盐酸特拉唑嗪在大鼠体内的排泄研究

目的建立HPLC-MS/MS分析方法测定大鼠排泄物(粪便、尿、胆汁)中盐酸特拉唑嗪含量,确定其在大鼠体内的主要排泄特征。方法大鼠单次灌胃给予盐酸特拉唑嗪5.0 mg·kg-1后,收集粪便、尿及胆汁样品,进行HPLC-MS/MS分析。电离源为ESI源,扫描方式为选择反应监测(SRM),用于定量分析的反应离子对分别为m/z 388→m/z 290.1605(特拉唑嗪)和m/z 498→m/z 179.0695(芍药苷,内标)。结果测得0~48 h原形药物在大鼠尿液中的累积排泄率为(8.66±1.58)%,粪便中的累积排泄率为(11.33±2.2)%,其中8~12 h的排泄速率最大;盐酸特拉唑嗪0~24 h胆汁中的累积排泄率为(2.1±0.56)%,在2~6 h胆汁中的排泄速率最大。结论盐酸特拉唑嗪在大鼠体内原形药物的累积排泄量较少,其主要以代谢物的形式进行排泄。     

LC-APCI-MS/MS法研究维氨酯在大鼠体内的排泄

目的：建立LC-APCI-MS/MS法测定大鼠胆汁、尿液和粪便中维氨酯的浓度,对该药在大鼠体内的排泄规律进行研究,为临床试验提供依据。方法：生物样本经处理后,采用AgilentTCC18色谱柱,甲醇-水-甲酸（9370.1）为流动相,辛伐他汀为内标,在三重四极杆串联质谱仪上,采用大气压化学离子化（APCI）、正离子方式选择性离子监测模式,维氨酯和内标的检测离子分别为m/z448/283和m/z419/285,分别测定尿液、胆汁和粪便中原型物的含量。结果：胆汁、尿样、粪便中维氨酯的回收率均大于89%,日间和日内的变异系数均小于10%。胆汁和尿液中维氨酯在0.0808～40.4ng/mL浓度范围内线性关系良好（r=0.9972和0.9949）,粪便中维氨酯在0.2525～101ng/mL浓度范围内线性关系良好（r=0.9990）,维氨酯的定量下限为0.2pg,方法符合生物样品分析要求。维氨酯在粪便中72h内、在尿液中96h内、在胆汁中24h内原型药的平均累积排泄量分别为12.9%、0.003%、0.0001%。结论：该方法灵敏度高,专属性强,样品前处理简便,分析速度快,可满足大鼠排泄研究中药物浓度测定的要求,大鼠灌胃给药（5mg/kg）后维氨酯从尿液和胆汁中排泄的原型药物很少。     

20(R)-25-OCH_3-PPD在大鼠体内代谢产物的鉴定

目的鉴定抗肿瘤药物20(R)-25-OCH3-PPD在大鼠体内的代谢产物。方法大鼠单次灌胃给予药物20(R)-25-OCH3-PPD(40 mg·kg-1),收集粪便、尿液及血浆。采用LC-MS/MS法,以多反应监测(MRM)和二级全扫描质谱(Full Scan MS2)方式,对大鼠粪便、尿液及血浆中代谢产物进行分析和鉴定。结果在粪中检测到原形药物及8个代谢物,在血浆中检测到原形药物和1个去甲基代谢物,在尿液中没有检测到相关代谢物。结论 20(R)-25-OCH3-PPD在大鼠体内代谢广泛。     

玳玳果黄酮降脂提取物体内效应组分排泄动力学研究

目的 建立同时测定大鼠尿液及粪便中提取物效应组分新橙皮苷和柚皮苷含量方法,研究大鼠口服玳玳果黄酮降脂提取物后的尿药排泄动力学及排泄特征。方法 采用UPLC-MS/MS建立效应组分新橙皮苷及柚皮苷在大鼠尿液及粪便的定量分析方法,计算口服玳玳果黄酮降脂提取物后不同时间点新橙皮苷及柚皮苷在尿液及粪便中的排泄率,并以亏量法计算尿液中的消除半衰期及消除速率常数,评价大鼠口服玳玳果黄酮降脂提取物后尿药排泄动力学及排泄特征。结果 所建立的UPLC-MS/MS定量分析方法专属性良好、标准曲线及线性范围良好,方法准确度与精密度、定量下限均符合有关规定,该方法能够满足大鼠尿液及粪便中效应组分的定量检测需要;口服72 h后,大鼠尿液中新橙皮苷、柚皮苷的平均累计排泄率分别为（1.76±0.76）‰和（1.39±0.57）‰;大鼠粪便中新橙皮苷、柚皮苷的平均累计排泄率分别为（52.45±6.30）%和（51.57±4.80）%;口服后效应组分新橙皮苷及柚皮苷在尿液及粪便中的排泄量分别在24~36 h和4~8 h达到峰值;72 h后仍有药物经尿液排泄,给药后24 h粪便累计排泄率便达坪值;亏量法计算得新橙皮苷消除速率常数为（0.080±0.021）·h^-1,消除半衰期为（9.41±3.22）h,柚皮苷消除速率常数为（0.077±0.017）·h^-1,消除半衰期为（9.51±2.97）h,新橙皮苷及柚皮苷的动力学参数间差异无统计学意义。结论 口服给药后效应组分原形即通过粪便较快地排出体外,粪便排泄是效应组分排出体外的主要途径,新橙皮苷及柚皮苷经尿液排泄的特征无明显差异。     

7-乙基-10-羟基喜树碱脂质体在大鼠体内的代谢和排泄

目的考察7-乙基-10-羟基喜树碱(SN-38)脂质体经静脉注射后,在大鼠尿液、粪便中的代谢产物以及以SN-38原形药物排泄的量。方法大鼠尾静脉单次给予2.77 mg/kg SN-38脂质体,分别于0～6、6～12、12～24、24～48 h分段收集尿液、粪便,采用UPLC/Q-TOFMS法对SN-38脂质体在大鼠尿液、粪便中的代谢产物进行鉴定,并且建立HPLC法,用于大鼠尿液及粪便样品中SN-38原形药物的排泄量的测定。结果 SN-38脂质体的在大鼠体内的代谢产物经鉴定为SN-38G。48 h内脂质体组共有1.57%的原形药物经过尿液排出,共有12.94%的SN-38原形药物经过粪便排出。结论 SN-38脂质体只有少部分以原形药物经尿液和粪便排出体外。     

南强菌素在大鼠体内的药动学、组织分布及排泄研究

目的研究海洋新骨架小分子南强菌素经单次静脉注射后在Wistar大鼠体内的药动学、组织分布及排泄特征。方法 48只Wistar大鼠(雌雄各半)分为8组(每组雌雄各三只),3组分别尾静脉注射南强菌素10、20、30 mg·kg-1,液相色谱-串联质谱法(LC-MS/MS)测定其血药浓度,DAS2.0计算药动学参数;其余5组单次尾静脉给予南强菌素20 mg·kg-1,其中3组大鼠给药后0.5、2、3 h麻醉处死、解剖测定南强菌素组织分布,1组给药后收集0² h、>22 h、>2⁴ h、>44 h、>4⁸ h、>88 h、>8²4 h的尿液粪便评价南强菌素的排泄过程,1组麻醉后插管收取024 h的尿液粪便评价南强菌素的排泄过程,1组麻醉后插管收取0² h、>22 h、>2¹6 h、>1616 h、>16²4 h胆汁评价胆汁排泄。结果大鼠分别静脉单次注射10、20、30 mg·kg-1南强菌素后,t蚝虔z分别为(2.09±0.68)、(2.44±0.35)、(2.57±1.33)h,AUC0-8 h分别为(3 378±544)、(3 492±460)、(4 451±573)μg·h·L-1;单次静脉给药20 mg·kg-1,0.5 h后肾脏组织中的南强菌素含量最高(1 736.8 ng·g-1),肺脏及脾脏次之;给药2 h后,多数组织中已经检测不到或仅能检测到极少量南强菌素;原型药物经尿样和胆汁的排泄率分别为1.87%和0.91%,粪便的排泄率极低,低于总给药量的0.01%。结论单次给予南强菌素,各剂量组的AUC0-8 h、ρmax和t蚝虔z用SPSS进行相关检验,无显著差异(P>0.05),表明在置信度(单双侧)0.05水平上剂量与AUC0-8 h、ρmax和t蚝虔z均不相关;原型药物经粪便和尿样排泄率较低,124 h胆汁评价胆汁排泄。结果大鼠分别静脉单次注射10、20、30 mg·kg-1南强菌素后,t蚝虔z分别为(2.09±0.68)、(2.44±0.35)、(2.57±1.33)h,AUC0-8 h分别为(3 378±544)、(3 492±460)、(4 451±573)μg·h·L-1;单次静脉给药20 mg·kg-1,0.5 h后肾脏组织中的南强菌素含量最高(1 736.8 ng·g-1),肺脏及脾脏次之;给药2 h后,多数组织中已经检测不到或仅能检测到极少量南强菌素;原型药物经尿样和胆汁的排泄率分别为1.87%和0.91%,粪便的排泄率极低,低于总给药量的0.01%。结论单次给予南强菌素,各剂量组的AUC0-8 h、ρmax和t蚝虔z用SPSS进行相关检验,无显著差异(P>0.05),表明在置信度(单双侧)0.05水平上剂量与AUC0-8 h、ρmax和t蚝虔z均不相关;原型药物经粪便和尿样排泄率较低,1²4 h内仅有1.87%从尿液中排出。     

毛蕊花糖苷在大鼠体内吸收、分布及排泄研究

目的:采用液相色谱-质谱联用(LC-MS/MS)法测定大鼠血浆及组织样品中毛蕊花糖苷的浓度,并探讨其在大鼠体内吸收、分布及排泄研究。方法:SD大鼠灌胃给予毛蕊花糖苷20,40,80,160 mg·kg^-1后,于不同时间点采血,给予40 mg·kg^-1剂量进行分布和排泄试验,测定血浆、组织和排泄物中的毛蕊花糖苷浓度,并用DAS 2.0软件拟合并计算药动学参数。结果:大鼠给药20,40,80,160 mg·kg^-1的毛蕊花糖苷后,药时曲线呈二室开放模型,主要药动学参数t_max,C_max,t_1/2α,AUC_0-t,AUC_0-∞,CL/F,V/F分别为(17.50±10.37)min、(0.313±0.04)mg·L^-1、(6.79±12.10)min、(21.39±4.03)mg·L^-1·min^-1、(22.39±3.89)mg·L^-1·min^-1、(1.83±0.30)L·min^-1·kg^-1、(179.10±52.77)L·kg^-1。大鼠给予40 mg·kg^-1的毛蕊花糖苷后,毛蕊花糖苷在尿液和粪便中36 h内的累积排泄百分数分别为(0.037±0.005)%、(0.004 2±0.000 8)%,胆汁中12 h内的累积排泄率基本为零。结论:毛蕊花糖苷在大鼠体内吸收符合一级动力学,分布在小肠和肺浓度最高,其次为胃和肌肉,其他组织都有少量的分布;且通过尿液、粪便和胆汁排泄量较少,其可能主要通过代谢过程进行消除。     

双靶向配体化力达霉素在大鼠体内药动学及组织分布和排泄

目的研究双靶向配体化力达霉素(DTLL)在大鼠体内的药动学特征及组织分布和排泄。方法单次iv给予Wistar大鼠[~(125)I]DTLL,给药剂量为2625 kBq·0.05 mg~(-1)·kg~(-1)。分别收集0～6 h内组织样本、0～24 h内血清样本以及0～168 h内尿液、粪便和胆汁样本,用液体闪烁仪分别检测样品放射性浓度,用WinNonlin软件和非房室模型统计矩法计算药动学参数,并分析[~(125)I]DTLL在体内的分布和排泄。结果DTLL原型药物的曲线下面积(AUC_(0-∞))为(184±33)h·μg·L~(-1),半衰期(t_(1/2))为(3.98±0.75)h,清除率(Cl)为(278±41)mL·h~(-1)·kg~(-1)。[~(125)I]DTLL iv给予大鼠后,广泛分布于全身各组织中,在主要脏器中均未发现蓄积现象;给药后0～168 h,粪便和尿液累积排泄分数分别为(10.4±6.6)%和(82.5±2.6)%,经粪尿总排泄量可达给药剂量的(92.9±7.4)%。结论 DTLL iv给予健康Wistar大鼠后可迅速分布于全身,可能不能通过血脑屏障,DTLL主要通过粪尿途径排泄。     

葛根素在大鼠体内的排泄过程与给药途径的相关性

目的 比较葛根素不同途径给药后的排泄过程.方法 太鼠经静脉或灌胃给予葛根素后,按一定时间段收集尿和粪便,以高效液相色谱荧光光谱法检测尿和粪样中的葛根素.结果 给大鼠灌胃葛根素混悬液后,葛根素由粪便中排泄的累积排泄率为41.56%,其中4～8h由粪便排泄量占由粪便排泄葛根素总量的75.26%,8～12h的排泄量占23.99%;12h内由尿中排泄的葛根素占给药量的0.64%,0～4h、4～8h葛根素由尿的排泄量分别占由尿排泄总量的27.91%和66.28%;24h内经粪便中排泄的葛根素约占排泄总量的98.40%.大鼠经尾静脉注射葛根素注射液24h内,葛根素由尿中排泄的累积排泄率为36.15%,而其中的97.43%是在前4h内排泄的;由粪便中排泄的葛根素占给药量的9.18%.而其中的99.19%是在给药后的8～12h之间排出的;24h内经尿中排泄的葛根素占排泄总量的79.64%.结论 葛根素的排泄与给药途径有关.大鼠灌胃给药后.葛根素主要经肠道排泄,而经静脉给药后,葛根素主要经肾脏排泄.     

灌胃射干合剂后大鼠体内盐酸麻黄碱药动学研究

目的：给大鼠灌胃射干合剂后,了解射干合剂中盐酸麻黄碱在大鼠血清中药动学。方法：采用液质联用技术测定盐酸麻黄碱含量,大鼠灌胃射干合剂（1.0 ml/100 g）后,盐酸麻黄碱血浓变化,采用药动学软件计算,求出盐酸麻黄碱的药动学参数;采用代谢笼技术,计算射干合剂中盐酸麻黄碱在24h内大鼠尿液、粪便中回收率。结果：得到盐酸麻黄碱的药动学参数为Tmax：（1.30±0.23）h,T1/2：（21.17±1.35）h,Cmax：（278.86±46.41）ng·ml-1,AUC0-∞：（1221.98±412.64）ng·ml-1,Vc/F：（1.70±0.15）L;盐酸麻黄碱在24 h内可在尿中回收85.66%;粪便中未能测得盐酸麻黄碱。结论：盐酸麻黄碱在大鼠体内24 h基本排泄完;服用射干合剂不会造成体内麻黄碱的蓄积;大鼠体内盐酸麻黄碱主要经肾脏排泄。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.