缓释盐酸布比卡因人血清白蛋白微球的研究

目的:制备缓释盐酸布比卡因人血清白蛋白微球(bupivacaine human serum albumin microspheres,Bupi-HSA-MS),并对其理化特性、体外释放、体内药动学、药效学进行评价。方法:采用高压电场法制备布比卡因人血清白蛋白微球,以高效毛细管电泳法测定微球的体外释放度。采用改良的RP-HPLC法测定体内布比卡因血药浓度,以家兔为实验对象,以针刺疼痛反应圈半径大小评价其麻醉效果。结果:微球的粒径分布集中,平均粒径为(108.9±2.6)μm,药物含量为31.56％,包封率为91.62％。体外释放结果表明,Bupi-HSA-MS具有明显缓释作用。药物动力学实验结果表明,注射剂组血药浓度达峰时间短,浓度高,药物驻留时间短。微球组峰浓度显著低于注射剂组并长时间维持低浓度。微球组的平均保留时间较对照组明显延长(P<0.01)。微球组皮下给药最大麻醉圈直径显著小于注射剂对照组(P<0.01),而微球组局麻持续时间较对照组明显延长(P<0.01)。结论:高压电场法是一种简单、易行的白蛋白微球制备新方法。Bupi-HSA-MS兔皮下给药,药物扩散少,局部麻醉作用持续时间长,是一种安全、长效的局部麻醉止痛新方法。     

靶向给药系统—甲氨蝶呤肝动脉栓塞微球动物体内行为的研究

本文研究交链的甲氨蝶呤明胶微球(MTX-ms),经动物肝动脉栓塞后的体内药动学过程和微球在体内的生物降解期限等。 肝动脉灌注MTX-ms后,外周血液中MTX血药浓度上升与下降缓慢,而灌注MTX溶液立即出现峰值并迅速下降;微球药物消除半衰期为MTX溶液的2.14倍,在16h的体内检测中,肝静脉局部的MTX-ms血药浓度始终高于MTX溶液组。 经肝动脉造影随访证实,微球属血管末梢栓塞剂,明胶微球在体内降解时间约一月。微球栓塞后对肿瘤血供的切断以及药物在局部缓释作用对肝癌治疗是有积极意义的。     

肝动脉栓塞用顺铂白蛋白微球的研究

按正交设计筛选乳化热固化法制备顺铂白蛋白微球的最佳工艺,并对影响微球粒径大小和体外释药速率的诸多因素进行了研究。该微球粒径范围为50.8～256μm。平均粒径为148.46μm,药物含量为51.16%(W/W)。兔肝动脉栓塞后,与对照组相比铂的分布半衰期延长336%,消除半衰期延长123%,体内最高血浓仅为对照组的30%。肝组织顺铂量显著增加(P<0.01),肾组织药物量明显降低(P<0.05),体内外相关性研究表明顺铂白蛋白微球体外累积溶出百分率与兔体内药物吸收分数呈显著相关(P<0.01)。     

关节腔内注射用氟比洛芬明胶微球

目的:制备关节腔注射用氟比洛芬明胶微球。方法:按均匀设计法筛选乳化冻凝法制备氟比洛芬明胶微球(FP GMS)的最佳制备工艺。结果:微球粒径范围为2.5～12.3μm,平均粒径为7.53μm,氟比洛芬含量为5.02%(w/w)。其体外释药符合Higuchi方程,稳定性实验表明,FP-GMS的稳定性良好,兔关节腔内注射后,与溶液剂对照组相比氟比洛芬体内平均驻留时间(MRT)显著延长(P<0.01),峰时比对照组延长2.03倍,峰浓度比对照组减小5.57倍。体内外相关性研究表明,FP-GMS体外累积溶出百分率与兔体内药物吸收分数呈显著相关(P<0.01)。结论:本法制备的氟比洛芬明胶微球粒径分布集中,粒径大小符合设计要求,体内外释药结果表明氟比洛芬明胶微球具有明显的缓释作用。     

吗啡布比卡因臂丛麻醉与术后镇痛的临床观察

目的:观察吗啡布比卡因混合液用于臂丛麻醉与术后镇痛的临床疗效,从而研究吗啡布比卡因用于臂丛麻醉与镇痛的机理。方法:将50例ASAⅠ～Ⅱ级患者,随机均分为2组。A组(对照组):0.375％布比卡因,B组(观察组):0.375％布比卡因+2 mg吗啡。用不同麻醉药25～35 mL作臂丛神经阻滞,注药后观察麻醉起效时间,阻滞完全时间,麻醉与术后镇痛持续时间(P<0.01)。结果:含有吗啡的B组麻醉与术后镇痛效果明显优于未加用吗啡的A组。结论:除中枢神经系统外,周围神经系统也可能存在多种阿片样物质和阿片受体。     

布比卡因缓释微球的制备及体外释药特性评价

目的研究布比卡因缓释微球制备方法并对其体外释药特性进行评价。方法采用紫外分光光度法测定布比卡因微球载药量、包封率;采用HPLC法测定微球体外释放;通过正交设计优选微球制备工艺;以乳酸羟基乙酸共聚物为载体,使用乳化溶剂挥发法制备布比卡因微球;用扫描电镜观察所得微球的粒径和形态;通过体外释药实验考察布比卡因乳酸羟基乙酸共聚物微球的缓释作用。结果微球载药量、包封率和体外释放的测定方法符合方法学要求;按照优选处方制备所得的微球为圆整球体,表面多孔,呈蜂窝状,粒径50~100μm之间的微球占80%;体外释放符合Ritger-Peppas方程,t1/2=242.05 h。结论乳化溶剂挥发法适用于布比卡因乳酸羟基乙酸共聚物微球的制备,所制得的微球形态圆整,在体外具有明显缓释作用。     

沙美特罗白蛋白微球在大鼠体内的药动学

目的:研究沙美特罗白蛋白微球在大鼠体内的药动学特征.方法:12只大鼠随机分成沙美特罗白蛋白微球组和沙美特罗溶液组,每组6只,分别灌胃给药(20 μg·kg -1)后不同时间取血,HPLC法测定血药浓度,用3P97软件计算药动学参数.结果:沙美特罗溶液和沙美特罗白蛋白微球在大鼠体内的主要药动学参数:tmax分别为(0.73±0.15)和(3.22±0.20)h,Cmax分别为(1.10±0.19)和(1.25±0.24) μg·ml-1,t1/2ka分别为(0.35±0.05)和(1.58±0.07)h,t1/2ke分别为(2.30±0.85)和(8.21±1.20)h,AUCo→∞分别为(1.55±0.25)和(3.45±0.55) mg·h·L-1.结论:与沙美特罗溶液相比,沙美特罗白蛋白微球具有明显的缓释效果,同时提高了药物的生物利用度.     

蛋白质多肽长效微球注射剂的体内药动学及分析方法研究进展*

长效微球注射剂作为一类处于热点研究中的新型释药系统，在蛋白质、多肽的递送中受到了日益广泛的重视和应用。但是，微球的释药机制复杂，蛋白质、多肽的体内药物分析又存在着诸多困难，因而蛋白质、多肽长效微球注射剂的体内药物释放及评价是此类药物制剂研发的瓶颈之一。现介绍近年来蛋白质、多肽长效微球注射剂的体内释药机制及药动学研究进展，并着重对蛋白质、多肽长效微球注射剂的体内药物分析方法进行综述。     

罗哌卡因和左旋布比卡因在小儿骶管麻醉中的临床效果

目的比较罗哌卡因和左旋布比卡因在在小儿骶管麻醉中的临床效果。方法 98例泌尿外科接受手术治疗的患儿,随机分为观察组与对照组,每组49例。在骶管麻醉中,观察组患儿给予左旋布比卡因,对照组患儿给予罗哌卡因。观察并比较两组患儿使用的临床效果。结果两组手术时间和术后1 h CHIPPS评分差异均无统计学意义(P>0.05)。观察组阻滞起效时间、镇痛持续时间和术后1 h CHIPPS评分均显著优于对照组(P<0.01)。两组围手术期间均未发生明显不良反应。结论小儿骶管阻滞麻醉止痛效果好,肌松良好,手术中患儿无痛苦,且术后患儿苏醒较快,在行骶管麻醉的同时也可以将药物加入到局麻药中进行术后的镇痛,极易被患儿及家属接受,也成为小儿骶管麻醉中的良好选择,而且经本次研究观察,作者认为:罗哌卡因和左旋布比卡因均能有效、安全的用于骶管麻醉,但左旋布比卡因具有更为显著的镇痛效果,有助于促进患儿术后更好更快恢复,值得临床考虑。     

小儿硬膜外腔内注入布比卡因、利多卡因的药动学研究

目的:研究小儿硬膜外腔内注入布比卡因及利多卡因的药动学特征,以探讨该麻醉方法的安全性和有效性。方法:30例择期行隐睾、疝气、鞘膜积液高位结扎术的患儿,给予利-布合剂(2%利多卡因5mg.kg-1+0.75%布比卡因1.875mg.kg-1),使用一次性注药于硬膜外腔的麻醉方法。采用高效液相色谱法测定患儿体内布比卡因、利多卡因的血药浓度,用DASver2.0药动学程序处理拟合,计算药动学参数。结果:小儿体内布比卡因、利多卡因的药-时曲线符合二室模型,利多卡因和布比卡因的药动学参数分别为:tmax为27.0、33.0min,t1/2β为43.97、73.52min,Cmax为2.411、1.475mg.L-1,AUC0～∞为144.714、168.541mg.min.L-1。结论:小儿硬膜外腔内给予局麻药剂量是安全、有效的。     

Kinetic and dynamic studies of liposomal bupivacaine and bupivacaine solution after subcutaneous injection in rats

The pharmacodynamics and pharmacokinetics of bupivacaine in solution and in liposome preparations following subcutaneous administration were studied in rats. Multilamellar vesicles entrapping bupivacaine solution were prepared. The local anaesthetic effect was estimated by the tail-flick test in Wistar rats treated with 1 mg bupivacaine in 0.2-mL preparations. Plasma concentrations of bupivacaine were determined by high-performance liquid chromatography. The results showed that both bupivacaine solution and bupivacaine liposomes revealed local anaesthetic effects in the initial tail-flick test (15 min after injection). With bupivacaine liposomes, the duration of action was 5-fold (447+/-28.9 vs 87+/-6.7 min), the maximum possible effect was 2-fold (100+/-0 vs 47.6+/-13%), and the peak plasma concentration (Cmax) was less than one-fifth (0.12+/-0.04 vs 0.65+/-0.04 microg mL(-1)) that with bupivacaine solution. The sensory block effect of bupivacaine solution completely resolved at 90 min, while the plasma concentration of bupivacaine was still more than half the Cmax. Bupivacaine liposomes resulted in a low and relatively constant plasma level (approx. 0.1 microg mL(-1)) and a pronounced local anaesthetic effect throughout the experimental period (> 7 h). In conclusion, bupivacaine liposomes elevated the intensity and prolonged the duration of the local anaesthetic effect of bupivacaine, and suppressed the systemic absorption rate of encapsulated bupivacaine.     

醋酸曲安奈德温敏凝胶药效学及滞留性

目的：制备关节腔注射用醋酸曲安奈德TAA温敏凝胶,考察其药效学和滞留性。方法：采用物理混合法制得TAA温敏凝胶,建立老鼠皮下气囊炎症模型,给予不同组分药物治疗后,通过对比皮下囊物理特征、组织切片的相关评价以及elisa试剂盒检测炎性因子TNF-α水平等来考察所制备的TAA温敏凝胶药效学及缓释性能,并通过小动物活体成像实验评价其滞留性。结果：药效学结果显示制备的TAA温敏凝胶相比于市售TAA混悬液对于气囊滑膜炎模型的炎症抑制作用更强、作用时间更持久。小动物活体成像实验结果显示制备的TAA温敏凝胶在体内滞留时间能达到9 d以上,能够达到缓释药物的目的,适用于关节腔局部用药的要求。结论：所制备的TAA温敏凝胶的炎症抑制作用强且持久,缓释效果及滞留性良好,有望成为新的关节腔给药传递系统。     

复方盐酸丁卡因注射液的制备及临床应用

目的：研究配制一种安全高效的口腔局部麻醉复方制剂。方法：配制复方盐酸丁卡因注射液,研究其质量控制标准,采用高效液相色谱法测定其含量,观察该制剂临床麻醉效果,并与2％盐酸普鲁卡因注射液作麻醉效果对照。结果：该制剂质量稳定,质量控制方法可行,其HPLC法测定丁卡因和利多卡因含量的平均回收率分别为98．8％、100．7％。临床应用麻醉效果明显优于对照组（P＜0．01）。结论：该注射液制备工艺可行,临床效果好,值得推广应用。     

Levobupivacaine: a new safer long acting local anaesthetic agent

The choice of local anaesthetic is influenced by several factors; it must provide effective anaesthesia and analgesia for the duration of the procedure and meet the expectations for post-operative pain management. Of primary concern is patient safety. Bupivacaine, currently the most widely used long acting local anaesthetic agent in both surgery and obstetrics, generally has a good safety record but its use has resulted in fatal cardiotoxicity, usually after accidental intravascular injection. Hence, for several years there has been a need for a long acting local anaesthetic, similar to bupivacaine, but with an improved cardiovascular safety profile. Levobupivacaine, the single enantiomer version of bupivacaine, offers a new long acting local anaesthetic, clinically equivalent in anaesthetic potency to bupivacaine, but with a reduced toxicity profile. Preclinical studies, from in vitro in single ion channels to whole large animal models, have unquestionably demonstrated that levobupivacaine is significantly less CNS toxic and cardiotoxic than bupivacaine. Cardiotoxicity is less easy to study in man, as the clinical signs are not usually seen until the CNS toxicity is marked, and well beyond that which is tolerable to volunteers or patients. Nevertheless, levobupivacaine has been shown to have less effect on myocardial contractility and QTc prolongation, early signs of cardiotoxicity, than bupivacaine in healthy subjects. In clinical use levobupivacaine has been shown to be equally efficacious as bupivacaine at comparable doses and concentrations, and has been found to produce similar anaesthetic characteristics (onset, duration and density of block). As levobupivacaine now becomes commercially available, the database available with which to make efficacy and safety comparisons with other local anaesthetics will increase, and the true value of this new long acting local anaesthetic should become even more apparent.     

Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats

Dextromethorphan has been used as an antitussive for more than 40 years and is considered a drug with a good margin of safety. The aim of the study was to evaluate whether dextromethorphan and its metabolites--3-methoxymorphinan and dextrorphan--had local anaesthetic effects. Using a method of sciatic nerve blockade in rats, the potencies and durations of actions of dextromethorphan and its metabolites on sciatic nerve blockades of motor function, proprioception, and nociception were evaluated. Lidocaine was used as control. We found that dextromethorphan and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception, and nociception. The ranks of potencies were lidocaine>dextromethorphan>3-methoxymorphinan>dextrorphan (P<0.01 for each comparison). Under an equi-potent basis, dextrorphan and 3-methoxymorphinan had durations of actions longer than that of lidocaine (P<0.05 for each comparison). Co-administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on sciatic nerve blockades. In conclusion, dextromethorphan and its metabolites - 3-methoxymorphinan and dextrorphan- had a local anaesthetic effect on sciatic nerve blockades of motor function, proprioception and nociception with durations of actions longer than that of lidocaine. Co-administration of dextromethorphan and its metabolites produced an additive effect on sciatic nerve blockades.     

氟尿嘧啶聚乳酸微球在PVR家免体内的研究

考察了在增生性玻璃体视网膜病变(PVR)家兔玻璃体中植入氟尿嘧啶聚乳酸微球后的体内药物动力学和药效学.采用HPLC法测定房水中药物浓度.结果表明,制品的体内消除半衰期从0.6h延长至379h.体外累积释放率与体内相应时间的吸收分数呈明显的正相关.药效学结果根据Ryan分级法进行评价,f检验结果表明微球组与生理盐水对照组、注射液组视网膜脱离发生率有显著性差异(P＜0.01),后两组间无显著性差异(P＞0.05).     

Different concentrations of local anaesthetics have different modes of action on human lymphocytes

Lidocaine and Bupivacaine inhibit in vitro 3H-TdR incorporation into peripheral lymphocytes, in a dose dependent ratio, either under PHA stimulus or not. Lidocaine added to cultures at various times from PHA stimulus show a reduced inhibition only when added after the 24th hour. This suggests a sensitizing action of PHA. Lidocaine effect on mitosis of doses between 2000 and 500 micrograms/ml was not completely reversible even when the drug was removed after only 15 min; between 200 and 50 micrograms/ml this effect is reversible. Lymphocyte viability by Trypan Blue exclusion is clearly unrelated to mitotic inhibition; it is however dose related. High Lidocaine and Bupivacaine concentration alter adhesion of cells to plastics and decrease lymphocyte aggregation by PHA. Electrophoretic mobility of lymphocytes incubated with 2000 micrograms/ml of Lidocaine is slower compared to controls; there is no change at 200 micrograms/ml. Local anaesthetics modify steric membrane structure reducing surface charge density. Increased Ca++ in the medium containing local anaesthetic increases lymphocyte stimulation index slightly only for Lidocaine and Bupivacaine doses, which neither alter membrane function nor interfere with lymphocyte viability nor electrophoretic mobility. Increased Na+ and K+ in the medium do not affect local anaesthetic action.     

B超引导下输卵管妊娠灶穿刺注射氨甲蝶呤的疗效比较

目的 比较B超引导下输卵管妊娠灶穿刺注射氨甲喋吟(MTX)法和MTX单次肌肉注射法治疗输卵管妊娠疗效的差异。 方法在B超引导下进行输卵管妊娠灶穿刺,注射MTX 10mg,同时口服米非司酮(50mg/d,5d为1疗程)。观察其疗效、毒副作用和输卵管通畅率,并与MTX 50mg单次肌注法+米非司酮(50mg/d,5d为1疗程)进行比较。 结果穿刺组和肌注组的成功率分别是91.30％(42/46)和74.8(77/103)(P<0.05)。前者HCG下降和阴转时间快于后者(15.7±6.3天和26.4±12.3)(P<0.05),但穿刺组腹痛加剧发生率较肌注组高,分别是63％和31％(P<0.001),且程度更严重(VAS5.6±2.1比4.1±1.7)(P<0.0005)。两组患侧输卵管通畅率结果相似,无统计学意义。 结论B超引导下输卵管妊娠灶穿刺注射MTX法比MTX单次肌肉注射法疗效更好,HCG阴转时间快,但前者更易致腹痛加剧,值得临床注意。     

丙种球蛋白佐治重症肺炎的疗效分析

目的评价大剂量丙种球蛋白在重症肺炎中的应用价值。方法选择我院重症肺炎患者82例,随机分为2组,治疗组40例,应用丙种球蛋白治疗;对照组42例,常规治疗。比较两组的临床症状、体征、呼吸衰竭改善情况及临床疗效。结果治疗组的退热时间及咳嗽、咳痰缓解时间、肺部音消失时间、痰菌阴转时间、住院时间均较对照组明显缩短(P<0.01),PaO2、PaCO2改善及呼吸衰竭纠正时间明显优于对照组(分别为P<0.01、P<0.05、P<0.01),治疗组疗效明显优于对照组(P<0.05)。结论静脉注射丙种球蛋白辅佐治疗重症肺炎是一种有效、安全、可靠的方法。