谈谈中药直肠给药

谈谈中药直肠给药谭毓治（江西省中医药研究所南昌３３０００６）王玉元（南昌市白马庙制药厂）中药直肠给药，从其源流来看，古已有之。然而，由于历史条件的限制，对中药直肠给药毕竟缺乏较全面、较系统的认识，时至今日，对中药直肠给药有哪些影响因素？怎样应用最有效...     

基于直肠给药系统的研究和最新进展

口服给药形式简单方便,是常规药物治疗的首选途径,然而对于禁食或其他原因不能口服的药物及服药依从性差的患者,直肠给药是一种安全的替代给药方式.直肠黏膜内血管丰富,给药可发挥局部或全身治疗作用,避免肝脏首过效应,防止胃酸及酶对药物的破坏作用,减少胃的刺激.但由于缺乏经证实的药代动力学研究和对给药器械依赖大,以及给药部位特殊...     

吗啡给药途径及其剂型研究进展

吗啡是从阿片中提取的一种生物碱,可直接作用于中枢神经系统和肠壁的阿片受体而产生镇痛作用,是治疗中、重度癌性疼痛的重要止痛药,其不良反应主要有眩晕、情绪改变、精神忧郁等[1].许多药学研究者希望通过改变其给药途径或剂型来减少其不良反应,并延长其镇痛作用持续时间.笔者根据近几年国内、外相关文献对该方面研究进展做一综述.     

直肠给药吸收促进剂研究概况

本文就直肠给药吸收促进剂研究情况作一概述。简要介绍直肠给药的作用机制、影响直肠给药的因素，详细讨论常用的吸收促进剂性质和应用，比较了不同促进剂的特征和优缺点。     

双黄连注射液家兔直肠给药的药代动力学和相对生物利用度研究

目的 :研究双黄连注射液家兔直肠给药的药代动力学和相对生物利用度 ,对保留灌肠和口服给药进行比较 ,为直肠给药的科学性提供理论依据。方法 :将双黄连注射液中主药金银花的有效成分绿原酸作为血药浓度定量分析的检测指标 ,根据药物由用药部位进入体循环的速度 (即吸收速率Ka)和药物进入体循环的相对量 ,即吸收程度 ,通常用血药浓度时间 (CT)曲线下面积作指标 ,观察直肠给药的吸收动力学变化。结果 :药代动力学数据说明保留灌肠组与口服组间的AUC存在显著性差异 (P <0 .0 5 )。灌肠剂的生物利用度为 10 0 % ,口服剂的相对生物利用度则为 80 .78% ;保留灌肠剂和口服剂的达峰时间 (Tp 值 )分别是 0 .75和 2 .4 8h ,有显著的统计学意义 (P <0 .0 5 ) ,说明保留灌肠在吸收速度方面优于口服 ;Cmax受吸收量和吸收时间的影响 ,保留灌肠剂的血清浓度峰值与口服剂的峰值间存在显著性差异 (P <0 .0 5 ) ,说明保留灌肠剂的血药浓度明显高于口服剂。结论 :双黄连注射液有效成分的吸收 ,直肠比口服给药快 ,血药浓度高 ,其吸收总量和生物利用度均高于口服给药     

双氯芬酸钠胶浆剂家兔直肠给药的药动学特征

目的 研究双氯芬酸钠胶浆剂直肠给药在家兔体内的药动学.方法 24只家兔随机分为2组,每组12只(♀♂各半),分别直肠给予双氯芬酸钠胶浆剂和栓剂(3 mg·ks-1),按试验方案采血,采用HPLC法测定血药浓度.结果 双氯芬酸钠胶浆剂组tmax为12.60 min,ρmax为8.39 mg·L-1(P＜0.001);双氯芬酸钠栓剂组tmax为94.46 min,ρmax为5.62 mg·L-1(P＜0.001).结论 双氯芬酸钠胶浆剂直肠给药后血药峰浓度高,且达峰时间短,优于双氯芬酸钠栓剂直肠给药.     

醋酸去氨加压素经家兔眼部给药后的药动学及药效学研究

比较醋酸去氨加压素经家兔眼部给药、静脉注射以及灌胃给药后的药动学及药效学特征,探索多肽类药物通过眼部给药进入全身循环的可行性。15只家兔随机分成3组(眼部给药, 7.0μg·kg^-1;静脉注射, 0.7μg·kg^-1;灌胃给药, 7.0μg·kg^-1),给药后按预定时间点心脏取血,采用酶联免疫法(ELISA)测定醋酸去氨加压素的血药浓度;另21只家兔随机分成3组(眼部给药, 7.0μg·kg^-1;静脉注射, 0.7μg·kg^-1;灌胃给药, 7.0μg·kg^-1)进行药效学研究,在给药前和给药后的预定时间段收集尿液。家兔静脉注射给药后峰浓度(C_max)为143.0 pg·mL^-1,血药浓度-时间曲线下的面积(AUC_0-t)为999.9 pg·h·mL^-1;眼部给药后达峰时间(t_max)为5 min, C_max为125.6 pg...     

阿胶低肽不同给药途径的药效学研究

目的:研究阿胶低肽不同给药途径的药效学。方法:皮下注射盐酸苯肼复制家兔贫血模型,分别给予模型家兔腹腔注射1～3kD阿胶低肽,灌胃<5kD阿胶低肽,灌胃5%阿胶水溶液,测定给药7d后的血红蛋白(Hb)、红细胞计数(RBC)、白细胞计数(WBC)值。分别给予健康小鼠腹腔注射1～3kD阿胶低肽,灌胃<5kD阿胶低肽,灌胃葡萄糖溶液,给药14d后测定小鼠负重游泳时间。腹腔注射氢化可的松复制免疫低下小鼠模型,分别给予模型小鼠腹腔注射1～3kD阿胶低肽,灌胃<5kD阿胶低肽,灌胃5%阿胶水溶液,给药6d后,测定小鼠脾重指数。结果:对于化学药物所致的贫血,1～3kD阿胶低肽可显著提升Hb,其作用高于<5kD阿胶低肽,但提升RBC和WBC的作用则与阿胶相当;阿胶低肽有抗疲劳作用;阿胶低肽可显著增加模型小鼠脾重指数。结论:阿胶低肽各种给药方式均有一定的免疫增强作用。     

一次性输液器在直肠给药中的应用

灌肠是将一定量的溶液通过肛管由肛门经直肠灌入结肠,帮助病员排除粪便和积存的气体,有时也借以输入药物,达到确定诊断和进行治疗的目的。近年来,我们用一次性输液器代替灌肠筒有选择地给予直肠用药,收到了满意效果,其方法如下:(1)取一次性输液器1根,去     

安定直肠给药镇静抗惊厥124例疗效观察

我科于1995年1月～1997年3月采用安定直肠给药和静脉给药观察其镇静止痉效果。报告如下。1 临床资料1.1 对象 为我院儿科住院病人124例,其中男72例,女52例、年龄4月～6岁。根据病情分为镇静治疗组62例、包括肺炎伴心衰30例,重度哮喘16例,高热16例;抗惊厥组治疗组62例,包括高热惊厥32例,癫痫14例,病毒性脑炎8例,闷热综合症8例。1.2 方法 患儿取侧卧位,暴露臀部,用5ml注射器。根据医嘱抽取所需量的安定注射液,加水稀释至2～3ml。选用婴儿胃管做肛管,涂油润滑后缓慢插入直肠内约6～8cm,将药液注入。然后再注入等量空气。（确保药量）迅速抽出肛管,压迫患儿肛门1min防止药液外     

Water Activity and Its Significance in Topical Dosage Forms

Unique properties of thermodynamic activity of solvents in topical semisolids and its effects on in vitro product performance have not been fully understood. Mechanistic investigation was undertaken to demonstrate the significance of thermodynamic potential of solvents [water activity (a_w) or solvent activity (a_s)] on in vitro performance of model topical formulations. Drug transport across synthetic membranes was found to decrease with decreasing water activity of formulations. Similarly, in vitro permeation of model permeant (caffeine) across porcine epidermis was found to decrease with decreasing water activity of formulations. Notably, relatively low water activity formulations (a_w, 0.78) induced dehydration in porcine skin associated with significant structural changes like detachment of individual stratum corneum layers. Inclusion of hydrating agents (propylene glycol) in low water activity (a_w, 0.78) formulations restored hydration levels and structural integrity of porcine skin. Most importantly, incremental inclusion of propylene glycol in low water activity formulations (a_w, 0.78) enhanced in vitro permeation of model permeant (fluorescein sodium). Further investigation revealed that variability in processing conditions (high shear mixing during emulsification step) could modulate water activity in semisolid formulations despite their compositional sameness. In retrospect, water activity was found to be a critical quality attribute of topical semisolid products which impacts overall product performance and drug delivery.     

亚甲蓝对创伤性休克兔肺损伤的保护作用

目的通过测定创伤性休克兔血浆超氧化物歧化酶（SOD）、丙二醛（MDA）变化以及肺组织病理学改变,评价亚甲蓝（MB）对创伤性休克的疗效及对肺缺血再灌注损伤的保护作用。方法将日本长耳大白兔18只随机分为3,组：对照组、创伤性休克生理盐水复苏组（NS组）和创伤性休克MB复苏组（MB组）,每组6只,记录休克前（T4）、休克末（T2）、复苏末（T3）,复苏后0．5h（T4）、2h（T5）、4h（T6）时间点平均动脉压（MAP）的变化,并测定血浆SOD、MDA,复苏后4h放血处死动物,取肺测定肺叶湿重／干重比,并观察肺形态病理学变化。结果对照组SOD、MDA在各时间点变化不明显。另外2组在MDA水平变化明显升高,且生理盐水复苏组高于MB复苏组（P〈0．05）,SOD明显降低,生理盐水复苏组明显低于MB复苏组（P〈0．05）。肺组织病理学观察显示亚甲蓝对缺血再灌注损伤肺具有保护作用。结论亚甲蓝可能通过抑制氧自由基（ROS）的过度生成,对创伤性休克及其引起的缺血再灌注肺损伤（L／R）产生保护作用。     

Rectal Mucosa Damage in Rabbits After Subchronical Application of Suppository Bases

The effect of suppository bases on rabbit rectal mucosa was investigated using six triglyceride bases, polyethylene glycol, and a triglyceride base combined with monoglycerides or fatty acids and methyl esters of those acids. Rectal irritation was evaluated and scored according to defined pathological features. Pure triglycerides and a triglyceride to which a nonionic surfactant was added caused severe mucosal damage with ulceration and inflammation. Hyperemia was characteristic for irritation by polyethylene glycol suppositories. Mucosal damage by a pure triglyceride combined with monoglycerides or fatty acids and methyl esters of those acids was similar but statistically less pronounced than with all other bases.     

亚甲蓝染色法在乳腺癌前哨淋巴结活检术中的临床应用研究

目的分析亚甲蓝染色法应用于乳腺癌前哨淋巴结活检术（SLNB）的临床效果。方法选取2011年7月-2013年3月经病理检验确诊的46例乳腺癌患者,均采用SLNB诊治,采用亚甲蓝和异硫蓝染色法患者分别有30例和16例,对SLNB的临床检出情况进行分析,并对亚甲蓝组和异硫蓝组患者的临床检出情况进行比较。结果46例采用SLNB诊治的患者成功检出率为95．6％,准确度为93．2％,敏感度为92．6％,假阴性率为7．4％,其中,亚甲蓝组成功检出率为96．7％、准确度为93．1％、敏感度为94．4％、假阴性率为5．6％,异硫蓝组成功检出率为93．8％、准确度为86．7％、敏感度为88．9％、假阴性率为11．1％,两组患者整体检出效果差异有统计学意义（P〈0．05）。结论亚甲蓝染色法应用于乳腺癌SLNB中效果显著,值得临床推广。     

甲硝唑素片及其肠溶片在家兔体内生物利用度比较

本文采用分光光度法对甲硝唑素片和肠溶片进行了生物利用度及药物动力学研究,结果表明肠溶片相对生物利用度为140%,其吸收及消除均较素片慢。     

莫西沙星治疗耐多药肺结核患者的药效学研究

目的探讨莫西沙星片口服给药和局部介入治疗用药量的依据。方法莫西沙星血清中浓度采用高效液相色谱法测定,时间-杀菌、MIC、MBC及耐药梯度等试验在体外检测。结果 10例肺结核患者血峰浓度于1.81h到达（3.11±0.53）mg/L,1次单剂量给药24h后最低血药浓度为（0.26±0.06）mg/L,表观分布容积V/FC为（150.02±32.63）L,该药MIC.MBC值为0.20mg/L,1mg/L,耐药梯度范围在0.20～8mg/L。结论服用莫西沙星片治疗耐药肺结核患者,体内血药浓度24h应维持在最低杀菌浓度之上,介入治疗用药浓度应在8μg/ml以上。     

顺式阿曲库铵用于不同性别患者的药效学研究

目的:研究性别差异对顺式阿曲库铵肌松效应的影响。方法:将拟在气管插管全身麻醉下行择期手术的患者28例,分为男性组、女性组,每组14例。血浆靶控输注丙泊酚3μg·mL~(-1)、瑞芬太尼3～6 ng·mL~(-1)、静脉注射顺式阿曲库铵0.15 mg·kg~(-1)行麻醉诱导,以单次颤搐刺激监测神经肌肉阻滞深度,待T_1达最低值行气管插管,并转换为四个成串刺激(TOF),血浆靶控输注丙泊酚3μg·mL~(-1)、瑞芬太尼3～6 ng·mL~(-1)维持麻醉。记录顺式阿曲库铵的肌松作用指标。结果:与女性组比较,男性组身高、体质量较大(P<0.05),但体质量指数差异无统计学意义(P>0.05);起效时间、T_1最大阻滞程度、最大阻滞持续时间、T_1 25%恢复时间、恢复指数差异均无统计学意义(P>0.05)。结论:单次静脉注射顺式阿曲库铵后肌松效应无性别差异。     

Drug Transport from Thin Applications of Topical Dosage Forms: Development of Methodology

There are presently no standards for in vitro research dealing with the release and delivery of drugs from semisolid dosage forms, largely because of inherent experimental difficulties. Among the problems, it has proven difficult to apply dosage forms to membranes mounted in in vitro diffusion cells in facsimile to the manner in which the dosage forms are applied clinically. In the present studies, methodology has been developed which allows films with thicknesses approaching clinical dimensions to be spread evenly over silicone rubber membranes. Using methyl p-aminobenzoate as a test permeant and gelled water and water/propylene glycol solvent systems as test vehicles, it has proven possible to spread films as thin as 75 µm, yielding highly reproducible delivery profiles. Using this application technique, it has been shown how the diffusive clearance of drug from films of fixed composition placed over a resistant membrane is dependent on the thickness of application. For a given medium and thickness of application, when the vehicle composition is enriched in propylene glycol, partitioning into the membrane is suppressed, resulting in a lessening of the absolute rate of delivery and, consequently, a prolongation of the period over which drug is released. Increasing the membrane's resistance, i.e., increasing the membrane's thickness, likewise slows down the absolute delivery rate, extending the effective period of total clearance of drug from the applied film.     

顺式阿曲库铵应用于不同年龄小儿的药效学研究

目的:研究不同剂量顺式阿曲库铵对不同年龄小儿气管插管的药效学。方法:择期小儿手术患者120例,ASAⅠ~Ⅱ级,按年龄段不同分为婴儿组(Ⅰ组)、幼儿组(Ⅱ组)和儿童组(Ⅲ组),再分别按2ED95或3ED95的剂量分组,共6组(Ⅰ2、Ⅰ3、Ⅱ2、Ⅱ3、Ⅲ2、Ⅲ3),每组20例。于5s内单次静脉注入顺式阿曲库铵0.10mg.kg-1(2ED95)或0.15mg.kg-1(3ED95),待TOF的T1为0时行气管插管,并对插管条件进行评级,观察阻滞起效时间、TOF无反应期、阻滞维持时间、肌松恢复指数、体内作用时间等指标。结果:Ⅰ3、Ⅱ3、Ⅲ3组起效时间较Ⅰ2、Ⅱ2、Ⅲ2组有显著性差异(P<0.05),且Ⅰ2、Ⅰ3组较其他组起效时间明显缩短(P<0.05);气管插管条件在Ⅰ3、Ⅱ3、Ⅲ3组为优的比率明显高于Ⅰ2、Ⅱ2、Ⅲ2组(P<0.05);Ⅰ3、Ⅱ3、Ⅲ3组的TOF无反应期、阻滞维持时间、体内作用时间明显长于Ⅰ2、Ⅱ2、Ⅲ2组(P<0.05);Ⅰ2组TOF无反应期、阻滞维持时间、体内作用时间明显长于Ⅱ2、Ⅲ2组(P<0.05);Ⅰ3组TOF无反应期、阻滞维持时间、体内作用时间明显长于Ⅱ3、Ⅲ3组(P<0.05);但是肌松恢复指数在各组无显著性差异(P>0.05)。结论:顺式阿曲库铵3ED95诱导剂量对婴、幼儿和儿童均是安全有效的,其起效和插管条件均较2ED95优,婴儿较年长儿更为敏感,表现在起效更快,临床阻滞时间长,且肌松恢复时间与剂量、年龄无关。     

Action of methylene blue and haemoglobin in rabbit aorta in relation to the surface of drug entry

Summary The effect of methylene blue and haemoglobin has been evaluated by using a procedure of restricting drug entry to one surface of rabbit aortic rings. In preparations precontracted with noradrenaline, methylene blue and haemoglobin produced, via the intima, an additional rapid and endothelium-dependent contraction. While haemoglobin was without effect via the adventitia, methylene blue produced a slow endothelium-independent contraction that was diminished but not abolished in reserpine-pretreated animals. This augmentation of the noradrenaline-induced contraction produced by methylene blue via the adventitia in reserpine-pretreated rabbits was observed also with phenylephrine but not with methoxamine. Methylene blue, when added to aortic rings incubated with ³H-(–)-noradrenaline, interfered with the neuronal uptake of this amine and enhanced the outflow of ³H. In conclusion, methylene blue and haemoglobin enhanced noradrenaline-induced contraction by an endothelium-dependent mechanism when applied via the intima. Haemoglobin is devoid of effects via the adventitia but methylene blue has indirect sympathomimetic effects. In experiments using intact rings with no restriction to drug entry it was found that the enhancement by haemoglobin of the tyramine-induced response was markedly less than that observed for noradrenaline for the same level of plateau contraction. This finding indicates that the endothelium-derived relaxing factor is more effective on smooth muscle cell layers in the vicinity of intima than on those close to adventitia. Send offprint requests to E. Morcillo at the above address