Search tips
Search criteria 


Logo of neurotherwww.springer.comThis journalToc AlertsSubmit OnlineOpen Choice
Neurotherapeutics. 2009 April; 6(2): 323–336.
PMCID: PMC2673491

Nanotechnology for delivery of drugs to the brain for epilepsy


Epilepsy results from aberrant electrical activity that can affect either a focal area or the entire brain. In treating epilepsy with drugs, the aim is to decrease seizure frequency and severity while minimizing toxicity to the brain and other tissues. Antiepileptic drugs (AEDs) are usually administered by oral and intravenous routes, but these drug treatments are not always effective. Drug access to the brain is severely limited by a number of biological factors, particularly the blood—brain barrier, which impedes the ability of AEDs to enter and remain in the brain. To improve the efficacy of AEDs, new drug delivery strategies are being developed; these methods fall into the three main categories: drug modification, blood—brain barrier modification, and direct drug delivery. Recently, all three methods have been improved through the use of drug-loaded nanoparticles.

Key Words: Epilepsy, seizures, antiepileptic drugs, blood—brain barrier, CNS delivery, drug delivery systems


1. De Tiège X, Laufs H, Boyd SG, et al. EEG-fMRI in children with pharmacoresistant focal epilepsy. Epilepsia. 2007;48:385–389. doi: 10.1111/j.1528-1167.2006.00951.x. [PubMed] [Cross Ref]
2. Pardridge WM. Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv. 2003;3:90–105. doi: 10.1124/mi.3.2.90. [PubMed] [Cross Ref]
3. Barnett GH. High-grade gliomas: diagnosis and treatment. Totowa, NJ: Humana Press; 2006.
4. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53. doi: 10.1038/nrn1824. [PubMed] [Cross Ref]
5. Fisher RS, Ho J. Potential new methods for antiepileptic drug delivery. CNS Drugs. 2002;16:579–593. doi: 10.2165/00023210-200216090-00001. [PubMed] [Cross Ref]
6. Müller RH. Colloidal carriers for controlled drug delivery and targeting: modification, characterization, and in vivo distribution. Boca Raton, FL: CRC Press; 1991.
7. Yang SC, Lu LF, Cai Y, Zhu JB, Liang BW, Yang CZ. Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. J Control Release. 1999;59:299–307. doi: 10.1016/S0168-3659(99)00007-3. [PubMed] [Cross Ref]
8. Muller RH, Petersen RD, Hommoss A, Pardeike J. Nanostructured lipid carriers (NLC) in cosmetic dermal products. Adv Drug Deliv Rev. 2007;59:522–530. doi: 10.1016/j.addr.2007.04.012. [PubMed] [Cross Ref]
9. Saad M, Garbuzenko OB, Ber E, et al. Receptor targeted polymers, dendrimers, liposomes: which nanocarrier is the most efficient for tumor-specific treatment and imaging? J Control Release. 2008;130:107–114. doi: 10.1016/j.jconrel.2008.05.024. [PMC free article] [PubMed] [Cross Ref]
10. Klingeler R, Hampel S, Büchner B. Carbon nanotube based biomedical agents for heating, temperature sensing and drug delivery. Int J Hyperthermia. 2008;24:496–505. doi: 10.1080/02656730802154786. [PubMed] [Cross Ref]
11. Couvreur P, Vauthier C. Nanotechnology: intelligent design to treat complex disease. Pharm Res. 2006;23:1417–1450. doi: 10.1007/s11095-006-0284-8. [PubMed] [Cross Ref]
12. Barratt GM. Therapeutic applications of colloidal drug carriers. Pharm Sci Technolo Today. 2000;3:163–171. doi: 10.1016/S1461-5347(00)00255-8. [PubMed] [Cross Ref]
13. Sharma A, Sharma US. Liposomes in drug delivery: progress and limitations. Int J Pharm. 1997;154:123–140. doi: 10.1016/S0378-5173(97)00135-X. [Cross Ref]
14. Dutt M, Khuller GK. Liposomes and PLG microparticles as sustained release antitubercular drug carriers: an in vitro-in vivo study. Int J Antimicrob Agents. 2001;18:245–252. doi: 10.1016/S0924-8579(01)00373-9. [PubMed] [Cross Ref]
15. Verdun C, Brasseur F, Vranckx H, Couvreur P, Roland M. Tissue distribution of doxorubicin associated with polyisohexylcyanoacrylate nanoparticles. Cancer Chemother Pharmacol. 1990;26:13–18. doi: 10.1007/BF02940287. [PubMed] [Cross Ref]
16. Date AA, Joshi MD, Patravale VB. Parasitic diseases: liposomes and polymeric nanoparticles versus lipid nanoparticles. Adv Drug Deliv Rev. 2007;59:505–521. doi: 10.1016/j.addr.2007.04.009. [PubMed] [Cross Ref]
17. Thome RG, Nicholson C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A. 2006;103:5567–5572. doi: 10.1073/pnas.0509425103. [PubMed] [Cross Ref]
18. Birnbaum DT, Kosmala JD, Brannon-Peppas L. Optimization of preparation techniques for poly(lactic acid-co-glycolic acid) nanoparticles. J Nanoparticle Res. 2000;2:173–181. doi: 10.1023/A:1010038908767. [Cross Ref]
19. Ito F, Fujimori H, Makino K. Incorporation of water-soluble drugs in PLGA microspheres. Colloids Surf B Biointerfaces. 2007;54:173–178. doi: 10.1016/j.colsurfb.2006.10.019. [PubMed] [Cross Ref]
20. MacKay J, Deen DF, Szoka FC. Distribution in brain of liposomes after convection enhanced delivery: modulation by particle charge, particle diameter, and presence of steric coating. Brain Res. 2005;1035:139–153. doi: 10.1016/j.brainres.2004.12.007. [PubMed] [Cross Ref]
21. Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000;21:2475–2490. doi: 10.1016/S0142-9612(00)00115-0. [PubMed] [Cross Ref]
22. Lockman PR, Mumper RJ, Khan MA, Allen DD. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm. 2002;28:1–13. doi: 10.1081/DDC-120001481. [PubMed] [Cross Ref]
23. Yasukawa T, Ogura Y, Sakurai E, Tabata Y, Kimura H. Intraocular sustained drug delivery using implantable polymeric devices. Adv Drug Deliv Rev. 2005;57:2033–2046. doi: 10.1016/j.addr.2005.09.005. [PubMed] [Cross Ref]
24. Paasonen L, Romberg B, Storm G, Yliperttula M, Urtti A, Hennink WE. Temperature-sensitive poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate)-coated liposomes for triggered contents release. Bioconjug Chem. 2007;18:2131–2136. doi: 10.1021/bc700245p. [PubMed] [Cross Ref]
25. Drummond DC, Zignani M, Leroux J. Current status of pH-sensitive liposomes in drug delivery. Prog Lipid Res. 2000;39:409–460. doi: 10.1016/S0163-7827(00)00011-4. [PubMed] [Cross Ref]
26. Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008;5:505–515. doi: 10.1021/mp800051m. [PMC free article] [PubMed] [Cross Ref]
27. Van Vlerken LE, Vyas TK, Amiji MM. Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery. Pharm Res. 2007;24:1405–1414. doi: 10.1007/s11095-007-9284-6. [PubMed] [Cross Ref]
28. Peracchia MT, Fattal E, Desmaële D, et al. Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J Control Release. 1999;60:121–128. doi: 10.1016/S0168-3659(99)00063-2. [PubMed] [Cross Ref]
29. Panagi Z, Beletsi A, Evangelatos G, Livaniou E, Ithakissios DS, Avgoustakis K. Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGA-mPEG nanoparticles. Int J Pharm. 2001;221:143–152. doi: 10.1016/S0378-5173(01)00676-7. [PubMed] [Cross Ref]
30. Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet. 2003;42:419–436. doi: 10.2165/00003088-200342050-00002. [PubMed] [Cross Ref]
31. Lee C-M, Choi Y, Huh EJ, et al. Polyethylene glycol (PEG) modified 99mTc-HMPAO-liposome for improving blood circulation and biodistribution: the effect of the extent of PEGylation. Cancer Biother Radiopharm. 2005;20:620–628. doi: 10.1089/cbr.2005.20.620. [PubMed] [Cross Ref]
32. Jeon SI, Lee JH, Andrade JD, De Gennes PG. Protein-surface interactions in the presence of polyethylene oxide: I. Simplified theory. J Colloid Interface Sci. 1991;142:149–158. doi: 10.1016/0021-9797(91)90043-8. [Cross Ref]
33. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102. doi: 10.1016/j.ijpharm.2005.10.010. [PubMed] [Cross Ref]
34. Rapoport S. Modulation of blood-brain barrier permeability. J Drug Target. 1996;3:417–425. doi: 10.3109/10611869609015962. [PubMed] [Cross Ref]
35. Béduneau A, Saulnier P, Benoit JP. Active targeting of brain tumors using nanocarriers. Biomaterials. 2007;28:4947–4967. doi: 10.1016/j.biomaterials.2007.06.011. [PubMed] [Cross Ref]
36. Schnyder A, Huwyler J. Drug transport to brain with targeted liposomes. NeuroRx. 2005;2:99–107. doi: 10.1602/neurorx.2.1.99. [PubMed] [Cross Ref]
37. Umezawa F, Eto Y. Liposome targeting to mouse brain: mannose as a recognition marker. Biochem Biophys Res Commun. 1988;153:1038–1044. doi: 10.1016/S0006-291X(88)81333-0. [PubMed] [Cross Ref]
38. Mora M, Sagristá ML, Trombetta D, Bonina FP, De Pasquale A, Saija A. Design and characterization of liposomes containing long-chain N-acy1PEs for brain delivery: penetration of liposomes incorporating GM1 into the rat brain. Pharm Res. 2002;19:1430–1438. doi: 10.1023/A:1020440229102. [PubMed] [Cross Ref]
39. Fenart L, Casanova A, Dehouck B, et al. Evaluation of effect of charge and lipid coating on ability of 60-nm nanoparticles to cross and in vitro model of the blood-brain barrier. J Pharmacol Exp Ther. 1999;291:1017–1022. [PubMed]
40. Allen DD, Lockman PR. The blood-brain barrier choline transporter as a brain drug delivery vector. Life Sci. 2003;73:1609–1615. doi: 10.1016/S0024-3205(03)00504-6. [PubMed] [Cross Ref]
41. Friese A, Seiller E, Quack G, Lorenz B, Kreuter J. Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system. Eur J Pharm Biopharm. 2000;49:103–109. doi: 10.1016/S0939-6411(99)00073-9. [PubMed] [Cross Ref]
42. Kreuter J, Shamenkov D, Petrov V, et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target. 2002;10:317–325. doi: 10.1080/10611860290031877. [PubMed] [Cross Ref]
43. Olivier JC. Drug transport to brain with targeted nanoparticles. NeuroRx. 2005;2:108–119. doi: 10.1602/neurorx.2.1.108. [PubMed] [Cross Ref]
44. Aktaş Y, Yemisci M, Andrieux K, et al. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjug Chem. 2005;16:1503–1511. doi: 10.1021/bc050217o. [PubMed] [Cross Ref]
45. Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci U S A. 1996;93:14164–14169. doi: 10.1073/pnas.93.24.14164. [PubMed] [Cross Ref]
46. Schnyder A, Krähenbühl S, Drewe J, Huwyler J. Targeting of daunomycin using biotinylated immunoliposomes: pharmacokinetics, tissue distribution and in vitro pharmacological effects. J Drug Target. 2005;13:325–335. doi: 10.1080/10611860500206674. [PubMed] [Cross Ref]
47. Huwyler J, Yang J, Pardridge WM. Receptor mediated delivery of daunomycin using immunoliposomes: pharmacokinetics and tissue distribution in the rat. J Pharmacol Exp Ther. 1997;282:1541–1546. [PubMed]
48. Cerletti A, Drewe J, Flicker G, Eberle AN, Huwyler J. Endocytosis and transcytosis of an immunoliposome-based brain drug delivery system. J Drug Target. 2000;8:435–446. doi: 10.3109/10611860008997919. [PubMed] [Cross Ref]
49. Kelly K. Gabapentin: antiepileptic mechanism of action. Neuropsychobiology. 1998;38:139–144. doi: 10.1159/000026529. [PubMed] [Cross Ref]
50. Trojnar MK, Wierzchowska-Cioch E, Krzyzanowski M, Jargiello M, Czuczwar SJ. New generation of valproic acid. Pol J Pharmacol. 2004;56:283–288. [PubMed]
51. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the fifth Eilat conference (EILAT V) Epilepsy Res. 2001;43:11–58. doi: 10.1016/S0920-1211(00)00171-6. [PubMed] [Cross Ref]
52. Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: design and clinical applications [Erratum in: Nat Rev Drug Discov 2008; 7:272] Nat Rev Drug Discov. 2008;7:255–270. doi: 10.1038/nrd2468. [PubMed] [Cross Ref]
53. Fechner J, Schwilden H, Schüttler J. Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection): a water-soluble propofol prodrug. Handb Exp Pharmacol. 2008;182:253–266. doi: 10.1007/978-3-540-74806-9_12. [PubMed] [Cross Ref]
54. Knapp LE, Kugler AR. Clinical experience with fosphenytoin in adults: pharmacokinetics, safety, and efficacy. J Child Neurol. 1998;13(Suppl 1):S15–S18. doi: 10.1177/0883073898013001051. [PubMed] [Cross Ref]
55. Cundy KC, Branch R, Chemov-Rogan T, et al. XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004;311:315–323. doi: 10.1124/jpet.104.067934. [PubMed] [Cross Ref]
56. Cundy KC, Annamalai T, Bu L, et al. XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonie absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther. 2004;311:324–333. doi: 10.1124/jpet.104.067959. [PubMed] [Cross Ref]
57. Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86–98. doi: 10.1602/neurorx.2.1.86. [PubMed] [Cross Ref]
58. Tishler DM, Weinberg KI, Hinton DR, Barbare N, Annett GM, Raffel C. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia. 1995;36:1–6. doi: 10.1111/j.1528-1157.1995.tb01657.x. [PubMed] [Cross Ref]
59. Potschka H, Fedrowitz M, Löscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003;306:124–131. doi: 10.1124/jpet.103.049858. [PubMed] [Cross Ref]
60. Aronica E, Gorter JA, Jansen GH, et al. Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors. Neuroscience. 2003;118:417–429. doi: 10.1016/S0306-4522(02)00992-2. [PubMed] [Cross Ref]
61. Sisodiya SM, Lin WR, Squier MV, Thorn M. Multidrug-resistance protein 1 in focal cortical dysplasia. Lancet. 2001;357:42–43. doi: 10.1016/S0140-6736(00)03573-X. [PubMed] [Cross Ref]
62. Dombrowski SM, Desai SY, Marroni M, et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia. 2001;42:1501–1506. doi: 10.1046/j.1528-1157.2001.12301.x. [PubMed] [Cross Ref]
63. Lazarowski A, Ramos AJ, García-Rivello H, Brusco A, Girardi E. Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model. Cell Mol Neurobiol. 2004;24:77–85. doi: 10.1023/B:CEMN.0000012726.43842.d2. [PubMed] [Cross Ref]
64. Chengyun D, Guoming L, Elia M, Catania M, Qunyuan X. Expression of multidrug resistance type 1 gene (MDR1) P-glycoprotein in intractable epilepsy with different aetiologies: a double-labelling and electron microscopy study. Neurol Sci. 2006;27:245–251. doi: 10.1007/s10072-006-0678-8. [PubMed] [Cross Ref]
65. Aronica E, Gorter JA, Ramkema M, et al. Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy. Epilepsia. 2004;45:441–451. doi: 10.1111/j.0013-9580.2004.57703.x. [PubMed] [Cross Ref]
66. Sisodiya SM, Martinian L, Scheffer GL, et al. Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein, and major vault protein in human epileptogenic pathologies. Neuropathol Appl Neurobiol. 2006;32:51–63. doi: 10.1111/j.1365-2990.2005.00699.x. [PubMed] [Cross Ref]
67. Vogelgesang S, Kunert-Keil C, Cascorbi I, et al. Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy. Clin Neuropathol. 2004;23:223–231. [PubMed]
68. Summers MA, Moore JL, McAuley JW. Use of verapamil as a potential P-glycoprotein inhibitor in a patient with refractory epilepsy. Ann Pharmacother. 2004;38:1631–1634. doi: 10.1345/aph.1E068. [PubMed] [Cross Ref]
69. Iannetti P, Spalice A, Parisi P. Calcium-channel blocker verapamil administration in prolonged and refractory status epilepticus. Epilepsia. 2005;46:967–969. doi: 10.1111/j.1528-1167.2005.59204.x. [PubMed] [Cross Ref]
70. Brandt C, Bethmann K, Gastens AM, Löscher W. The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis. 2006;24:202–211. doi: 10.1016/j.nbd.2006.06.014. [PubMed] [Cross Ref]
71. Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control. 2003;10:159–165. [PubMed]
72. Van Vliet EA, Redeker S, Aronica E, Edelbroek PM, Gorter JA. Expression of multidrug transporters MRP1, MRP2, and BCRP shortly after status epilepticus, during the latent period, and in chronic epileptic rats. Epilepsia. 2005;46:1569–1580. doi: 10.1111/j.1528-1167.2005.00250.x. [PubMed] [Cross Ref]
73. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007;52:333–346. doi: 10.1016/j.neuropharm.2006.07.038. [PubMed] [Cross Ref]
74. Cerveny L, Pavek P, Malakova J, Staud F, Fendrich Z. Lack of interactions between breast cancer resistance protein (BCRP/ ABCG2) and selected antiepileptic agents. Epilepsia. 2006;47:461–468. doi: 10.1111/j.1528-1167.2006.00453.x. [PubMed] [Cross Ref]
75. Haluska M, Anthony ML. Osmotic blood-brain barrier modification for the treatment of malignant brain tumors. Clin J Oncol Nurs. 2004;8:263–267. doi: 10.1188/04.CJON.263-267. [PubMed] [Cross Ref]
76. Siegal T, Rubinstein R, Bokstein F, et al. In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. J Neurosurg. 2000;92:599–605. doi: 10.3171/jns.2000.92.4.0599. [PubMed] [Cross Ref]
77. Kraemer DF, Fortin D, Doolittle ND, Neuwelt EA. Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival. Neurosurgery. 2001;48:1033–1040. doi: 10.1097/00006123-200105000-00013. [PubMed] [Cross Ref]
78. Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery. 1998;42:1083–1099. doi: 10.1097/00006123-199805000-00082. [PubMed] [Cross Ref]
79. Marchi N, Angelov L, Masaryk T, et al. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia. 2007;48:732–742. doi: 10.1111/j.1528-1167.2007.00988.x. [PMC free article] [PubMed] [Cross Ref]
80. van Vliet EA, da Costa Araújo S, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain. 2007;130:521–534. doi: 10.1093/brain/awl318. [PubMed] [Cross Ref]
81. Bakhshi S, North RB. Implantable pumps for drug delivery to the brain. J Neurooncol. 1995;26:133–139. doi: 10.1007/BF01060219. [PubMed] [Cross Ref]
82. Pardridge WM. Drug delivery to the brain. J Cereb Blood Flow Metab. 1997;17:713–731. doi: 10.1097/00004647-199707000-00001. [PubMed] [Cross Ref]
83. Brightman MM, Kaya M. Permeable endothelium and the interstitial space of brain. Cell Mol Neurobiol. 2000;20:111–130. doi: 10.1023/A:1006944203934. [PubMed] [Cross Ref]
84. Tao A, Tao L, Nicholson C. Cell cavities increase tortuosity in brain extracellular space. J Theor Biol. 2005;234:525–536. doi: 10.1016/j.jtbi.2004.12.009. [PubMed] [Cross Ref]
85. Pardridge WM. Transport of small molecules through the blood-brain barrier: biology and methodology. Adv Drug Deliv Rev. 1995;15:5–36. doi: 10.1016/0169-409X(95)00003-P. [Cross Ref]
86. Aird RB. A study of intrathecal, cerebrospinal fluid-to-brain exchange. Exp Neurol. 1984;86:342–358. doi: 10.1016/0014-4886(84)90192-4. [PubMed] [Cross Ref]
87. Billiau A, Heremans H, Ververken D, Van Damme J, Carton H, De Somer P. Tissue distribution of human interferons after exogenous administration in rabbits, monkeys, and mice. Arch Virol. 1981;68:19–25. doi: 10.1007/BF01315163. [PubMed] [Cross Ref]
88. Covell DG, Narang PK, Poplack DG. Kinetic model for disposition of 6-mercaptopurine in monkey plasma and cerebrospinal fluid. Am J Physiol Regul Integr Comp Physiol. 1985;17:R147–R156. [PubMed]
89. Serralta A, Barcia JA, Ortiz P, Durán C, Hernández ME, Alós M. Effect of intracerebroventricular continuous infusion of valproic acid versus single i.p. and i.c.v. injections in the amygdala kindling epilepsy model. Epilepsy Res. 2006;70:15–26. doi: 10.1016/j.eplepsyres.2006.02.003. [PubMed] [Cross Ref]
90. Boogerd W, van den Bent MJ, Koehler PJ, et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer. 2004;40:2726–2733. doi: 10.1016/j.ejca.2004.08.012. [PubMed] [Cross Ref]
91. Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery. 2000;47:49–54. doi: 10.1097/00006123-200007000-00011. [PubMed] [Cross Ref]
92. Oommen J, Kraus A, Fisher R. Intraventricular administration of gabapentin in the rat increases flurothyl seizure threshold. Neurosci Lett. 2007;417:308–311. doi: 10.1016/j.neulet.2007.02.051. [PubMed] [Cross Ref]
93. Yildirim M, Marangoz C. Anticonvulsant effects of focal and intiacerebroventricular adenosine on penicillin-induced epileptiform activity in rats. Brain Res. 2007;1127:193–200. doi: 10.1016/j.brainres.2006.10.024. [PubMed] [Cross Ref]
94. Saltzman WM, Olbricht WL. Building drug delivery into tissue engineering. Nat Rev Drug Discov. 2002;1:177–187. doi: 10.1038/nrd744. [PubMed] [Cross Ref]
95. Fung LK, Ewend MG, Sills A, et al. Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res. 1998;58:672–684. [PubMed]
96. Fung LK, Shin M, Tyler B, Brem H, Saltzman WM. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm Res. 1996;13:671–682. doi: 10.1023/A:1016083113123. [PubMed] [Cross Ref]
97. Sawyer AJ, Piepmeier JM, Saltzman WM. New methods for direct delivery of chemotherapy for treating brain tumors. Yale J Biol Med. 2006;79:141–152. [PMC free article] [PubMed]
98. Kokaia M, Aebischer P, Elmér E, et al. Seizure suppression in kindling epilepsy by intracerebral implants of GABA-but not by noradrenaline-releasing polymer matrices. Exp Brain Res. 1994;100:385–394. doi: 10.1007/BF02738399. [PubMed] [Cross Ref]
99. Kubek MJ, Liang D, Byrd KE, Domb AJ. Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation. Brain Res. 1998;809:189–197. doi: 10.1016/S0006-8993(98)00860-9. [PubMed] [Cross Ref]
100. Tamargo RJ, Rossell LA, Kossoff EH, Tyler BM, Ewend MG, Aryanpur JJ. The intracerebral administration of phenytoin using controlled-release polymers reduces experimental seizures in rats. Epilepsy Res. 2002;48:145–155. doi: 10.1016/S0920-1211(01)00330-8. [PubMed] [Cross Ref]
101. Saltzman WM, Langer R. Transport rates of proteins in porous materials with known microgeometry. Biophys J. 1989;55:163–171. doi: 10.1016/S0006-3495(89)82788-2. [PubMed] [Cross Ref]
102. Lopez T, Ortiz E, Quintana P, Gonzalez RD. A nanostructured titania bioceramic implantable device capable of drug delivery to the temporal lobe of the brain. Colloids Surf A Physicochem Eng Asp. 2007;300:3–10. doi: 10.1016/j.colsurfa.2006.10.060. [Cross Ref]
103. Lopez T, Quintana P, Ascencio J, Gonzalez RD. The determination of dielectric constants of mixtures used in the treatment of epilepsy and the encapsulation of phenytoin in a titania matrix. Colloids Surf A Physicochem Eng Asp. 2007;300:99–105. doi: 10.1016/j.colsurfa.2006.10.061. [Cross Ref]
104. Tolmacheva EA, Van Luijtelaar G. Absence seizures are reduced by the enhancement of GABA-ergic inhibition in the hippocampus in WAG/Rij rats. Neurosci Lett. 2007;416:17–21. doi: 10.1016/j.neulet.2007.01.038. [PubMed] [Cross Ref]
105. Mirnajafi-Zadeh J, Mortazavi M, Fathollahi Y, Alasvand Zarasvand M, Reza Palizvan M. Effect of transient hippocampal inhibition on amygdaloid kindled seizures and amygdaloid kindling rate. Brain Res. 2002;954:220–226. doi: 10.1016/S0006-8993(02)03292-4. [PubMed] [Cross Ref]
106. Anschel DJ, Ortega EL, Kraus AC, Fisher RS. Focally injected adenosine prevents seizures in the rat. Exp Neurol. 2004;190:544–547. doi: 10.1016/j.expneurol.2004.07.017. [PubMed] [Cross Ref]
107. Rossetti F, Rodrigues MCA, de Oliveira JAC, Garcia-Cairasco N. EEG wavelet analyses of the striatum-substantia nigra pars reticulata-superior colliculus circuitry: audiogenic seizures and anticonvulsant drug administration in Wistar audiogenic rats (War strain) Epilepsy Res. 2006;72:192–208. doi: 10.1016/j.eplepsyres.2006.08.001. [PubMed] [Cross Ref]
108. Gasior M, White NA, Rogawski MA. Prolonged attenuation of amygdala-kindled seizure measures in rats by convection-enhanced delivery of the N-type calcium channel antagonists ω-conotoxin GVIA and ω-conotoxin MVIIA. J Pharmacol Exp Ther. 2007;323:458–468. doi: 10.1124/jpet.107.125047. [PMC free article] [PubMed] [Cross Ref]
109. Morrison PF, Chen MY, Chadwick RS, Lonser RR, Oldfield EH. Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics [Erratum in: Am J Physiol Regul Integr Comp Physiol 2002;282(6):section R following table of contents] Am J Physiol Regul Integr Comp Physiol. 1999;277:R1218–R1229. [PubMed]
110. Chen MY, Hoffer A, Morrison PF, et al. Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg. 2005;103:311–319. doi: 10.3171/jns.2005.103.2.0311. [PubMed] [Cross Ref]
111. Chen MY, Lonser RR, Morrison PF, Governale LS, Oldfield EH. Variables affecting convection-enhanced delivery to the striatum: a systemic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg. 1999;90:315–320. doi: 10.3171/jns.1999.90.2.0315. [PubMed] [Cross Ref]
112. Raghavan R, Brady M, Rodriguez-Ponce M, Hartlep A, Pedain C, Sampson J. Convection-enhanced delivery of therapeutics for brain disease and its optimization. Neurosurg Focus. 2006;20(4):E12–E12. doi: 10.3171/foc.2006.20.4.7. [PubMed] [Cross Ref]
113. Neeves KB, Lo CT, Foley CP, Saltzman WM, Olbricht WL. Fabrication and characterization of microfluidic probes for convection enhanced drug delivery. J Control Release. 2006;111:252–262. doi: 10.1016/j.jconrel.2005.11.018. [PubMed] [Cross Ref]
114. Heiss JD, Walbridge S, Morrison P, et al. Local distribution and toxicity of prolonged hippocampal infusion of muscimol. J Neurosurg. 2005;103:1035–1045. doi: 10.3171/jns.2005.103.6.1035. [PMC free article] [PubMed] [Cross Ref]
115. Zara GP, Cavalli R, Bargoni A, Fundarò A, Vighetto D, Gasco MR. Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues. J Drug Target. 2002;10:327–335. doi: 10.1080/10611860290031868. [PubMed] [Cross Ref]
116. Yan Q, Matheson C, Sun J, Radeke MJ, Feinstein SC, Miller JA. Distribution of intracerebral ventricularly administered neurotrophins in rat brain and its correlation with Trk receptor expression. Exp Neurol. 1994;127:23–36. doi: 10.1006/exnr.1994.1076. [PubMed] [Cross Ref]

Articles from Neurotherapeutics are provided here courtesy of Springer