伊马替尼与烯丙基氨基格尔德霉素联用于大鼠模型的药动学

目的:研究伊马替尼与烯丙基氨基格尔德霉素(17-AAG)联合应用在大鼠体内的药动学,评价药物间的相互作用及联合用药的合理性。方法:用同一剂量组,两种用药方案分别单次给药,用药方案:伊马替尼40 mg.kg-1,伊马替尼40 mg.kg-1加17-AAG15 mg.kg-1。测定大鼠灌胃给药后伊马替尼的血药浓度,采用HPLC法测定大鼠血药浓度,用3p87软件估算药动学参数,SPSS软件进行参数比较。结果:大鼠灌胃给药后伊马替尼的药动学规律可用一室模型来描述。伊马替尼单用及伊马替尼与17-AAG联用的主要药动学参数t1/2、Cmax、tmax、AUC经t检验,均有显著性差异(P<0.05)。结论:伊马替尼与17-AAG联合应用后其药动学特征发生改变,两组分有药动学的相互作用。     

单硝酸异山梨酯与阿魏酸在大鼠体内的药动学及相互作用

目的:建立用于同时测定大鼠血浆中单硝酸异山梨酯、阿魏酸的HPLC-UV分析方法,并用于研究单硝酸异山梨酯与阿魏酸在大鼠体内药动学的相互作用。方法:将18只雄性SD大鼠随机分成单硝酸异山梨酯组、阿魏酸钠组以及硝酸异山梨酯和阿魏酸钠联合给药组,于给药后规定时间点采集血样,HPLC-UV法测定二者的血药浓度,采用DAS 2.0药动学软件处理血药浓度数据,用SPSS 19.0统计学软件对所得药动学数据进行统计学差异分析。结果:大鼠静脉注射单硝酸异山梨酯和阿魏酸钠后,两药单用以及联用的药动学过程均为三室模型。联合用药后,单硝酸异山梨酯的Vd和CL与单独用药时相比显著性降低,而阿魏酸的Vd、CL和t1/2与单独用药时相比显著性增加,两药的其他药动学参数MRT,AUC0-t则无显著性变化。结论:本方法可用于大鼠体内单硝酸异山梨酯和阿魏酸的药动学研究。单硝酸异山梨酯和阿魏酸钠联合用药后各自的药动学参数均发生明显变化,两药有药动学的相互作用。     

培美曲赛二钠与奥沙利铂在Beagle犬体内的药动学相互作用

目的探讨在Beagle犬体内,培美曲赛二钠和奥沙利铂联合用药前后药动学变化规律。方法采用自身对照随机交叉法,将9只Beagle犬随机分成培美曲赛二钠组、奥沙利铂组以及培美曲赛二钠和奥沙利铂联合给药组,经静脉给药后,于不同时间点采集血样,LC-MS/MS法测定二者的血药浓度,DAS3.2.1统计矩法计算药动学参数,AUC和Cmax用"生物等效性与生物利用度"模块下的90%可信区间法进行统计。结果与单独给药比较,联合使用培美曲赛二钠和奥沙利铂的主要药动学参数t1/2、CLint和MRT均无显著性差异(P>0.05);药物单用与合用组的AUC和Cmax在90%可信区间的生物等效性统计结果合格,tmax检验结果差异无统计学意义(P>0.05)。结论 Beagle犬同时注射培美曲赛二钠和奥沙利铂不存在显著的药动学相互作用。     

地高辛的个体化给药方案

目的在中国医院开展地高辛的临床药动学服务,达到地高辛用药个体化。方法根据不同患者的血清肌酐,计算患者的药动学参数。根据药动学参数,制定和调整给药方案。结果发现16例使用地高辛的患者不合理用药达到87.5%,及时调整了给药方案后,所有患者的血药浓度均在有效浓度范围。结论应根据地高辛的药动学参数开展临床药动学服务。     

氟喹诺酮类最佳给药方案的选择

目的:选择氟喹诺酮类抗菌药的最佳给药方案.方法:通过查阅国内外有关文献并结合临床用药经验,对本类药物最佳的给药方案加以论述.结果:药动学参数如AUIC、Cmax/MIC及PAE理论对氟喹诺酮类给药方案的选择具有指导作用.结论:临床应用氟喹诺酮类抗菌药必须从药动学特性、抗生素后效应及联合用药等方面予以考虑,选择最佳的给药方案.     

阿米卡星经纤维支气管镜和静脉给药的药动学比较

目的 :比较阿米卡星 (AMK)气管内与静脉给药后药动学参数的差异。方法 :对 16例肾功能正常 ,采用不同给药方法 ,使用AMK治疗的住院患者 ,用TDX法测定血药浓度 ,分析药动学参数。结果 :显示两种给药途径的药时曲线均符合二室模型 ,主要药动学参数比较无显著差异 (P >0 .0 5 ) ,气管内给药的绝对生物利用度为 94 % ,疗效确切。结论 :采用气管内给药法 ,可降低血药浓度 ,增加用药的安全性     

左乙拉西坦儿童生理发育药动学模型的建立和剂量优化

目的:探讨生理发育因素对左乙拉西坦(LEV)在儿童体内药动学特征的影响,评价和优化LEV给药剂量,促进个体化用药.方法:根据203例0.42～15岁癫痫患者的LEV血药浓度及相关临床资料建立群体药动学模型,考察生理发育因素对LEV药动学参数的影响方式和强度.基于模型,模拟和评价不同体质量和年龄段的儿童患者的LEV给药方...     

麦考酚酸制剂体内药动学参数、临床疗效及不良反应影响因素的研究进展

目的:了解麦考酚酸(MPA)制剂体内药动学参数、临床疗效及不良反应影响因素的研究进展,为临床合理用药提供循证依据。方法:查阅近年来国内外文献,从基因多态性、患者机体因素和药物因素等方面对MPA的体内药动学参数、临床疗效和不良反应的影响进行归纳和总结。结果与结论:吗替麦考酚酯(MMF)和麦考酚钠(EC-MPS)为MPA的2种常用制剂。MMF为器官和组织移植术后抗免疫排斥反应的一线用药,其体内药动学参数、临床疗效和不良反应发生率受基因多态性、患者机体因素(种族、血清白蛋白水平、术后时间和并发症等)和药物因素(联合用药、药物剂型和给药剂量)等影响。     

常用药动学公式的拓展及应用

目的:应用药动学理论指导临床合理用药。方法:对基本药动学公式进行拓展和转换,得到临床实用的新公式;创建实用药动学参数表,应用该表得到临床需要的药动学参数。结果:有了实用药动学参数表,随时可考察临床用药的合理性,结合血药浓度监测,可做到用药个体化。结论:实用药动学参数表可作为指导个体化用药的重要工具。     

头孢呋辛钠药动学的研究进展

目的:介绍头孢呋辛钠药动学的研究进展。方法:查阅并归纳近年来国内、外关于头孢呋辛钠药动学的相关文献。结果与结论:头孢呋辛钠在胃肠道吸收不佳,故主要以注射方式给药,给药后吸收迅速,t1/2β为1.1～1.5h;其在体内分布广泛,于体液、组织中和骨中达到或接近治疗水平;其不经过代谢,主要以原型通过肾小球滤过和肾小管排泄,至少有95%的原型药在尿液中检出;与丙磺舒合用可延长其t1/2β;其药动学行为符合二室开放模型,给药方案、患者生理病理条件、是否联合用药及联合用药的种类可影响其药动学行为。头孢呋辛钠在使用时需进行血药浓度监测,防止耐药及交叉耐药的发生,以取得最好的疗效并最大限度地降低毒副反应。     

石榴健胃胶囊中非法添加尼扎替丁、西咪替丁、法莫替丁、盐酸雷尼替丁和拉呋替丁的检测

目的:建立石榴健胃胶囊中非法添加尼扎替丁、西咪替丁、法莫替丁、盐酸雷尼替丁和拉呋替丁的分析方法.方法:采用高效液相色谱法,以十八烷基硅烷键合硅胶为填充剂的C18柱(4.6 mm×250 mm,5 μm),以甲醇(A)-水(每1 000 mL含磷酸0.3 mL和己烷磺酸钠0.94g)(B)梯度洗脱[0～25 min,A:23％,B:77％;25～ 40 min,A:23％→90％,B:77％→10％;40 ～ 50min,A:23％,B:77％];流量为1.0 mL·min -1;柱温小于30 ℃;检测波长为220 nm.结果:尼扎替丁、西咪替丁、法莫替丁、盐酸雷尼替丁和拉呋替丁的线性范围分别为0.020 34 ～2.542 μg(r ＝0.999 9)、0.020 78～2 598 μg(r＝0.999 9)、0.018 86～2.357 μg(r＝0.999 9)、0.019 66～2.457 μg(r＝1)和0.022 06 ～ 2.757 μg(r ＝0.999 9);回收率(n＝6)分别为101.53％、94.09％、92.24％、93.44％和96.38％;RSD分别为0.81％、0.53％、0.49％、0.90％和0.92％.结论:该方法选择性强,灵敏度高,重复性好,亦可作为石榴健胃胶囊预防非法添加尼扎替丁、西咪替丁、法莫替丁、盐酸雷尼替丁和拉呋替丁的有效分析方法.     

拉呋替丁胶囊的人体药动学研究

目的:研究拉呋替丁胶囊在健康人体内的药动学。方法:12名健康志愿者分为男、女2组,分别交叉单剂量口服拉呋替丁胶囊10、20mg后,用高效液相色谱-荧光检测法测定血浆中拉呋替丁浓度,用DAS软件求算药动学参数。结果:口服拉呋替丁胶囊10、20mg后的主要药动学参数分别为:tma(x1.27±0.41)、(1.13±0.47)h,Cma(x165.98±43.01)、(344.22±70.70)μg·L-1,AUC0～16(673.96±196.84)、(1459.10±403.44)μg·h·L-1,AUC0～∞(752.82±196.84)、(1506.57±409.08)μg·h·L-1。结论:拉呋替丁胶囊口服后吸收迅速和完全,在健康受试者体内的药动学过程基本符合口服一级一室模型。     

新型消化性溃疡治疗药拉呋替丁

拉呋替丁是一种新型非竞争性组胺H2 受体拮抗药 ,通过阻断组胺H2 受体和辣椒素感受神经减少胃酸分泌、促进胃粘膜再生、增加胃粘膜血流量以及增加胃粘液等机制发挥抗消化性溃疡作用。同其他组胺H2 受体拮抗药相比 ,本品具有疗效显著、不良反应少和治愈后不易复发等优点     

HPLC法测定拉呋替丁及其片剂的含量

目的　建立拉呋替丁及其片剂的高效液相色谱含量测定法。方法　以Shim packODSC18为色谱柱 ,甲醇 0 2mol·L 1醋酸胺溶液 三乙胺 (70∶30∶0 1)为流动相 ,检测波长为 2 75nm。结果　线性系数r =0 9998,平均回收率为 99 6 % (RSD =1 5 % ,n =9)。结论　本方法简便、快速、准确 ,可用于拉呋替丁及其片剂的质量控制。     

Pharmacological and therapeutic properties of lafutidine (stogar and protecadin), a novel histamine H2 receptor antagonist with gastroprotective activity]

Potent antisecretory agents, such as histamine H2-receptor antagonists and proton pump inhibitors, have achieved great improvement in peptic ulcer therapy. It has, however, been reported that incidence of ulcer relapse is high after discontinuation of these drugs. Insufficient efficacy against NSAID-induced ulcers is also critical. Lafutidine is a novel histamine H2 antagonist with gastroprotective activity. Lafutidine exhibited potent and long-lasting H2 antagonism and prolonged antisecretion. In addition, lafutidine showed a gastroprotective effect against noxious agents-induced gastric mucosal damage through capsaicin-sensitive afferent nerves. Lafutidine showed antiulcer activities against acute ulcer models, prevented gastric ulcer relapse of acetic ulcer, and accelerated the healing of indomethacin-induced antral ulcers in rats. These results suggest the advantage of the combined antisecretory and gastroprotective activities. In clinical studies, lafutidine showed prolonged antisecretion, healing effect against gastric and duodenal ulcers and gastritis, and its potency was equal or superior to that of conventional H2 antagonists. Additionally, lafutidine induced a high transition rate to the E0 stage determined by endoscopical ultrasonography, suggesting the high quality of ulcer healing. Furthermore, effectiveness of lafutidine against NSAIDs-induced ulcer was high. From these results, lafutidine is equal or superior to conventional H2 antagonists in antiulcer potency, and it may be useful for the prevention of ulcer relapse and or treatment of NSAIDs-induced gastroduodenal damage.     

Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats.

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.     

Effect of lafutidine on CGRP release from cultured rat dorsal root ganglion cells

Lafutidine increased capsaicin-stimulated CGRP release from isolated rat stomach without changing basal CGRP levels. In order to clarify the mechanism of this effect, we used cultured rat DRG cells and measured CGRP release. (1) DRG cells were treated with each drug, and the CGRP content of the supernatant was determined by EIA. (2) RGM-1 cells were co-cultured with DRG cells through a cell culture insert, and capsaicin-evoked CGRP release from the DRG cells was determined when lafutidine or PGE₂ was added to the RGM-1 cells. (3) The supernatant of isolated rat stomach incubated with lafutidine was added to cultured DRG cells, and capsaicin-evoked CGRP release was determined. PGE2, but not lafutidine, augmented capsaicin-evoked CGRP release from DRG cells. Lafutidine did not modulate CGRP release from DRG cells, even though it sensitized CGRP-containing afferent nerves in the rat stomach. Lafutidne and PGE₂ may have different mechanisms of sensitization.     

Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.     

Pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration in healthy subjects: comparison with famotidine

Lafutidine, a histamine H(2)-receptor antagonist, inhibits gastric acid secretion during the daytime, however, the relationship between the plasma concentration and the drug response remains unclear. The aim of this study was to compare the pharmacokinetic and pharmacodynamic properties of lafutidine and famotidine following postprandial oral administration. After a lafutidine tablet (10 mg), famotidine tablet (20 mg), or water only (control) was administered, blood samples were taken and intragastric pH was measured. The plasma concentrations of lafutidine and famotidine were determined by HPLC, and the median intragastric pH values per 30 min were used as the degrees of gastric acid suppression. Data were analyzed based on a one-compartment pharmacokinetic model and a sigmoid E(max) pharmacodynamic model. Lafutidine plasma concentrations rapidly increased after administration; famotidine required some time to increase the plasma concentrations, requiring an absorption lag time in the pharmacokinetic model. Between the plasma concentration and DeltapH (the difference in intragastric pH by the drug vs. control), lafutidine showed an anticlockwise hysteresis loop which indicated equilibration delay between the plasma concentration and effect site, requiring an effect site compartment in the pharmacodynamic model; famotidine showed more parallel relationship. These results indicated that the pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration were different from those of famotidine at least 4.5 h after dosing.     

Sensitizing effects of lafutidine on CGRP-containing afferent nerves in the rat stomach

1. Capsaicin sensitive afferent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal afferents in the rat stomach, exerting many pharmacological effects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). 2. Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory effect, exerted via histamine H(2) receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical deafferentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive afferent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to afferent nerves, we conducted the following studies. 3. We determined CGRP and NO release from rat stomach and specific [(3)H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. 4. Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no effect on specific [(3)H]-RTX and capsaicin binding to VR1. 5. In conclusion, our findings demonstrate that lafutidine modulates the activity of capsaicin sensitive afferent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action.