尼莫地平鼻用冻干脂质体的制备及大鼠鼻黏膜吸收

采用改良乙醇注入法制备了尼莫地平脂质体，运用均匀设计试验优化了脂质体处方，并考察了冷冻干燥工艺与处方因素对其冻干脂质体性质的影响。在优化冻干工艺条件下，甘露醇和蔗糖合用为冻干保护剂，可得到外观良好、易于重建的冻干脂质体，冻干前后的药物包封率分别为97．1％和96．2％，粒径分别为175．1nm和227．9nm。-20℃及4℃贮存3个月，粒径和包封率无显著变化。采用大鼠在体鼻腔循环灌流法，考察了尼莫地平鼻用脂质体及其冻干重建制剂的鼻黏膜吸收规律。结果表明不同药物浓度脂质体及冻干重建脂质体的鼻黏膜吸收速率常数K无显著性差异，药物吸收呈一级动力学特征。     

阿替洛尔鼻用凝胶剂对纤毛毒性的评价

目的：评价阿替洛尔鼻用凝胶剂的纤毛毒性。方法：以在体蟾蜍上腭粘膜纤毛为材料，以纤毛持续运动时间及电镜观察为评价指标。结果：阿替洛尔凝胶剂对纤毛持续运动时间无显著影响，电镜观察亦显示纤毛排列较整齐，分布较均匀。结论：阿替洛尔凝胶可用于鼻腔给药。     

盐酸米托蒽醌脂质体的药效学及毒性研究

目的对盐酸米托蒽醌脂质体(Mit-lipo)与盐酸米托蒽醌普通制剂(Mit-inj)进行药效学及毒性比较研究。方法采用小鼠肝癌H22、小鼠前列腺癌RM-1移植肿瘤模型探讨Mit-lipo的抗肿瘤作用;犬急性毒性、大鼠和犬长期毒性研究比较Mit-lipo和Mit-inj毒性差异。结果 Mit-lipo 1、2、4和6 mg.kg-1各剂量对H22实体瘤的抑瘤率分别为75.1%、76.5%、90.1%和93.8%,也可剂量依赖性抑制小鼠前列腺癌RM-1肿瘤的生长,与等剂量的Mit-inj相比疗效明显增强。犬急性毒性结果表明Mit-lipo最大耐受剂量(MTD)为2.0 mg.kg-1,毒性表现为轻微至中度的皮肤毒性,给药4周后皮肤毒性逐渐减轻。大鼠长期毒性结果表明Mit-lipo可明显降低Mit-inj引起的骨髓毒性,并产生新的皮肤毒性反应。犬长期毒性结果表明Mit-lipo 0.1、0.3和0.45mg.kg-1组主要毒性反应为轻微至轻度的皮肤毒性反应,主要毒性靶器官为睾丸和皮肤,MTD为0.45 mg.kg-1,Mit-inj0.45 mg.kg-1可致WBC和PLT值降低和睾丸毒性病变。结论与普通制剂相比,米托蒽醌脂质体的体内抑瘤效果明显增强,且骨髓毒性明显降低。     

普萘洛尔鼻用制剂的纤毛毒性

目的：筛选一种合适的剂型以降低鼻用制剂的鼻纤毛毒性。方法：以盐酸普萘洛尔为模型药物,分别制备微球剂、复合乳剂和环糊精包合物。以在体蟾蜍上腭粘膜纤毛为动物模型,评价上述鼻用制剂对盐酸普萘洛尔纤毛毒性的改善作用。结果：微球剂能有效地降低盐酸普萘洛尔的纤毛毒性;复合乳剂因包裹率较低,而环糊精因与药物的结合常数较小,使这2种制剂对纤毛毒性均无明显的改善作用。结论：微球剂是降低药物鼻纤毛毒性的一种较为理想的剂型,机理主要是它的缓释作用。     

胰岛素鼻腔喷雾剂的大鼠鼻纤毛毒性考察

目的：考察胰岛素鼻腔喷雾剂的鼻纤毛毒性。方法：扫描电镜观察鼻喷雾剂对大卤粘膜表面形态的影响。结果：大鼠给予胰岛素鼻喷雾剂后,扫描电镜观察,其鼻中卫粘膜的纤毛形态与给予生理盐水的对照组无显著差异。结论：上述胰岛素鼻喷雾剂无急性鼻粘膜纤毛毒性。     

利巴韦林鼻用温敏凝胶的鼻腔纤毛毒性研究

目的:研究利巴韦林鼻用温敏凝胶及其处方中原料和辅料对鼻腔纤毛运动的影响。方法:采用在体蟾蜍上颚模型法,分别给予原料药利巴韦林(0·5%),辅料泊洛沙姆407(20%)、泊洛沙姆188(2·0%)、聚乙二醇6000(2·0%)、苯扎氯氨(0·01%)和自制的利巴韦林鼻用温敏凝胶,检测纤毛持续摆动时间,显微镜下观察纤毛形态学改变。结果:利巴韦林原料(0·5%)、泊洛沙姆407(20%)、泊洛沙姆188(2·0%)、聚乙二醇6000(2·0%)、苯扎氯氨(0·01%)及利巴韦林鼻用温敏凝胶均对鼻腔纤毛运动无明显影响,相对于生理氯化钠溶液,纤毛持续摆动时间的相对百分率在87·9%～97·6%之间。结论:利巴韦林鼻用温敏凝胶无明显鼻腔纤毛毒性,可以用于鼻腔给药。     

药物的鼻粘膜纤毛毒性及评价方法

提出一种新的评价方法─在体蟾蜍上腭模型,研究对乙酰氨基酚、盐酸普罗帕酮等8种药物溶液或混悬液对纤毛运动的影响,并与扫描电镜法及离体蟾蜍上腭模型比较。结果表明,在体模型简便易行,结果可靠,适用面广,是一种较理想的鼻纤毛毒性评价方法。离体模型不宜评价混悬型及粘稠性药物制剂的鼻纤毛毒性,但能进行受试药物与对照药物的同体比较,对于溶液型制剂是一种优良的评价方法。由8种药物的评价结果提示,药物对纤毛运动的影响较普遍,应予重视。     

α-2b干扰素鼻用喷雾剂的制备及其对黏膜纤毛毒性的研究

目的：制备α-2b干扰素鼻用喷雾剂，并研究其对鼻腔黏膜纤毛的毒性。方法：按正交试验设计优化处方。制备α-2b干扰素鼻用喷雾剂，考察其初步稳定性，并采用在体蟾蜍上腭模型法，研究α-2b干扰素鼻用喷雾剂、空白鼻用喷雾剂和干扰素溶液对鼻黏膜纤毛的影响，分别计算纤毛持续摆动时间的相对百分率。结果：自制α-2b干扰素鼻用喷雾剂稳定性良好，α-2b干扰素溶液、空白鼻用喷雾剂和合药鼻用喷雾剂对蟾蜍上腭纤毛持续摆动时间的相对百分率分别为99．2％，90．0％和85．7％，与阴性对照（1％盐酸麻黄素溶液）均无显著性差异（P〉0．05），表明自制α-2b干扰索鼻用喷霉剂对蟾蜍上腭纤毛运动基本无影响。结论：自制α-2b干扰素鼻用喷雾剂的物理化学性质优良，稳定性良好，对黏膜纤毛的毒性较小，有望用于鼻腔给药。     

Lithium Chloride Toxicity and Pharmacodynamics in Inbred Mice

Abstract Inbred strains of male mice (C3H, DBA, BALB, C57) were used to determine whether genetic factors play a role in lithium toxicity. Significant differences in the LD50 for LiCl were observed between the mouse strains after a subcutaneous injection of 37° isotonic LiCl. The LD50 values in the C3H, DBA, BALB and C57 strains were 17.4, 17.6, 18.2 and 19.4 mmol/kg, respectively. Significant differences were also observed between the mouse strains in the concentrations of lithium in plasma, heart, liver, kidney and brain 2 hrs. after a subcutaneous injection of 15.1 or 18.2 mmol/kg LiCl, but the lithium concentrations were not related in an obvious manner to LiCl toxicity. The results show that genetic factors can influence the toxicity and pharmacodynamics of lithium.     

The Influence of Drugs on Nasal Ciliary Movement

Drugs in nasal preparations, for local use as well as for systemic use, should not interfere with the self-cleaning capacity of the nose, effectuated by the ciliary epithelium. Many drugs and additives, however, have a negative effect on nasal ciliary function. Examples of ciliotoxic agents are lipophilic and mercuric preservatives, local anesthetics, antihistamines, propranolol, and absorption enhancers such as the bile salts. Cholinergic drugs and -adrenergic drugs exert a ciliostimulatory effect. It is the purpose of this review to summarize the present knowledge of ciliotoxicity of drugs and additives and to give recommendations for the use of ciliofriendly drugs in nasal preparations.     

齐多夫定肉豆蔻酯脂质体与齐多夫定对实验动物毒性作用比较研究

目的研究齐多夫定肉豆蔻酯脂质体与齐多夫定对实验动物的毒性作用。方法采用昆明种小鼠,观察两种剂型药物的急性LD50。将昆明种小鼠分成3组,观察两种剂型药物对小鼠的行为活动、体重以及脏器系数的影响。采用Bagle犬分成3组,观察两种剂型药物对犬的行为活动、体重、脏器系数、血液学指标、血清生化值、脏器病理的影响。结果AZT组的LD50为12.50mg·kg^-1,AZT-ML组的LD50为20.30mg·kg^-1。AZT-ML组小鼠的行为活动基本正常,其体重、脏器系数的改变较AZT组明显减轻。AZT-ML组犬的行为活动基本正常、其体重、脏器系数、血液学指标、血清生化值、脏器病理的改变较AZT组明显减轻。结论与AZT相比,AZT-ML对实验动物机体的损害及毒性作用显著降低。     

蛋白激酶C ε亚型在AVP调节休克血管MLC20磷酸化水平及MLCK/MLCP活性中的作用

目的研究蛋白激酶C（PKC）ε亚型在精氨酸血管加压素（AVP）调节休克血管肌球蛋白轻链（MLC20）磷酸化及缺氧血管平滑肌细胞（VSMC）肌球蛋白轻链激酶（MLCK）和肌球蛋白轻链磷酸酶（MLCP）活性中的作用。方法采用大鼠失血性休克模型和缺氧培养VSMC,观察PKCε亚型在AVP调节失血性休克大鼠肠系膜上动脉（SMA）血管平滑肌MLC20磷酸化水平中的作用,同时检测缺氧VSMC中MLCK和MLCP活性的变化。结果失血性休克后SMA血管平滑肌MLC20磷酸化水平降低,同时缺氧VSMC的MLCP活性明显升高,MLCK活性明显降低;AVP处理可显著升高MLC20磷酸化水平和抑制缺氧VSMC的MLCP活性升高,特异性的PKCε抑制肽可明显拮抗AVP升高MLC20磷酸化、降低MLCP的作用;而AVP和PKCε抑制肽对MLCK活性的变化无明显影响。结论AVP可通过PKCε亚型来发挥改善休克血管反应性的作用,其机制可能是通过抑制MLCP活性、升高MLC20磷酸化水平,进而增强血管平滑肌细胞钙敏感性升高血管反应性。     

Effects of Pharmaceutical Compounds on Ciliary Beating in Human Nasal Epithelial Cells: A Comparative Study of Cell Culture Models

Purpose. To test two in vitro human nasal epithelial cell culture systems for their ability to screen the effects of pharmaceutical compounds on ciliary beating. Methods. Human nasal epithelial cells were cultured as monolayer and in a sequential monolayer-suspension culture with in vitro ciliogenesis. The influence of reference cilio-stimulatory compounds (glycocholate, isoprenaline), reference cilio-inhibitory compounds (chlorocresol, diphenhydramine) and pH on ciliary beating was investigated using computerized microscope photometry. Results. Sodium glycocholate (0.5% w/v) maximally and reversibly increased CBF of the cells in both culture systems by 26 ± 4% (monolayer) and 18 ± 6% (suspension). Similarly, isoprenaline (10^-3 M) maximally, but irreversibly increased CBF of the cells by 14 ± 3% (monolayer) and 17 ± 4% (suspension). Chlorocresol (0.005% w/ v) reversibly reduced the CBF of the cells by 50 ± 6% (monolayer) and 34 ± 4% (suspension); at a higher concentration (0.1% w/v) it resulted in instantaneous and irreversible ciliostasis. Diphenhydramine (0.1% w/v) reversibly reduced CBF in both culture systems by 45 ± 13% (monolayer) and 69 ± 5% (suspension); irreversible cilio-stasis occurred in less than 2 minutes in both culture systems upon cell exposure to diphenhydramine (1.0% w/v). In the monolayer culture system, CBF was stable only within the physiological pH range of 6.5–8.0; ciliary beating in the suspension culture remained stable within a pH range of 4.0–10.0. Conclusions. Both cell culture systems are suitable for screening the effects of pharmaceutical compounds on ciliary beating. Especially the sequential monolayer-suspension culture appears to be very promising as ciliary activity can be preserved for as long as 6 months.     

Liposomes as delivery systems for nasal vaccination: strategies and outcomes

Importance of the field: Among the particulate systems that have been envisaged in vaccine delivery, liposomes are very attractive. These phospholipid vesicles can indeed deliver a wide range of molecules. They have been shown to enhance considerably the immunogenicity of weak protein antigens or synthetic peptides. Also, they offer a wide range of pharmaceutical options for the design of vaccines. In the past decade, the nasal mucosa has emerged as an effective route for vaccine delivery, together with the opportunity to develop non-invasive approaches in vaccination.

Areas covered in this review: This review focuses on the recent strategies and outcomes that have been developed around the use of liposomes in nasal vaccination.

What the reader will gain: The various formulation parameters, including lipid composition, size, charge and mucoadhesiveness, that have been investigated in the design of liposomal vaccine candidates dedicated to nasal vaccination are outlined. Also, an overview of the immunological and protective responses obtained with the developed formulations is presented.

Take home message: This review illustrates the high potential of liposomes as nasal vaccine delivery systems.     

Transfer of Dopamine in the Olfactory Pathway Following Nasal Administration in Mice

Purpose. The aim of the study was to investigate whetherdopamine is transferred along the olfactory pathway to the brain followingnasal administration to mice. Methods. [³H]-Dopamine was administered nasally or intravenouslyto female mice. Brain tissue samples were excised and the radioactivecontent was measured. The precise localisation of dopamineradioactivity in the brain was studied using autoradiography. The presence ofdopamine or its metabolites in the olfactory bulb and mucosa wasascertained using thin layer chromatography (TLC). Results. After administration of [³H]-dopamine into the rightnostril, the amount of dopamine in the right bulb increased with time until,after 4 h, it was 27 times higher than in the left bulb. Among the otherbrain tissue samples, significantly higher amount of radioactivity wasdetected in the lateral olfactory tract. Radioactivity in the right olfactorybulb was shown by autoradiography to be selectively located in theperipheral layers 1 to 4 h after administration. Selective uptake ofradioactivity was not seen in other regions of the brain. TLC dataindicated that approximately 75% and 10% of the radioactivity in theolfactory bulb and mucosa, respectively, coeluted with dopamine. Conclusions. The results indicate that unchanged dopamine istransferred into the olfactory bulb following nasal administration of[³H]-dopamine.     

胰岛素鼻腔给药微球剂的制备及药效学研究

目的 :制备胰岛素鼻腔给药微球剂并进行药效学研究。方法 :以可溶性淀粉为原料 ,利用聚乙二醇法制备淀粉微球 ,吸附胰岛素 ,制得含胰岛素的淀粉微球。根据Baldwin法进行药效学研究。结果 :制得的胰岛素微球鼻腔给药后可使血液中血糖浓度下降35 2%。结论 :胰岛素微球经鼻腔给药可明显降低血糖水平 ,药物作用呈现缓释特征。