甘辛喷雾剂的鼻黏膜纤毛毒性评价

目的:确定适宜的药物浓度,评价甘辛喷雾剂及处方各组分对鼻黏膜纤毛功能的影响.方法:用光学显微镜观察离体蛙口腔上腭纤毛在药物溶液作用下持续摆动时间,以此作为指标考查不同药物浓度和组分对蛙口腔黏膜纤毛功能的影响.结果:4%甘辛喷雾剂对纤毛运动影响最小,与对照组药物相比,4%甘辛喷雾剂和处方中各组分对蛙口腔黏膜纤毛的影响弱于滴通鼻炎水(P＜0.01).结论:甘辛喷雾剂对鼻黏膜纤毛的功能无明显损伤作用.     

Nephrotoxicity of bromobenzene in mice

I.p. administration of bromobenzene to male mice at doses ranging from 0 to 9.4 mmol/kg resulted in a dose-dependent increase in blood urea nitrogen (BUN) and serum glutamic-pyruvic transaminase (SGPT) activity and a decrease in renal cortical accumulation of para-aminohippurate (PAH) and tetraethylammonium (TEA). Induction of renal and hepatic mixed-function oxidases by beta-naphthoflavone (BNF) did not result in any alterations in the hepatotoxic or nephrotoxic response to bromobenzene. Renal and hepatic non-protein sulfhydryl (NPSH) concentrations were decreased significantly 1 h after administration of bromobenzene (7.5 mmol/kg) and were maximally depleted in both organs to 18% of control after 7 h. Depletion of renal NPSH by bromobenzene was dose-dependent up to 9.4 mmol/kg. Treatment of mice with diethyl maleate (DEM) (0.6 ml/kg) 60 min prior to bromobenzene administration resulted in greater hepatotoxicity, evidenced by increased SGPT, while renal toxicity was unchanged. These data demonstrate that large doses of bromobenzene produce functional alterations in the kidney.     

鼻腔给药系统的研究新进展

近年来药物的鼻腔给药系统受到了越来越多的关注.全球众多制药行业都在致力于基因和多肽类药物新型鼻腔给药系统的研发.现阐述了鼻腔生理特点和药物鼻黏膜转运机制及其影响因素,并对近年来鼻腔给药系统的促吸收途径和发展动向作一概述.     

重组水蛭素-2在家兔鼻黏膜中降解的体外实验

目的考察重组水蛭素-2(rHV2)在家兔鼻黏膜中的降解情况。方法建立用HPLC测定家兔鼻黏膜和肠黏膜组织匀浆液中rHV2浓度的方法；测定不同浓度rHV2在家兔鼻黏膜组织匀浆液中及rHV2在不同pH值的家兔鼻黏膜组织匀浆液中的降解；比较家兔鼻黏膜和肠黏膜组织匀浆液对rHV2的降解；考察rHV2在家兔鼻黏膜酶提取液中的稳定性以及加入酶抑制剂对rHV2在家兔鼻黏膜组织匀浆液降解的抑制作用。结果rHV2在鼻黏膜匀浆液中的降解具有明显的药物浓度和pH依赖性；rHV2在鼻黏膜匀浆液中的稳定性优于在肠黏膜匀浆液中的稳定性；鼻黏膜酶提取液对rHV2的降解作用较小；酶抑制剂杆菌肽对rHV2在鼻黏膜匀浆液中的降解具有一定的抑制作用。结论与口服给药途径相比，rHV2鼻腔给药更有优势。     

眼镜蛇神经毒素粉末剂的鼻黏膜纤毛毒性考察

目的:考察浙江产眼镜蛇神经毒素鼻用粉末剂(神经毒素粉剂)的鼻黏膜纤毛毒性。方法:以在体蟾蜍上腭模型,观察神经毒素粉剂对鼻纤毛摆动的影响;运用组织病理学方法,在给于家兔神经毒素粉剂后1,3,5,7d时,取鼻中隔黏膜进行光学显微镜观察。结果:神经毒素粉剂抑制鼻纤毛摆动强度,但停止用药后8~9h纤毛摆动可完全恢复,且纤毛形态无明显改变;家兔给予神经毒素粉剂后1,3,5d,其鼻中隔黏膜与空白对照组差异无显著性。第7天,黏膜上皮松化,黏膜轻度充血,但基底膜完整。结论:神经毒素粉剂无急性不可逆性鼻黏膜纤毛毒性。     

黄芩苷脂质体、β-环糊精包合物及磷脂复合物鼻黏膜渗透性及毒性研究

为提高鼻腔给药后脑内药物浓度,本文探讨了以脂质体、β-环糊精包合物和磷脂复合物为黄芩苷载药体系的体外离体动物鼻黏膜渗透性及鼻腔毒性。采用猪、羊、兔鼻黏膜,以体外扩散池装置进行鼻黏膜渗透实验,HPLC法测定接受池中药物累积渗透量,以表观渗透系数为评价标准,考察脂质体、β-环糊精包合物及磷脂复合物载药系统对黄芩苷在离体动物鼻黏膜的透过性,从而筛选出黄芩苷经鼻给药最佳载药形式;采用在体法考察黄芩苷及其磷脂复合物对蟾蜍上颚黏膜纤毛运动的影响和大鼠鼻黏膜长期毒性。3种黄芩苷载药体系的表观渗透系数均明显高于黄芩苷（P<0.05）,滞后时间也比黄芩苷短,提示3种载药载体均可提高黄芩苷的鼻黏膜渗透性,同时磷脂复合物的表观渗透系数明显高于脂质体和环糊精包合物,表明黄芩苷磷脂复合物鼻黏膜渗透性明显优于另外两种载药体系（P<0.05）。黄芩苷磷脂复合物对纤毛运动无影响,对大鼠鼻黏膜也无明显刺激性。结果表明,磷脂复合物为黄芩苷经鼻给药最佳载药形式,能明显提高其鼻黏膜渗透性,对鼻黏膜无毒性,可用于鼻腔给药。

      

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.     

鼻内镜手术对鼻窦炎伴鼻息肉患者嗅觉功能的影响

目的 研究鼻内镜手术对鼻窦炎伴鼻息肉患者嗅觉功能的影响.方法 98例鼻窦炎伴鼻息肉患者,随机分为观察组和对照组,每组49例.对照组患者实施常规摘除手术进行治疗,观察组患者实施鼻内镜手术进行治疗.比较两组患者治疗效果、并发症发生情况及治疗前后鼻气道总阻力、嗅觉功能评分.结果 观察组患者的治疗总有效率为100.00％,明显...     

表皮生长因子治疗鼻中隔粘膜糜烂性鼻出血

目的：观察表皮生长因子治疗鼻中隔粘膜糜烂性鼻出血的疗效。方法：治疗组６２例（男性２９例，女性３３例；年龄３５±ｓ６ａ）用０．２％表皮生长因子明胶海绵敷贴在鼻中隔的糜烂面上，并用该药液滴鼻，每次４滴，ｑｉｄ×１０ｄ。对照组３０例（男性１４例，女性１６例，年龄３２±５ａ）用０．２５％氯霉素明胶海绵敷贴，并用此药滴鼻，每次４滴，ｑｉｄ×１０ｄ。结果：治疗组出血停止，鼻腔干燥，刺痛感消失，粘膜恢复正常的平均天数及复发率均低于对照组（Ｐ＜０．０１），未见不良反应。结论：表皮生长因子可作为治疗鼻中隔粘膜糜烂性鼻出血的满意制剂。     

甲磺酸二氢麦角毒碱溶液鼻黏膜吸收的研究

目的:研究甲磺酸二氢麦角毒碱溶液鼻黏膜吸收规律。方法:考察甲磺酸二氢麦角毒碱在大鼠鼻腔洗出液中的稳定性,在此基础上,以大鼠在体鼻循环为实验模型,研究甲磺酸二氢麦角毒碱溶液的鼻黏膜吸收规律。结果:甲磺酸二氢麦角毒碱在鼻黏膜洗出液中稳定性良好,当循环液体积为5 mL,流速为2．5 mL·min-1时,甲磺酸二氢麦角毒碱溶液鼻黏膜吸收速率常数K不随药物浓度发生变化。结论:甲磺酸二氢麦角毒碱溶液鼻黏膜吸收机制为被动扩散,吸收符合一级动力学,其鼻黏膜平均吸收速率常数K为5．94×10-3min-1。     

壳聚糖载体对药物鼻腔吸收的促进作用

目的:研究伊文思蓝鼻腔给药壳聚糖载体的促吸收作用及其对鼻腔黏膜的毒性。方法:小鼠鼻腔给伊文思蓝的壳聚糖溶液后,采用荧光显微镜观察脑部伊文思蓝的分布;紫外法测定小鼠脑部其含量;通过鼻腔黏膜切片考察壳聚糖对大鼠鼻腔黏膜毒性。结果:壳聚糖对伊文思蓝经鼻吸收入脑具有促进作用,伊文思蓝在脑前、中、后部均有分布;壳聚糖载体对大鼠鼻黏膜毒性较小。结论:壳聚糖是水溶性药物经鼻吸收入脑的优良载体。     

In vitro activation of the corticosteroid ciclesonide in animal nasal mucosal homogenates

Ciclesonide, a new corticosteroid for allergic rhinitis, is administered as an inactive parent compound that is converted by esterases to the pharmacologically active metabolite, desisobutyryl-ciclesonide (des-CIC). This study investigated the in vitro activation of ciclesonide in nasal mucosa of multiple animal species. Nasal mucosal homogenates from rats, guinea-pigs, rabbits and dogs were incubated with ciclesonide 0.5 micromol/l (0.271 microg/ml) or 5 micromol/l (2.71 microg/ml) for up to 120 min. Concentrations of ciclesonide and des-CIC were measured by high-performance liquid chromatography with tandem mass spectrometry. Ciclesonide was metabolized to des-CIC in nasal mucosal homogenates of each species. The initial velocities of des-CIC formation ranged from 0.0038 to 0.0150 nmol/min/mg protein and 0.0319 to 0.0983 nmol/min/mg protein in nasal mucosal homogenates incubated with ciclesonide 0.5 micromol/l and 5 micromol/l, respectively. Furthermore, the initial velocities of ciclesonide metabolism ranged from 0.0032 to 0.0142 nmol/min/mg protein and 0.0445 to 0.1316 nmol/min/mg protein in nasal mucosal homogenates incubated with ciclesonide 0.5 micromol/l and 5 micromol/l, respectively. This study confirms that ciclesonide is converted to des-CIC in nasal mucosal homogenates without any marked differences among animal species.     

Propylene oxide in blood and soluble nonprotein thiols in nasal mucosa and other tissues of male Fischer 344/N rats exposed to propylene oxide vapors--relevance of glutathione depletion for propylene oxide-induced rat nasal tumors.

High concentrations of propylene oxide (PO) induced inflammation in the respiratory nasal mucosa (RNM) of rodents. Concentrations > or =300 ppm caused nasal tumors. In order to investigate if glutathione depletion could be relevant for these effects, we determined in PO exposed male Fischer 344/N rats PO in blood and soluble nonprotein SH-groups (NPSH) in RNM and other tissues. Rats were exposed once (6 h) to PO concentrations between 0 and 750 ppm, and repeatedly for up to 20 days (6 h, 5 days/week) to concentrations between 0 and 500 ppm. At the end of the exposures, PO in blood and NPSH in tissues were determined. PO in blood was dependent on concentration and duration of exposure. After the 1-day exposures, NPSH depletion was most distinctive (RNM > liver > lung). Compared to controls, NPSH levels were 43% at 50 ppm PO in RNM and 16% at > or =300 ppm in both RNM and liver. Lung NPSH fell linearly to 20% at 750 ppm. After repeated exposures over 3 and 20 days to 5, 25, 50, 300, and 500 ppm, NPSH losses were less pronounced. At both time points, NPSH were 90%, 70%, 50%, 30%, and 30% of the control values in RNM. Liver NPSH decreased to 80% and 50% at 300 and 500 ppm, respectively. After 20 days, lung NPSH declined to 70% (300 ppm) and 50% (500 ppm). We conclude that continuous, severe perturbation of GSH in RNM following repeated high PO exposures may lead to inflammatory lesions and cell proliferation, critical steps on the path towards tumorigenicity.     

脑靶向鼻腔给药的研究进展

目的阐述鼻腔的生理特点和药物由鼻黏膜转运入脑的机制及其影响因素。方法依据近年来的29篇中外文文献,对药物的鼻腔脑靶向实验手段、离体在体模型、鼻黏膜的毒性等方面的研究进展进行阐述。结果鼻黏膜给药途径在脑内递药领域具有独特优势,其在脑部疾病治疗方面具有独到之处,值得进一步深入研究。结论药物的鼻腔脑靶向给药将受到越来越多的关注。     

硝酸铈对豚鼠变应性鼻炎鼻黏膜的影响

目的探讨1%硝酸铈溶液对豚鼠变应性鼻炎鼻黏膜的影响。方法健康豚鼠39只随机分成正常对照组,变应性鼻炎组：用2,4-二异氰酸甲苯酯（2,4-Toluene-Dissocya-nate,TDI）作致敏原,经鼻腔滴入建立变应性鼻炎模型。治疗期间变应性鼻炎组（n=30）动物随机分成3组：阳性对照组（n=10）、药物治疗对照组（n=10）、硝酸铈治疗组（n=10）,正常对照组（n=9）设为阴性对照组,治疗15d。观察症状体征、鼻分泌物涂片、鼻黏膜组胺含量和光镜和电镜下鼻黏膜组织形态学的变化。结果阳性对照组出现鼻痒、喷嚏、流清涕,鼻分泌物嗜酸性粒细胞增多,鼻黏膜组胺含量增多,嗜酸性粒细胞浸润,鼻黏膜细胞超微结构改变。与阳性对照组相比,硝酸铈治疗组上述变化明显减轻。结论 1%硝酸铈溶液能有效控制豚鼠变应性鼻炎的症状体征,使鼻黏膜嗜酸性粒细胞减少、组胺含量减低。     

In vitro metabolism of dexamethasone cipecilate,a novel synthetic corticosteroid,in human liver and nasal mucosa

1. Dexamethasone cipecilate (DX-CP, 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione 21-cyclohexanecarboxylate 17-cyclopropanecarboxylate) is a novel synthetic corticosteroid used to treat allergic rhinitis. The pharmacological effect of DX-CP is considered to be mainly due to its active de-esterified metabolite (DX-17-CPC). To investigate the in vitro metabolism of DX-CP in human liver, DX-CP was incubated with human liver microsomes and S9. In addition, a metabolism study of DX-CP with human nasal mucosa was carried out in order to elucidate whether DX-17-CPC is formed in nasal mucosa, the site of action of DX-CP.

2. DX-17-CPC was the major metabolite in both liver microsomes and S9. Two new epoxide metabolites, UK1 and UK2, were detected in liver S9, while only UK1 was detected in liver microsomes. This suggests that cytosol enzymes are responsible for the formation of UK2.

3. In human nasal mucosa, DX-CP was mainly transformed into DX-17-CPC. By using recombinant human carboxylesterases (CESs), the reaction was shown to be catalyzed by CES2.

4. These results provide the evidence that the active metabolite DX-17-CPC is the main contributor to the pharmacological action after the intranasal administration of DX-CP to humans.

     

Histopathological changes of the nasal mucosa induced by smoking

Changes in the histopathology of the respiratory epithelium in response to cigarette smoking have been studied in depth in the lungs, but data on the nasal lining are lacking. The aim of the present retrospective study was to investigate the histological changes that occur in the nasal mucosa of smokers compared with non-smokers. The study group included 47 patients who underwent partial resection of the inferior turbinates. Archival nasal tissue samples were collected and examined by light microscopy: the number of goblet cells was counted, and the degree of inflammation, congestion, and edema was graded as mild, moderate, or severe. Epithelial thickness was measured as well. Findings were compared between smokers (n?=?21) and non-smokers (n?=?26). On statistical analysis, significant differences were found between the smokers and non-smokers in mean number of goblet cells in the nasal epithelium, 43.43?±?16.80 vs. 16.23?±?5.65 respectively (p?<?0.0001), mean edema grade, 2.43?±?0.75 vs. 1.12?±?0.33 respectively (p?<?0.0001), and mean epithelial thickness, 111.9?±?25.8 μm vs. 60.4?±?18.4 μm respectively (p?<?0.0001). The corresponding mean values of congestion were 2?±?0.71 and 1.27?±?0.67 (p < 0.001), and of inflammation, 1.81?±?0.60 and 1.81?±?0.85 (NS). In conclusion, the histopathological findings in the nasal mucosa of smokers resemble reported findings in the bronchial respiratory epithelium. The main differences from non-smokers are greater goblet cell hyperplasia and thicker epithelium.     

Postnatal toxicity of chronically administered paraquat in mice and interactions with oxygen and bromobenzene.

The purpose of this study was to investigate the effect of chronic paraquat administration on developing mice and to examine the interaction of chronic paraquat exposure with 100% oxygen and the hepatotoxin bromobenzene. Paraquat was administered at 50 and 100 ppm in the drinking water to pregnant mice beginning at Day 8 of gestation, with continued exposure to the newborns up to 42 days after birth. Neither paraquat treatment altered the postnatal growth rate; however, 100 ppm but not 50 ppm paraquat significantly increased the postnatal mortality. Both 50- and 100-ppm paraquat-treated mice were sensitized to the onset of oxygen toxicity, determined by a significant reduction in the LT50 at 42 days after birth. An enhanced sensitivity to oxygen toxicity was also detectable in 100 ppm but not 50 ppm mice at Days 1 and 28 after birth. In 42-day-old mice, 50 and 100 ppm paraquat treatment also significantly reduced the LT50 after 3100 mg/kg ip (LD85) bromobenzene. These observations suggest that the toxicity of paraquat may be mediated through an interaction with oxygen and describe possible interactions that could occur with the environmental use of paraquat.     

蛋白激酶C、Bcl-2及Bax在变应性鼻炎鼻黏膜中的表达及意义

目的探讨变应性鼻炎（AR）患者鼻黏膜蛋白激酶C（PKC）、抗凋亡基因Bcl-2及促凋亡基因Bax蛋白的表达水平,以进一步了解AR的发病机制。方法应用免疫组织化学的方法检测26例AR患者（AR组）鼻黏膜及10例下鼻甲组织中（对照组）PKC、Bcl-2及Bax的表达。结果PKC、Bcl-2及Bax在2组中均有表达,AR组中PKC主要表达在嗜酸粒细胞、血管内皮细胞及腺体细胞,Bcl-2蛋白主要表达于鼻黏膜腺体细胞和上皮层,与对照组相比差异有统计学意义（P〈0.01）。Bax蛋白与Bcl-2蛋白表达部位一致,2组表达水平差异无统计学意义（P〉0.05）。结论AR鼻黏膜蛋白激酶C、抗凋亡基因Bcl-2蛋白表达上调,是AR嗜酸粒细胞增多、鼻分泌物增多及鼻黏膜上皮破坏的机制之一。     

Nephrotoxicity of phenolic bromobenzene metabolites in the mouse

Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 μmol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53–2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in adose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced in vivo administration of 4-bromocatechol could not be distinguishe histogically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.