ＜ ０．０５）；定量脑电图ｆｐ１导联。波功率值从１．０５±０．８３上升到２．０８±２．２２（Ｐ＜０．０５），ｆ３和ｆ４导联β１波功率值从1．７５±１．３５高到３．１１±３．５１（Ｐ＜０．０５）；唾液氨茶碱含量为７．６±０．９ μｇ／ｍｌ。心电图Ｒ波及脑电图ａ２波的变化与唾液氨茶碱含量呈正相关（ｒ值分别为０、８２６４和０．７９３３）。１０例口服安慰剂健康受试者，其心电图和脑电图改变均无统计学显著性。结论 治疗浓度氨茶碱能引起人体心电和脑电的改变，效应强度与游离药物浓度有关。     

Differential effects of cimetidine on theophylline metabolic pathways

Summary The effects of cimetidine (1 g/day) on theophylline disposition and metabolism were examined in smokers and non-smokers for single dose intravenous and chronic oral administration of theophylline. In the intravenous study the effect of cimetidine on plasma theophylline clearance was more marked in smokers (22.7% reduction) than in non-smokers (12.2% reduction). Similarly, in the multiple dose study the effect of cimetidine on theophylline clearance was greater in smokers (28.3% decrease) than in non-smokers (11.3% decrease). The reduction in clearance was largely due to a reduction in metabolic clearances by 3-demethylation (Cl_3DM) and 1-demethylation (Cl_1DM) with no significant effect on clearance by 8-oxidation (Cl_80X). There was a strong correlation between Cl_3DM and Cl_1DM (r=0.98, p<0.001) in both control and cimetidine study phases, whereas other correlations between partial clearances were less marked and were not apparent during the cimetidine phase. The results are consistent with the view that 1- and 3-demethylation of theophylline are carried out by a common form of cytochrome P-450 which is selectively induced by cigarette smoking and preferentially inhibited by cimetidine.     

柱切换高效液相色谱法测定茶碱血药浓度

本文采用HPLC柱切换法,建立了茶碱的血浓度测定方法。预处理柱(50×5mmID)内装μBondapak C_(?),37—50/μm,纯水为预处理流动相;分析柱(150×5mmID),固定相为HITACHI GEL3056(ODS),5μm,甲醇:乙腈:水(25∶5∶70,v/v)的混合溶液为分析流动相,273nm 波长处检测。该方法在于自动净化和富集样品,操作简便快速,血浆可直接进样。茶碱血浓度在0.5～40μg/ml 范围内线性关系良好(r=0.9998),血浆中最低检测浓度为50ng/ml。方法的绝对回收率平均为96.02%,日内RSD%为1.00%～2.70%,日间RSD%为0.94%～2.57%。用本法和FPIA 法进行了比较研究,两种方法测定结果经回归分析,相关性良好(r=0.9963,P<0.01)。     

茶碱透皮贴片的制备及其体外渗透性研究

目的:制备茶碱透皮贴片,并考察其体外经皮渗透性。方法:以丙烯酸酯压敏胶为骨架材料,月桂氮酮和丙二醇为促渗剂,用离体人皮和Franz扩散池作为体外经皮释药模型,研究茶碱贴片体外渗透性。结果:茶碱贴片中的药物经皮渗透符合零级动力学,4%月桂氮酮和20%丙二醇有较好的促进渗透作用,其增渗倍数分别为不含促渗剂的茶碱对照贴片的2.30和2.04倍。结论:茶碱贴片体外经皮渗透作用较好。     

Effect of miocamycin on theophylline kinetics in children

Summary The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h^–1), the mean total body clearance (1.71 vs 1.8 ml·min·kg^–1) and the mean apparent volume of distribution (0.57 vs 0.58 l·kg^–1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.