阿魏酸长期给药后对大鼠灌服氯沙坦钾的药动学影响

目的 研究长期给药阿魏酸对大鼠体内氯沙坦及其代谢物E-3174的药动学影响。方法 12只健康♂ SD大鼠随机分成2组（每组6只）,试验组每天灌胃50 mg·kg^-1阿魏酸,连续诱导7 d;对照组灌胃等体积0.5%CMC-Na。第8天给药30 min后,给予氯沙坦钾（5 mg·kg^-1）。分别于给药前和给药后0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,24 h大鼠尾静脉取血,血样处理后采用UPLC-MS/MS检测大鼠血浆中氯沙坦及E-3174的浓度。结果 虽然2组大鼠体内氯沙坦各项药动学参数对比均无统计学意义,但是试验组大鼠体内E-3174的AUC（0-t）、AUC（0-∞）和Cmax显著增高（P<0.05）;CL/F、Tmax显著降低（P<0.05）。结论 大鼠长期给药阿魏酸后虽然未能引起氯沙坦原形药物药动学的变化,但可使其活性代谢产物E-3174代谢减慢,浓度增高,药时曲线下面积增大。     

兔胆总管部分结扎肝硬化模型的建立

目的:探讨通过手术造成胆总管狭窄制备兔胆汁性肝硬化模型的可行性.方法:分离并部分结扎新西兰兔胆总管,结扎时分别与不同孔径的硬塑料管共同结扎或不用塑料管垫衬,结扎后将导管抽出,形成孔径分别为0、0.6 mm、1.0 mm和1.6 mm的狭窄胆总管.存活兔于结扎14周后处死,观察其胆道系统变化情况.结扎前及结扎术后根据兔存活情况于1、2、4、11周经耳中央动脉抽血1.5 mL测血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆红素(TBIL)、直接胆红素(DBIL)、总蛋白(TP)、白蛋白(ALB).结果:兔胆总管部分结扎后有2种现象,一为肝内胆管形成球囊样扩张伴有胆石沉积,此类无明显肝纤维化表现;二为胆总管自狭窄以上呈不同程度扩张,有的呈现串珠样扩张,但无包裹性胆石沉积,此类肝纤维化程度较重.术后第1周,ALT、AST、TBIL、DBIL明显升高,第2周,ALT、AST、TP、ALB下降,TBIL、DBIL降至正常.结论:对新西兰兔进行胆总管部分结扎术可建立胆管阻塞型肝硬化模型.     

莫西沙星灌胃给药在肺炎大鼠血液及肺组织中的药代动力学特点分析

目的研究莫西沙星灌胃给药在肺炎大鼠血液及肺组织中的药代动力学特点。方法首先采用灌胃给药的方式给肺炎链球菌肺炎大鼠模型灌莫西沙星,其次利用微透析技术对肺炎大鼠进行血液和肺部附近组织同时采样的操作,然后使用液相色谱法对莫西沙星的分散药量进行测量,最后计算并分析药代动力学指标。实验后,观察肺炎大鼠血液和肺组织的T_(max)、C_(max)、t_(1/2)A、UC0-∞AUC肺/AUC血液药代动力学参数。结果血液和肺组织内的游离药物的T_(max)、C_(max)数值都比较高,在二者同时减小之后,药物在肺部的穿透率比再血浆中大的多。与此同时,在血液内消除半衰期(t_(1/2))比肺组织内的小,差异显著,P <0.05。结论莫西沙星灌胃给药一定的剂量下,肺炎大鼠体内的药物有助于更好的消除肺炎链球菌,从而得到好的治疗。     

地高辛固体脂质纳米粒的制备及家兔体内的药动学

以单硬脂酸甘油酯为脂质材料,采用溶剂扩散法所制的地高辛固体脂质纳米粒于4℃贮存3个月,平均粒径增大,但包封率和载药量无显著变化.家兔静脉注射地高辛纳米粒或自制溶液剂后,A UC分别为(90.3±27.5)和(82.4±34.2)ng·h·ml-1.两者的分布容积有较大差异,提示固体脂质纳米粒静注后可改变药物在体内的分布.     

核磁共振检查对胆道梗阻病变良、恶性鉴别诊断的方法对比研究

目的:探讨磁共振不同成像方法-MRCP、MRCP与T1和T2加权平扫、MRCP加T1和T2加权平扫以及动态增强扫描对胆道梗阻疾病的良、恶性鉴别诊断价值.材料和方法:回顾分析63例经临床及病理证实的胆道梗阻病例MRI资料,由两位有经验的影像学医师分别采用上述成像方法及组合,依次获得对胆道梗阻良、恶性病变鉴别诊断的准确性、敏感性及特异性.结果:MRCP结合T1和T2加权平扫对胆道梗阻良、恶性病变鉴别诊断的准确性、敏感性及特异性高于单独MRCP,P值＜0.05,有显著性差异.MRCP加T1和T2加权平扫以及动态增强扫描对胆道梗阻良、恶性病变鉴别诊断的准确性、敏感性及特异性与MRCP加T1和T2加权平扫相比差异无显著性,P值＞0.05.结论:MRCP不能取代常规的MR扫描,常规非增强MR扫描可以增加对胆道梗阻良、恶性疾病鉴别诊断的准确性、敏感性和特异性.MRCP加T1和T2加权平扫以及动态增强扫描经统计学处理并不能显著改善鉴别诊断的准确性、敏感性和特异性,但对判定恶性病变周围血管是否受侵以及受侵的程度,对临床确定肿瘤的是否可切除性具有很大的指导意义.     

Pharmacokinetics of Cinacalcet Hydrochloride When Administered with Ketoconazole

BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole. SUBJECTS AND METHODS: Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms. RESULTS: Twenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments. CONCLUSIONS: Co-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.     

阿魏酸在血瘀证兔体内的药代动力学

为验证及研究症治药动学假说（ｓｙｎｄｒｏｍｅａｎｄＴｒｅａｔｍｅｎｔＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓ，Ｓ＆ＴＰＫ）的客观性和基本规律，本文以ＲＰ－ＨＰＬＣ法同时测定了活血祛瘀药物阿魏酸在正常及高分子右旋糖酐所制血瘀症（微循环障碍）兔体内经时浓度，以ＭＣＰＫＰ药动学程序在ＣＯＭＰＡＱ８０３８６机上自动拟合了药动学参数。统计结果表明，与正常组相比，阿魏酸在血瘀症兔体内的分布容积（Ｖ＿１和Ｖ＿Ｂ）及消除速率（ＣＬＢ）显著减小（Ｐ＜０．０５），半衰期（ｔ＿（１／２β）及相同时间段曲线下面积（ＡＵＱ）非常显著增加（Ｐ＜０．０１）。结论：实验结果基本符合Ｓ＆ＴＰＫ的观点：即同一药物在不同证兔体内的药代动力学参数经统计学处理有显著差异。     

Pharmacokinetics of Bisphosphonates in Rabbits

Abstract: Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The ¹⁴C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P<0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P=0.016). At 24 hr, plasma concentration of tiludronate was 12±6.6%, of etidronate 18±2.5%, of clodronate 0.8±0.2%, and of pamidronate 1.4±0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC_0–24hr for tiludronate and etidronate was 9–11 times larger than for clodronate. AUC_0–24hr for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9–15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2–1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of tiludronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates.     

医源性胆道损伤的处理体会

目的探讨医源性胆道损伤不同时机的发现、不同类型的预防及处理。方法回顾1995年1月～2009年12月收治的21例胆管损伤患者的临床资料,分析其发生的原因、部位、发现的时机及不同类型的处理方法,跟踪追访其治疗效果。结果 21例患者,治愈17例,死亡2例(全身衰竭死亡1例,并发心肌梗死死亡1例),继发性胆管狭窄2例,经再次择期行Roux-Y吻合均获治愈。随访19例,时间1～13年,随访患者均未出现胆管炎或胆瘘等症状。结论医源性胆管损伤危害是严重的,术中及时发现胆管损伤是及时处理的前提,术后诊断要及时,术式选择要合理,但避免损伤才是整个处理的关键。     

贝母素甲在家兔体内的药动学

建立了LC-MS/MS法测定贝母素甲在家兔血浆中的含量,研究灌胃及静注给予贝母素甲后家兔体内的药动学特征.以卡马西平为内标,采用C18色谱柱,以乙腈- 10 mmol/L甲酸铵溶液(35:65)为流动相,ESI源正离子模式,多反应离子(MRM)检测,监测离子对m/z 432.4→414.4(贝母素甲)和m/z 237.1→194.2(卡马西平).贝母素甲在0.8～200 ng/ml浓度范围内线性关系良好,提取回收率88.5％～98.3％,日内、日间RSD均小于15％.家兔灌胃及静注给予贝母素甲后体内分别呈二室及三室开放模型,主要药动学参数如下:cmax (48.31士7.40)和(84.39±15.39) ng/ml,AUC0 →∞(270.08±80.17)和(50.72±14.02) ng·ml-1h-1,t1/2 (6.38±3.11)和(2.19±1.07)h.     

水苏碱在家兔体内的药物动力学研究

目的：研究水苏碱在家兔体内的药物动力学。方法：采用HPLC法测定从家兔耳静脉注射盐酸水苏碱溶液后不同时间的血浓度。用3P97药动学程序对血药浓度-时间数据进行拟合。结果：主要药动学参数为AUC=1712．50min·μg·ml^-1,Vc=11．80L·kg^-1,t1／2α=32．46（min）,t1／2β=189．61min,K21=3．97×10^-3min^-1,K10=1．97×10^-2min^-1,K12=1．36×10^-7min^-1,CLs=0．23L·kg^-1·min^-1。结论：水苏碱在家兔体内呈二室模型.     

腹腔镜胆总管探查术的临床分析

目的 探讨腹腔镜胆总管切开取石术(LCBDE)中应用开腹器械取石的可行性.方法 回顾性分析我院36例LCBDE取石的临床资料.胆总管切开后以纤维胆道镜检查确定结石的部位、大小及数量,以常规开腹胆道取石器械进行胆道取石,并与同期3 6例开腹手术进行比较.结果 LCBDE组36例手术均获成功,无中转开腹.常规于术后4周行T管造影,34例示结石取净;胆道残余结石2例,均于术后6周经T管窦道胆道镜取石治愈.在手术时间上,LCBDE组与开腹手术组相比无显著性差异(P＞0.05);术后住院时间较开腹手术组明显缩短(P＜0.05).两组均留置T管,均无胆瘘、胆管狭窄或出血病例,均痊愈出院.LCBDE组36例随访6～4 8个月均无异常.结论 严格选择手术适应证,应用开腹器械进行腹腔镜胆道取石安全有效、操作容易、成本低、手术时间短.     

Pharmacokinetics of lopromide Liposomes in Rabbits

Purpose. The dose-proportionality of pharmacokinetics of an iodinated contrast medium, iopromide, encapsulated into liposomes was investigated. Methods. Following single intravenous administration of 150 mg iodine/kg (potential diagnostic dose) and a five-fold higher dose in rabbits the pattern of elimination was studied until 7 d and the blood concentrations were monitored up to 72 h after administration. The iodine concentration in the liver was calculated on the basis of the blood concentration and related to the concentration measured in the rabbit liver. Results. The dose-normalized blood concentration-time profiles of the encapsulated iodine were not superimposable. Contrary to the low dose a steady-state concentration of 2.8 mg iodine/mL was observed in blood for 60 min after the high dose administration indicating a saturation of the liposomal liver uptake. For both doses the elimination of iodine occurred predominantly via the kidneys and was complete 7 d after administration. The dose-normalized amounts of iodine excreted with the urine were similar for both dose groups. From the blood data it was calculated that doses up to about 300 mg iodine/kg should result in a dose-proportional increase of liposomal liver uptake before saturation occurs. This was confirmed by the measured iodine liver concentrations after increasing the doses stepwise from 150 to 750 mg iodine/kg. Conclusions. In rabbits for the dose range 150 to 750 mg iodine/kg iopromide liposomes reveal dose-dependent pharmacokinetics due to a saturation in liver uptake which occurs for doses of 300 mg iodine/kg corresponding to 300 mg lipid/kg onwards.     

Bile Duct Obstruction Leads to Increased Intestinal Expression of Breast Cancer Resistance Protein With Reduced Gastrointestinal Absorption of Imatinib

Liver dysfunction reduces systemic clearance of drugs that are primarily eliminated by the liver. However, liver dysfunction can cause a reduction in the plasma concentration profiles of certain drugs, including several tyrosine kinase inhibitors, after oral administration. The aim of the present study was to clarify the reduction in oral absorption of a tyrosine kinase inhibitor, imatinib, and the mechanisms of action involved under conditions of hepatic dysfunction, focusing on intestinal transporters. The maximum plasma concentration of imatinib after oral administration in mice subjected to bile duct ligation (BDL) was lower than that in sham-operated mice, whereas the plasma concentration profile after intravenous administration was essentially unaffected by BDL. The change in maximum plasma concentration was compatible with a reduction in small intestinal permeability of imatinib observed in the in situ closed loop. Gene expression of abcg2 was increased in BDL mice compared with that in sham-operated mice. Expression of breast cancer resistance protein and P-glycoprotein in the small intestinal brush border membrane fraction from BDL mice was also increased compared with that in sham-operated mice. In summary, the intestinal absorption and permeability of imatinib was decreased in BDL mice, and this may be attributed to the up-regulation of the efflux transporter(s).     

Longmire手术治疗肝胆管结石临床观察

目的总结Longmire（左肝胆管空肠吻合）手术治疗肝胆管结石15例经验。方法回顾分析1990年1月-2008年12月襄城县中西医结合医院及襄城县人民医院收治的15例肝胆管结石的临床资料。结果15例中12例治愈,3例出现胆汁瘘及膈下感染,无死亡病例。结论Longmire手术治疗肝胆管结石效果良好。     

ERCP引导下腔内射频消融联合支架置入治疗恶性胆管肿瘤合并梗阻的临床疗效及短期预后分析

目的 分析经内镜逆行性胰胆管造影术(ERCP)引导下腔内射频消融联合支架置入治疗恶性胆管肿瘤合并梗阻的临床疗效及短期预后.方法 回顾性分析2013年4月—2016年1月就诊治疗的90例恶性胆管肿瘤合并梗阻患者的临床资料,根据治疗方式的不同分为观察组和对照组,每组45例.观察组采用ERCP引导下腔内射频消融联合支架置入治疗,对照组采用ERCP引导下支架置入治疗.比较并分析两组的临床疗效、随访预后情况及术后并发症情况.结果 治疗后,两组血清总胆红素、γ-谷氨酰转肽酶和碱性磷酸酶均低于治疗前(P<0.01),且观察组低于对照组(P<0.01).观察组胆道通畅时间、生存时间、12个月存活率、黄疸有效缓解率均明显多于或高于对照组(P<0.01).两组术后1个月并发症总发生率比较差异无统计学意义(P>0.05).结论 ERCP引导下腔内射频消融联合支架置入治疗恶性胆管肿瘤合并梗阻,可显著的改善黄疸及肝功能情况,且可有效的延长胆道通畅时间及生存时间,可作为临床治疗恶性胆管肿瘤合并梗阻的优选治疗方式.     

医源性胆管损伤临床研究

目的 研究医源性胆管损伤的原因、预防和处理方法.方法 对1980年1月-2005年8月我院诊治的55例医源性胆管损伤的临床资料进行回顾性分析.结果 对术中及术后不同时期发现的胆管损伤分别进行胆道修复、引流及胆肠吻合等方法处理,经1～25年随访,临床治愈率达96.4%(53/55).结论 胆囊切除术时Calot三角区解剖不清是发生医源性胆管损伤的主要原因.胆管损伤应早发现,及时处理.根据损伤的情况和术后时间选择不同的处理方法.     

Bioavailability and Pharmacokinetics in Man of Orally Administered Theophylline

Abstract The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half-lives from about 3–16 hours and plasma clearance values of about 16.5–115 ml kg^-1 hr^-1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory β-phase (V_dβ) were within the range 0.394–0.616 1 kg^-1 with a mean value of 0.484 1 kg^-1 ±0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one-compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr^-1 were found for the administered microparticulate theohylline tablet preparation, Nuelin® from Riker Laboratories. A wide range of lag-times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half-life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.     

Pharmacokinetics of Intravenously Administered L-5-Hydroxytryptophan in Man

Abstract The pharmacokinetics of 5-hydroxytryptophan were investigated in relation to intravenous administration of single doses of the amino acid (0.2 mg/kg b.wt.) to five patients pretreated for one week with carbidopa, an L-aromatic amino acid decarboxylase inhibitor. The plasma concentration/time lapse of 5-hydroxytryptophan exhibited bi-exponential disposition characteristics and the data obtained could be closely fitted to an open two compartment pharmacokinetic model with elimination taking place from the central compartment. The apparent composite 1. order rate constants α and β were 1.433 hr^-1 ± 0.177 S.D. and 0.113 hi^-1 ± 0.012 hr^-1 S.D., respectively. The biological half-life of 5-hydroxytryptophan under the experimental conditions was thus about 6 hours. The apparent volume of the central compartment, V_c, was found to be 0.336 1 kg^-1 ± 0.059 S.D. and the plasma clearance 0.105 1 hr^-1 kg^-1 ± 0.015 S.D. The derived pharmacokinetic constants were used for doses regimen calculations and predetermination of the plasma concentration/time lapse, during continuous intravenous infusion therapy. Measured plasma concentrations of 5-hydroxytryptophan during infusion deviated by less than 10 per cent from the predicted values. However, the infusions had to be stopped in four of the experiments because the patients became nauseated and vomited after total doses of only 36-128 mg.