嗅神经及其伴行静脉的临床解剖学研究
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摘要
目的观察嗅神经及其伴行静脉在显微解剖、组织学及影像图像上的形态特征,完善嗅神经的形态学资料,探讨筛孔静脉在颅内外感染中的意义,为鼻腔顶部、颅前窝等手术中保护病人嗅觉功能提供临床解剖学资料,为经鼻给药通路治疗中枢神经系统疾病提供形态学依据。
方法①选取成人头颅湿标本30例(60侧)经灌注明胶颜料后显微解剖观察嗅神经的走形和分布、颅前窝底和面部静脉的走行和分布,另选5例(10侧)成人头颅湿标本灌注墨水和造影剂,经显微解剖后取下嗅粘膜,进行X线扫描;②选取成人头颅干性标本30例(60侧)进行显微解剖学观测;③随机选取3例(6侧)经灌注明胶颜料的上述湿性标本,从每例标本的上鼻甲和鼻中隔粘膜上分别取2块组织,共12块,进行HE染色和VG染色,观察嗅神经及其伴行静脉的组织学特点;④收集51例(97侧)经证实无面部静脉异常的全脑血管数字减影血管造影(DSA)系列图像的静脉相,观察颅前窝底及面部静脉的走行和分布。
结果1、嗅神经的形态观察:①显微解剖发现嗅神经(嗅丝)由硬脑膜形成的嗅鞘包裹,嗅鞘内存在一潜在的腔隙。嗅神经位于嗅粘膜上,呈马蹄铁型分布,分鼻甲侧和鼻中隔侧。鼻甲侧嗅神经分布于上鼻甲和中鼻甲垂直部粘膜的筛骨面,鼻中隔侧嗅神经分布于鼻中隔粘膜的筛骨面,鼻甲和鼻中隔粘膜的鼻腔面未见嗅神经分布。鼻甲侧嗅神经数为(10.33±1.81)条,嗅神经根部直径为(0.90±0.22)mm。鼻中隔侧嗅神经数为(6.28±1.04)条,嗅神经根部直径为(1.17±0.24)mm。嗅粘膜鼻中隔侧嗅神经长度为(5.91±1.95)mm,医学参考值范围(95%)上限为9.73 mm;嗅粘膜鼻甲侧嗅神经长度为(10.22±2.20)mm,医学参考值范围(95%)上限为14.53 mm。干性标本观察发现每侧筛孔分布呈两列,分别与嗅神经的鼻甲侧和鼻中隔侧相对应。每侧筛孔数为(16.33±2.79)个,筛孔最大径为(1.09±0.52)mm。②HE染色和VG染色可见嗅区粘膜表面的嗅上皮为假复层柱状上皮,固有层多为结缔组织,嗅神经内膜、束膜和外膜清晰可见,神经外膜外可见由一层致密的结缔组织围成的嗅鞘结构。③X片可见嗅鞘内可以透过造影剂。2、筛孔静脉的形态观察:①显微解剖发现,筛孔静脉走行于嗅鞘内,与嗅神经伴行,通过筛孔向颅内引流,与颅内的嗅静脉、额叶皮质静脉或硬膜静脉相交通。②HE染色可见筛孔静脉位于嗅鞘内,管壁较薄。VG染色未见筛孔静脉中膜含有平滑肌细胞。③DSA发现68.6%的成人存在筛孔静脉使面部静脉与颅内静脉直接交通,筛孔静脉入颅后与额叶皮质静脉或额下静脉吻合。
结论①深入系统的观察嗅神经及其伴行静脉,丰富了解剖学和影像学资料;②熟悉嗅神经的形态特征,有助于神经外科手术入路的选择和手术过程中更好地保护嗅神经,避免术后并发症的发生;③嗅粘膜鼻中隔侧距筛板下10 mm,鼻甲侧距筛板下15 mm以外极少存在嗅神经,在此范围手术操作较为安全;④人的面部静脉与颅内静脉之间存在经筛孔静脉直接交通的途径,这一途径可能是颅内外感染更为直接的通路;⑤嗅鞘结构和筛孔静脉的存在,为经鼻给药治疗中枢神经系统疾病提供了可能的形态学依据。
Objectives To provide morphological data of olfactory nerves for preserving olfactory function in the operation of nasal cavity roof and anterior cranial fossae, to study the significance of cribriform foramina vein in intra- and extracranial infection, and to provide a possible pathway how nasal administration deliver drugs into the brain to treat central nervous system diseases, morphological features of olfactory nerve and its accompanying vein were observed by way of microanatomy, histology and imageology.
Methods①Thirty formalin fixed adult cadaver heads (60 sides) perfused with gelatin and pigment were employed by microanatomy dissection to observe the morphological features of olfactory nerve and its accompanying vein. Another five (10 sides) formalin fixed adult cadaver heads which were injected with constrast medium via cribriform foramina, were scanned by X-ray.②Thirty dry skulls (60 sides) were observed by microanatomy dissection.③From the 30 formalin fixed adult cadaver heads mentioned above, we dissected superior nasal concha and septum mucosa in three (6 sides) specimen, then selecting 2 parts of olfactory mucosa and 2 olfactory nerves randomly in each specimen to do HE and VG staining.④Cerebral angiograms of 51 patients who underwented DSA without abnormal craniofacial veins were obtained to investigate the cribriform foramina vein.
Results 1, Morphology of olfactory nerves:①The dura mater which surrounded olfactory nerves thinned out and became continuous with the periosteum in the ethmoid bone. A larvaceous space was identified around the dural sheath of olfactory nerves as they exited the cribriform foramina. Olfactory nerves which were dividied into nasal concha group and septum group looked like horseshoes. Nasal concha group were located at the ethmoid bone side of superior nasal concha mucosa while septum group were located at the ethmoid bone side of septum mucosa. In nasal cavity side of nasal concha mucosa and septum mucosa, no olfactory nerves were found. The number of fila olfactoria was (10.33±1.81) and diameter of fila olfactoria root was (0.90±0.22) mm in nasal concha group compared with (6.28±1.04) and (1.17±0.24) mm in septum group. The length of fila olfactoria was (10.22±2.20) mm in nasal concha group and the upper limit of medical reference value(95%) was 14.53 mm compared with (5.91±1.95) mm and the upper limit of medical reference value(95%) 9.73 mm in septum group,. In the dry skulls, we found cribriform foramina divided into two sides, each side corresponding nasal concha group and septum group olfactory nerve.The number of cribriform foramina in each side was (16.33±2.79), longer diameter of cribriform foramina was (1.09±0.52) mm.②Olfactory nerves and cribriform foramina veins were found in the sheath of olfactory nerves. The dural sheath of olfactory nerves could be observed outside of epineurium by HE and VG staining.③The dural sheath of olfactory nerve developed an image in X-ray film. It certified that the sheath could penetrate constrast medium. 2, Morphology of cribriform foramina vein:①Microanatomical dissection showed cribriform foramina veins accompanied with olfactory nerves passed inside the dural sheath of olfactory nerves. Cribriform foramina vein could passed through the cribriform foramina and continued its course intracranially as a olfactory vein or frontal cortical vein or dura mater vein.②By HE staining, we found that olfactory epithelium on the surface of olfactory region mucosa was pseudostratified columnar epithelium, the lamina propria of the olfactory region mucosa was mainly about connective tissue and many veins cut through it. Olfactory nerves were also found in the lamina propria. The epineurium, perineurium and endoneurium of olfactory nerve could be seen clearly outside the nerve. Inside of the dural sheath of olfactory nerve, one or more cribriform foramina veins were found around olfactory nerve.③DSA angiograms showed that about 68.6% patient exist a portion of the nasal mucosa drained intracranially via cribriform foramina vein that crossed the floor of the anterior cranial fossa to continue as a frontal cortical vein or inferior frontal vein.
Conclusion①Study the olfactory nerve and its accompanying vein systematically and comprehensively, enriched related anatomy knowledge.②Study the anatomical features, which help to preserve olfactory nerve and its accompanying vein in neurosurgical planning and procedure to avoid postoperative complications.③Olfactory nerves extended only 10 mm or less below cribriform plate in nasal septum group and 15 mm or less below cribriform plate in nasal concha group, thus cutting the nasal septum 10 mm below the cribriform plate and the nasal concha 15 mm below the cribriform plate should preserve olfaction.④Cribriform foramina vein may be a direct communication connecting the nasal and paranasal mucosa to intracranial vein. This vein may be a direct pathway of intra- and extracranial infection.⑤The existence of dural sheath of olfactory nerve and cribriform foramina vein would provide a direct pathway delivering drugs into the brain from nasal administration to treat central nervous system diseases.
方法①选取成人头颅湿标本30例(60侧)经灌注明胶颜料后显微解剖观察嗅神经的走形和分布、颅前窝底和面部静脉的走行和分布,另选5例(10侧)成人头颅湿标本灌注墨水和造影剂,经显微解剖后取下嗅粘膜,进行X线扫描;②选取成人头颅干性标本30例(60侧)进行显微解剖学观测;③随机选取3例(6侧)经灌注明胶颜料的上述湿性标本,从每例标本的上鼻甲和鼻中隔粘膜上分别取2块组织,共12块,进行HE染色和VG染色,观察嗅神经及其伴行静脉的组织学特点;④收集51例(97侧)经证实无面部静脉异常的全脑血管数字减影血管造影(DSA)系列图像的静脉相,观察颅前窝底及面部静脉的走行和分布。
结果1、嗅神经的形态观察:①显微解剖发现嗅神经(嗅丝)由硬脑膜形成的嗅鞘包裹,嗅鞘内存在一潜在的腔隙。嗅神经位于嗅粘膜上,呈马蹄铁型分布,分鼻甲侧和鼻中隔侧。鼻甲侧嗅神经分布于上鼻甲和中鼻甲垂直部粘膜的筛骨面,鼻中隔侧嗅神经分布于鼻中隔粘膜的筛骨面,鼻甲和鼻中隔粘膜的鼻腔面未见嗅神经分布。鼻甲侧嗅神经数为(10.33±1.81)条,嗅神经根部直径为(0.90±0.22)mm。鼻中隔侧嗅神经数为(6.28±1.04)条,嗅神经根部直径为(1.17±0.24)mm。嗅粘膜鼻中隔侧嗅神经长度为(5.91±1.95)mm,医学参考值范围(95%)上限为9.73 mm;嗅粘膜鼻甲侧嗅神经长度为(10.22±2.20)mm,医学参考值范围(95%)上限为14.53 mm。干性标本观察发现每侧筛孔分布呈两列,分别与嗅神经的鼻甲侧和鼻中隔侧相对应。每侧筛孔数为(16.33±2.79)个,筛孔最大径为(1.09±0.52)mm。②HE染色和VG染色可见嗅区粘膜表面的嗅上皮为假复层柱状上皮,固有层多为结缔组织,嗅神经内膜、束膜和外膜清晰可见,神经外膜外可见由一层致密的结缔组织围成的嗅鞘结构。③X片可见嗅鞘内可以透过造影剂。2、筛孔静脉的形态观察:①显微解剖发现,筛孔静脉走行于嗅鞘内,与嗅神经伴行,通过筛孔向颅内引流,与颅内的嗅静脉、额叶皮质静脉或硬膜静脉相交通。②HE染色可见筛孔静脉位于嗅鞘内,管壁较薄。VG染色未见筛孔静脉中膜含有平滑肌细胞。③DSA发现68.6%的成人存在筛孔静脉使面部静脉与颅内静脉直接交通,筛孔静脉入颅后与额叶皮质静脉或额下静脉吻合。
结论①深入系统的观察嗅神经及其伴行静脉,丰富了解剖学和影像学资料;②熟悉嗅神经的形态特征,有助于神经外科手术入路的选择和手术过程中更好地保护嗅神经,避免术后并发症的发生;③嗅粘膜鼻中隔侧距筛板下10 mm,鼻甲侧距筛板下15 mm以外极少存在嗅神经,在此范围手术操作较为安全;④人的面部静脉与颅内静脉之间存在经筛孔静脉直接交通的途径,这一途径可能是颅内外感染更为直接的通路;⑤嗅鞘结构和筛孔静脉的存在,为经鼻给药治疗中枢神经系统疾病提供了可能的形态学依据。
Objectives To provide morphological data of olfactory nerves for preserving olfactory function in the operation of nasal cavity roof and anterior cranial fossae, to study the significance of cribriform foramina vein in intra- and extracranial infection, and to provide a possible pathway how nasal administration deliver drugs into the brain to treat central nervous system diseases, morphological features of olfactory nerve and its accompanying vein were observed by way of microanatomy, histology and imageology.
Methods①Thirty formalin fixed adult cadaver heads (60 sides) perfused with gelatin and pigment were employed by microanatomy dissection to observe the morphological features of olfactory nerve and its accompanying vein. Another five (10 sides) formalin fixed adult cadaver heads which were injected with constrast medium via cribriform foramina, were scanned by X-ray.②Thirty dry skulls (60 sides) were observed by microanatomy dissection.③From the 30 formalin fixed adult cadaver heads mentioned above, we dissected superior nasal concha and septum mucosa in three (6 sides) specimen, then selecting 2 parts of olfactory mucosa and 2 olfactory nerves randomly in each specimen to do HE and VG staining.④Cerebral angiograms of 51 patients who underwented DSA without abnormal craniofacial veins were obtained to investigate the cribriform foramina vein.
Results 1, Morphology of olfactory nerves:①The dura mater which surrounded olfactory nerves thinned out and became continuous with the periosteum in the ethmoid bone. A larvaceous space was identified around the dural sheath of olfactory nerves as they exited the cribriform foramina. Olfactory nerves which were dividied into nasal concha group and septum group looked like horseshoes. Nasal concha group were located at the ethmoid bone side of superior nasal concha mucosa while septum group were located at the ethmoid bone side of septum mucosa. In nasal cavity side of nasal concha mucosa and septum mucosa, no olfactory nerves were found. The number of fila olfactoria was (10.33±1.81) and diameter of fila olfactoria root was (0.90±0.22) mm in nasal concha group compared with (6.28±1.04) and (1.17±0.24) mm in septum group. The length of fila olfactoria was (10.22±2.20) mm in nasal concha group and the upper limit of medical reference value(95%) was 14.53 mm compared with (5.91±1.95) mm and the upper limit of medical reference value(95%) 9.73 mm in septum group,. In the dry skulls, we found cribriform foramina divided into two sides, each side corresponding nasal concha group and septum group olfactory nerve.The number of cribriform foramina in each side was (16.33±2.79), longer diameter of cribriform foramina was (1.09±0.52) mm.②Olfactory nerves and cribriform foramina veins were found in the sheath of olfactory nerves. The dural sheath of olfactory nerves could be observed outside of epineurium by HE and VG staining.③The dural sheath of olfactory nerve developed an image in X-ray film. It certified that the sheath could penetrate constrast medium. 2, Morphology of cribriform foramina vein:①Microanatomical dissection showed cribriform foramina veins accompanied with olfactory nerves passed inside the dural sheath of olfactory nerves. Cribriform foramina vein could passed through the cribriform foramina and continued its course intracranially as a olfactory vein or frontal cortical vein or dura mater vein.②By HE staining, we found that olfactory epithelium on the surface of olfactory region mucosa was pseudostratified columnar epithelium, the lamina propria of the olfactory region mucosa was mainly about connective tissue and many veins cut through it. Olfactory nerves were also found in the lamina propria. The epineurium, perineurium and endoneurium of olfactory nerve could be seen clearly outside the nerve. Inside of the dural sheath of olfactory nerve, one or more cribriform foramina veins were found around olfactory nerve.③DSA angiograms showed that about 68.6% patient exist a portion of the nasal mucosa drained intracranially via cribriform foramina vein that crossed the floor of the anterior cranial fossa to continue as a frontal cortical vein or inferior frontal vein.
Conclusion①Study the olfactory nerve and its accompanying vein systematically and comprehensively, enriched related anatomy knowledge.②Study the anatomical features, which help to preserve olfactory nerve and its accompanying vein in neurosurgical planning and procedure to avoid postoperative complications.③Olfactory nerves extended only 10 mm or less below cribriform plate in nasal septum group and 15 mm or less below cribriform plate in nasal concha group, thus cutting the nasal septum 10 mm below the cribriform plate and the nasal concha 15 mm below the cribriform plate should preserve olfaction.④Cribriform foramina vein may be a direct communication connecting the nasal and paranasal mucosa to intracranial vein. This vein may be a direct pathway of intra- and extracranial infection.⑤The existence of dural sheath of olfactory nerve and cribriform foramina vein would provide a direct pathway delivering drugs into the brain from nasal administration to treat central nervous system diseases.
引文
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43. Wayne George Kleintjes. Forehead anatomy: Arterial variations and venous link of the midline forehead flap. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2007, 60:593-606.
44.张致身.人脑血管解剖与临床.第1版.北京:科学技术文献出版社, 2004: 223-275.
45. Frey WH 2nd. Neurologic agents for nasal administration the brain. World Intellectual Property Organization. 1991, 7:947.
46. Vyas TK, Shahiwala A, Marathe S, et al. Intranasal drug delivery for brain targeting. Curr Drug Deliv. 2005, 2(2):165-175.
47. Kern W, Born J, Schreiber H, et al. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes, 1999, 48:557-563.
48. Shelley K, Paech MJ. The clinical applications of intranasal opioids. Curr Drug Deliv. 2008, 5(1):55-58.
49. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006, 46(Suppl 4):192-201.
50. Costantino HR, Illum L, Brandt G, et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007, 337(1-2):1-24.
51. Okuyama S. The first attempt at radioisotopic evaluation of the integrity of the nose-brain barrier. Life Sci. 1997, 60(21):1881-1884.
52. Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002, 5(6):514-516.
53.赵红梅,刘新峰.经鼻给药—有效避开血脑屏障的中枢用药途径.中国临床神经科学, 2003, 11(3):320-322.
54. Thorne RG, Emory CR,Ala TA,et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res, 1995, 692:278-282.
55. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000, 11(1):1-18.
56. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006, 46 Suppl 4:192-201.
1. Hanson LR, Frey WH 2nd. Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS. J Neuroimmune Pharmacol. 2007, 2(1):81-86.
2. Vyas TK, Tiwari SB, Amiji MM. Formulation and physiological factors influencing CNS delivery upon intranasal administration. Crit Rev Ther Drug Carrier Syst. 2006, 23(4):319-347.
3. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006, 46 Suppl 4:192-201.
4. Merkus FW, van den Berg MP. Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory. Drugs R D. 2007, 8(3):133-144.
5. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005, 2(1):3-14.
6. Pan W, Kastin AJ. Polypeptide delivery across the blood-brain barrier. Curr Drug Targets CNS Neurol Disord. 2004, 3(2):131-136.
7. Pardridge WM. Blood-brain barrier drug targeting enables neuroprotection in brain ischemia following delayed intravenous administration of neurotrophins. Adv Exp Med Biol. 2002, 513:397-430.
8. Calabria AR, Shusta EV. Blood-brain barrier genomics and proteomics: elucidating phenotype, identifying disease targets and enabling brain drug delivery. Drug Discov Today. 2006, 11(17-18):792-799.
9. Thorne RG, Emory CR, Ala TA, et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res, 1995, 692:278-282.
10. Frey WH, Liu J, Thorne RG, et al. Intrannsal delivery of 125I-labeled nerve growth factor to the brain via the olfactory route.In:Iqbal K, Mortimer JA, Winblad R,et al,eds. Research advances in Alzheimer’s disease and related disorders. Chichester: John Wiley & Sons Ltd, 1995:329-335.
11. Chen XQ, Fawcett JR, Rahman YE, et al. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis, 1998, 1:35-44.
12. N Jones, The nose and paranasal sinuses physiology and anatomy, Adv. Drug Deliv. Rev. 2001, 5:15–19.
13. Hornung DE. Nasal anatomy and the sense of smell. Adv Otorhinolaryngol. 2006, 63:1-22.
14.卜国铉.鼻科学.第2版.上海:上海科学技术出版社, 2000:26-75.
15. HilgerPA .Applied anatomy and physiology of the nose. In Adams, GL, Boies LR, Hilger PA ,editors.Boies's Fundamental of Otolaryngology 6th ed. Philadelphia,Saumders,1989:177-195.
16. Madara JL, Barenberg D, Carlson S. Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol. 1986, 102(6):2125-2136.
17. Citi S. Protein kinase inhibitors prevent junction dissociation induced by low extracellular calcium in MDCK epithelial cells. J Cell Biol. 1992, 117(1):169-178.
18.朱长庚.神经解剖学.第一版.北京:人民卫生出版社,2002:994-1003.
19. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000, 11(1):1-18.
20. Reiss CS, Plakhov IV, Komatsu, T. Viral replication in the olfactory receptorneurons and entry into the olfactory bulb and brain. Ann. NY Acad. Sci. 1998, 30: 751–761.
21. Frey WH 2nd. Neurologic agents for nasal administration the brain.World Intellectual Property Organization.1991:947.
22. Thorne, RG, Frey WH 2nd. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet. 2001, 40(12): 907–946.
23. Frey WH 2nd. Bypassing the blood–brain barrier to delivery thereapeutic agents to the brain and spinal cord. Drug Deliv Technol.2002, 5:46–49.
24. Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain.Nat Neurosci.2002, 5: 514–516.
25. Illum L. Nasal drug delivery-possibilities, problems and solutions. Journal of Controlled Release 2003, 87: 187–198.
26. Kristensson K, Olsson Y,. Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol. 1971, 19: 145–154.
27. Wang Y, Aun R, Tse FLS. Brain uptake of dihydroergotamine after intravenous and nasal administration in the rat. Biopharm. Drug Dispos. 1998, 19: 571–575.
28. Chou KJ, Donovan MD. Distribution of antihistamines into the CSF following intranasal delivery. Biopharm. Drug Dispos. 1997, 18: 335–346.
29. Chow HS, Chen Z, Natsuura GT. Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J. Pharm. Sci. 1999, 88: 754–758.
30. Faber HK. The early lesions of poliomyelitis after intranasal inoculation. J.Pediatr. 1938, 13: 10–37.
31. Okuyama S. The first attempt at radioisotopic evaluation of the integrity of the nose-brain barrier. Life Sci. 1997, 60(21):1881-1884.
32. Costantino HR, Illum L, Brandt G, et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007, 337(1-2):1-24.
33. Shelley K, Paech MJ. The clinical applications of intranasal opioids. Curr Drug Deliv. 2008, 5(1):55-58.
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16. Pan W, Kastin AJ. Polypeptide delivery across the blood-brain barrier. Curr Drug Targets CNS Neurol Disord. 2004, 3(2):131-136.
17. Pardridge WM. Blood-brain barrier drug targeting enables neuroprotection in brain ischemia following delayed intravenous administration of neurotrophins. Adv Exp Med Biol. 2002, 513:397-430.
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42. Schaller B. Physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. Brain Res Brain Res Rev. 2004, 46(3):243-260.
43. Wayne George Kleintjes. Forehead anatomy: Arterial variations and venous link of the midline forehead flap. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2007, 60:593-606.
44.张致身.人脑血管解剖与临床.第1版.北京:科学技术文献出版社, 2004: 223-275.
45. Frey WH 2nd. Neurologic agents for nasal administration the brain. World Intellectual Property Organization. 1991, 7:947.
46. Vyas TK, Shahiwala A, Marathe S, et al. Intranasal drug delivery for brain targeting. Curr Drug Deliv. 2005, 2(2):165-175.
47. Kern W, Born J, Schreiber H, et al. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes, 1999, 48:557-563.
48. Shelley K, Paech MJ. The clinical applications of intranasal opioids. Curr Drug Deliv. 2008, 5(1):55-58.
49. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006, 46(Suppl 4):192-201.
50. Costantino HR, Illum L, Brandt G, et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007, 337(1-2):1-24.
51. Okuyama S. The first attempt at radioisotopic evaluation of the integrity of the nose-brain barrier. Life Sci. 1997, 60(21):1881-1884.
52. Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002, 5(6):514-516.
53.赵红梅,刘新峰.经鼻给药—有效避开血脑屏障的中枢用药途径.中国临床神经科学, 2003, 11(3):320-322.
54. Thorne RG, Emory CR,Ala TA,et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res, 1995, 692:278-282.
55. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000, 11(1):1-18.
56. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006, 46 Suppl 4:192-201.
1. Hanson LR, Frey WH 2nd. Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS. J Neuroimmune Pharmacol. 2007, 2(1):81-86.
2. Vyas TK, Tiwari SB, Amiji MM. Formulation and physiological factors influencing CNS delivery upon intranasal administration. Crit Rev Ther Drug Carrier Syst. 2006, 23(4):319-347.
3. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006, 46 Suppl 4:192-201.
4. Merkus FW, van den Berg MP. Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory. Drugs R D. 2007, 8(3):133-144.
5. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005, 2(1):3-14.
6. Pan W, Kastin AJ. Polypeptide delivery across the blood-brain barrier. Curr Drug Targets CNS Neurol Disord. 2004, 3(2):131-136.
7. Pardridge WM. Blood-brain barrier drug targeting enables neuroprotection in brain ischemia following delayed intravenous administration of neurotrophins. Adv Exp Med Biol. 2002, 513:397-430.
8. Calabria AR, Shusta EV. Blood-brain barrier genomics and proteomics: elucidating phenotype, identifying disease targets and enabling brain drug delivery. Drug Discov Today. 2006, 11(17-18):792-799.
9. Thorne RG, Emory CR, Ala TA, et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res, 1995, 692:278-282.
10. Frey WH, Liu J, Thorne RG, et al. Intrannsal delivery of 125I-labeled nerve growth factor to the brain via the olfactory route.In:Iqbal K, Mortimer JA, Winblad R,et al,eds. Research advances in Alzheimer’s disease and related disorders. Chichester: John Wiley & Sons Ltd, 1995:329-335.
11. Chen XQ, Fawcett JR, Rahman YE, et al. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis, 1998, 1:35-44.
12. N Jones, The nose and paranasal sinuses physiology and anatomy, Adv. Drug Deliv. Rev. 2001, 5:15–19.
13. Hornung DE. Nasal anatomy and the sense of smell. Adv Otorhinolaryngol. 2006, 63:1-22.
14.卜国铉.鼻科学.第2版.上海:上海科学技术出版社, 2000:26-75.
15. HilgerPA .Applied anatomy and physiology of the nose. In Adams, GL, Boies LR, Hilger PA ,editors.Boies's Fundamental of Otolaryngology 6th ed. Philadelphia,Saumders,1989:177-195.
16. Madara JL, Barenberg D, Carlson S. Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol. 1986, 102(6):2125-2136.
17. Citi S. Protein kinase inhibitors prevent junction dissociation induced by low extracellular calcium in MDCK epithelial cells. J Cell Biol. 1992, 117(1):169-178.
18.朱长庚.神经解剖学.第一版.北京:人民卫生出版社,2002:994-1003.
19. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000, 11(1):1-18.
20. Reiss CS, Plakhov IV, Komatsu, T. Viral replication in the olfactory receptorneurons and entry into the olfactory bulb and brain. Ann. NY Acad. Sci. 1998, 30: 751–761.
21. Frey WH 2nd. Neurologic agents for nasal administration the brain.World Intellectual Property Organization.1991:947.
22. Thorne, RG, Frey WH 2nd. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet. 2001, 40(12): 907–946.
23. Frey WH 2nd. Bypassing the blood–brain barrier to delivery thereapeutic agents to the brain and spinal cord. Drug Deliv Technol.2002, 5:46–49.
24. Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain.Nat Neurosci.2002, 5: 514–516.
25. Illum L. Nasal drug delivery-possibilities, problems and solutions. Journal of Controlled Release 2003, 87: 187–198.
26. Kristensson K, Olsson Y,. Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol. 1971, 19: 145–154.
27. Wang Y, Aun R, Tse FLS. Brain uptake of dihydroergotamine after intravenous and nasal administration in the rat. Biopharm. Drug Dispos. 1998, 19: 571–575.
28. Chou KJ, Donovan MD. Distribution of antihistamines into the CSF following intranasal delivery. Biopharm. Drug Dispos. 1997, 18: 335–346.
29. Chow HS, Chen Z, Natsuura GT. Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J. Pharm. Sci. 1999, 88: 754–758.
30. Faber HK. The early lesions of poliomyelitis after intranasal inoculation. J.Pediatr. 1938, 13: 10–37.
31. Okuyama S. The first attempt at radioisotopic evaluation of the integrity of the nose-brain barrier. Life Sci. 1997, 60(21):1881-1884.
32. Costantino HR, Illum L, Brandt G, et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007, 337(1-2):1-24.
33. Shelley K, Paech MJ. The clinical applications of intranasal opioids. Curr Drug Deliv. 2008, 5(1):55-58.