Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems

Advanced Drug Delivery Reviews

Volumn 36, Issue 2-3, 1999, Pages 229-254

  Bodor, Nicholas ^a   Buchwald, Peter ^a  

^a UNIVERSITY OF FLORIDA   (United States)

Author keywords

Blood brain barrier; Brain targeted redox analog; Cyclodextrin; Estradiol; Neuropeptides; Octanol water partition; P glycoprotein; Retrometabolic design; Zidovudine (AZT)

Indexed keywords

BLOOD; BRAIN; DRUG PRODUCTS; METABOLISM; NEUROPHYSIOLOGY; PROTEINS;

BLOOD-BRAIN BARRIER; BRAIN-TARGETED REDOX ANALOG; CYCLODEXTRIN; ESTRADIOL; NEUROPEPTIDES; P-GLYCOPROTEIN;

CONTROLLED DRUG DELIVERY;

ACICLOVIR; ANTIVIRUS AGENT; CHLORAMBUCIL; CYCLOSPORIN; DEXAMETHASONE; ELMUSTINE; ENKEPHALIN; ESTRADIOL; ESTROGEN; FELODIPINE; GANCICLOVIR; GLYCOPROTEIN P; INDOMETACIN; KYOTORPHIN; LOMUSTINE; NAPROXEN; NEUROPEPTIDE; PENICILLIN G; PHENYTOIN; PROGESTERONE; PROPOFOL; PROPRANOLOL; PROTIRELIN; RIBAVIRIN; STIRIPENTOL; TACRINE; TRIFLURIDINE; UNINDEXED DRUG; ZIDOVUDINE;

BLOOD BRAIN BARRIER; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG METABOLISM; DRUG PENETRATION; DRUG TARGETING; HUMAN; NONHUMAN; PARTITION COEFFICIENT; PRIORITY JOURNAL; REVIEW;

EID: 0033526158     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0169-409X(98)00090-8     Document Type: Review

References (161)

1. C. Crone, A.M. Thompson, Permeability of brain capillaries, in: C. Crone, N.A. Lassen (Eds.), Capillary Permeability. The Transfer of Molecules and Ions Between Capillary Blood and Tissue, Munksgaard, Copenhagen, 1970, pp. 447-453.
2. Oldendorf W.H. Lipid solubility and drug penetration of the blood-brain barrier. Proc. Soc. Exp. Biol. Med. 147:1974;813-816.
3. S.I. Rapoport, Blood-Brain Barrier in Physiology and Medicine, Raven Press, New York, 1976.
4. M. Bradbury, The Concept of a Blood-Brain Barrier, Wiley, New York, 1979.
5. Bodor N., Brewster M.E. Problems of delivery of drugs to the brain. Pharmacol. Ther. 19:1983;337-386.
6. J.D. Fenstermacher, S.I. Rapoport, Blood-brain barrier, in: E.M. Renkin, C.C. Michel (Eds.), Handbook of Physiology, Section 2: The Cardiovascular System, Vol. 4, Microcirculation, Part 2, Am. Physiol. Soc., Bethesda, 1984, pp. 969-1000.
7. M.W.B.E. Bradbury, Physiology and Pharmacology of the Blood-Brain Barrier, Springer, Berlin, 1992.
8. Begley D.J. The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J. Pharm. Pharmacol. 48:1996;136-146.
9. C. Crone, The blood-brain barrier: a modified tight epithelium, in: A.J. Suckling, M.G. Rumsby, M.W.B. Bradbury (Eds.), The Blood-Brain Barrier in Health and Disease, Ellis Horwood, Chichester, 1986, pp. 17-40.
10. W.M. Pardridge, Peptide Drug Delivery to the Brain, Raven Press, New York, 1991.
11. N.J. Abbott, M. Bundgaard, H.F. Cserr, Comparative physiology of the blood-brain barrier, in: A.J. Suckling, M.G. Rumsby, M.W.B. Bradbury (Eds.), The Blood-Brain Barrier in Health and Disease, Ellis Horwood, Chichester, 1986, pp. 52-72.
12. Q.R. Smith, Quantitation of blood-brain barrier permeability, in: E.A. Neuwelt (Ed.), Implications of the Blood-Brain Barrier and its Manipulation, Plenum, New York, 1989, pp. 85-113.
13. Stewart P.A., Tuor U.I. Blood-eye barriers in the rat: correlation of ultrastructure with function. J. Comp. Neurol. 340:1994;566-576.
14. Regier D.A., Boyd J.H., Burke J.D. Jr., Rae D.S., Myers J.K., Kramer M., Robins L.N., George L.K., Karno M., Locke B.Z. One-month prevalence of mental disorders in the United States. Arch. Gen. Psychiatry. 45:1988;977-986.
15. P. Ehrlich, Das Sauerstoff Bedürfnis des Organismus. Eine farbenanalytische Studie, Hirschwald, Berlin, 1885.
16. Spatz H. Die Bedeutung der vitalen Farbung für die Lehre vom Stoffaustasch zwischen dem Zentralnervensystem und dem übrigen Korper. Arch. Psychiat. Nervenkrank. 101:1933;267-358.
17. C. Crone, The Diffusion of Some Organic Nonelectrolytes from Blood to Brain Tissue, Munksgaard, Copenhagen, 1961 (in Danish, English summary).
18. Reese T.S., Karnovsky M.J. Fine structural localisation of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34:1967;207-217.
19. Ghersi-Egea J.F., Leninger-Muller B., Suleman G., Siest G., Minn A. Localization of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J. Neurochem. 62:1994;1089-1096.
20. Brownlees J., Williams C.H. Peptidases, peptides, and the mammalian blood-brain barrier. J. Neurochem. 60:1993;793-803.
21. Krogh A. The active and passive exchanges of inorganic ions through the surfaces of living cells and through living membranes generally. Proc. R. Soc. B. 133:1946;140-200.
22. Crone C. Facilitated transport of glucose from blood into brain. J. Physiol. 181:1965;103-113.
23. Lund-Andersen H. Transport of glucose from blood to brain. Physiol. Rev. 59:1979;305-352.
24. Barza M. Anatomical barriers for antimicrobial agents. Eur. J. Clin. Microbiol. Infect. Dis. 12(Suppl. 1):1993;S31-S35.
25. Deguchi Y., Nozawa K., Yamada S., Yokoyama Y., Kimura R. Quantitative evaluation of brain distribution and blood-brain barrier efflux transport of probenicid in rats by microdialysis: possible involvement of the monocarboxylic acid transport system. J. Pharmacol. Exp. Ther. 280:1997;551-560.
26. Suzuki H., Terasaki T., Sugiyama Y. Role of efflux transport across the blood-brain barrier and blood-cerebrospinal fluid barrier on the disposition of xenobiotics in the central nervous system. Adv. Drug Deliv. Rev. 25:1997;257-285.
27. Tsuji A., Tamai I., Sakata A., Tenda Y., Terasaki T. Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. Biochem. Pharmacol. 46:1993;1096-1099.
28. Schinkel A.H., Smit J.J.M., van Tellingen O., Beijnen J.H., Wagenaar E., van Deemter L., Mol C.A.A.M., van der Walk M.A., Robanus-Maadag E.C., te Riele H.P.J., Berns A.J.M., Borst P. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 77:1994;491-502.
29. Schinkel A.H., Wagenaar E., Mol C.A.A.M., van Deemter L. P-Glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:1996;2517-2524.
30. Tsuji A., Tamai I. Blood-brain barrier function of P-glycoprotein. Adv. Drug Deliv. Rev. 25:1997;287-298.
31. van Asperen J., Mayer U., van Tellingen O., Beijnen J.H. The functional role of P-glycoprotein in the blood-brain barrier. J. Pharm. Sci. 86:1997;881-884.
32. Stein W.D. Kinetics of multidrug transporter (P-glycoprotein) and its reversal. Physiol. Rev. 77:1997;545-590.
33. Hansch C., Dunn III J. Linear relationships between lipophilic character and biological activity of drugs. J. Pharm. Sci. 61:1972;1-19.
34. Hansch C., Clayton J.M. Lipophilic character and biological activity of drugs. II. The parabolic case. J. Pharm. Sci. 62:1973;1-21.
35. Kubinyi H. Lipophilicity and drug activity. Prog. Drug Res. 23:1979;97-198.
36. Seydel J.K., Schaper K.J. Quantitative structure-pharmacokinetic relationships and drug design. Pharmacol. Ther. 15:1982;131-181.
37. C. Hansch, A. Leo, D. Hoekman, Exploring QSAR. Hydrophobic, Electronic, and Steric Constants, American Chemical Society, Washington, DC, 1995.
38. Hansch C., Muir R.M., Fujita T., Maloney P.P., Geiger F., Streich M. The correlation of biological activity of plant growth regulators and chloromycetin derivatives with Hammett constants and partition coefficients. J. Am. Chem. Soc. 85:1963;2817-2825.
39. Franks N.P., Lieb W.R. Where do general anaesthetics act? Nature. 274:1978;339-342.
40. Barton A.F.M. Solubility parameters. Chem. Rev. 75:1975;731-753.
41. 2 receptor histamine antagonists. J. Med. Chem. 31:1988;656-671.
42. Abraham M.H., Chadha H.S., Mitchell R.C. Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. J. Pharm. Sci. 83:1994;1257-1268.
43. Chikhale E.G., Ng K.-Y., Burton P.S., Borchardt R.T. Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides. Pharm. Res. 11:1994;412-419.
44. Salminen T., Pulli A., Taskinen J. Relationship between immobilised artificial membrane chromatographic retention and the brain penetration of structurally diverse drugs. J. Pharm. Biomed. Anal. 15:1997;469-477.
45. W.D. Stein, Transport and Diffusion Across Cell Membranes, Academic Press, Orlando, 1986.
46. Leahy D.E., Morris J.J., Taylor P.J., Wait A.R. Model solvent system for QSAR. Part 2. Fragment values ('f-values') for the 'critical quartet'. J. Chem. Soc., Perkin Trans. 2:1992;723-731.
47. Seiler P. Interconversion of lipophilicities from hydrocarbon/water systems into the octanol/water system. Eur. J. Med. Chem. 9:1974;473-479.
48. Abraham M.H., Chadha H.S., Whiting G.S., Mitchell R.C. Hydrogen bonding. 32. An analysis of water-octanol and water-alkane partitioning and the Δlog P parameter of Seiler. J. Pharm. Sci. 83:1994;1085-1100.
49. Levin V.A. Relationship of octanol/water partition coefficients and molecular weight to rat brain capillary permeability. J. Med. Chem. 23:1980;682-684.
50. Pardridge W.M., Triguero D., Yang J., Cancilla P.A. Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J. Pharmacol. Exp. Ther. 253:1990;884-891.
51. Rapoport S.I., Ohno K., Pettigrew K.D. Drug entry into brain. Brain Res. 172:1979;354-359.
52. D.J. Begley, Peptides and the blood-brain barrier, in: M.W.B. Bradbury (Ed.), Handbook of Experimental Pharmacology, Vol. 103, Physiology and Pharmacology of the Blood-Brain Barrier, Springer, Berlin, 1992, pp. 151-203.
53. N.H. Greig, Drug entry into the brain and its pharmacologic manipulation, in: M.W.B. Bradbury (Ed.), Handbook of Experimental Pharmacology, Vol. 103, Physiology and Pharmacology of the Blood-Brain Barrier, Springer, Berlin, 1992, pp. 487-523.
54. Gratton J.A., Abraham M.H., Bradbury M.W., Chadha H.S. Molecular factors influencing drug transfer across the blood-brain barrier. J. Pharm. Pharmacol. 49:1997;1211-1216.
55. Hansch C., Steward A.R., Anderson S.M., Bentley D. The parabolic dependence of drug action upon lipophilic character as revealed by a study of hypnotics. J. Med. Chem. 11:1968;1-21.
56. V.J. Stella, Prodrugs: an overview and definition, in: T. Higuchi, V.J. Stella (Eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society, Washington, DC, 1975, pp. 1-115.
57. H. Bundgaard (Ed.), Design of Prodrugs, Elsevier, Amsterdam, 1985.
58. Bodor N., Kaminski J.J. Prodrugs and site-specific chemical delivery systems. Annu. Rep. Med. Chem. 22:1987;303-313.
59. Bodor N. Soft drugs: principles and methods for the design of safe drugs. Med. Res. Rev. 3:1984;449-469.
60. N. Bodor, Soft drugs, in: R. Dulbecco (Ed.), Encyclopedia of Human Biology, Vol. 7, Academic Press, San Diego, 1991, pp. 101-117.
61. Bodor N. Drug targeting and retrometabolic drug design approaches. Adv. Drug Deliv. Rev. 14:1994;157-166.
62. N. Bodor, Retrometabolic approaches to drug targeting, in: R. Rapaka (Ed.), NIDA Research Monograph Series, Vol. 154, Membranes and Barriers: Targeted Drug Delivery, NIDA, Rockville, 1995, pp. 1-27.
63. Bodor N., Buchwald P. Drug targeting via retrometabolic approaches. Pharmacol. Ther. 76:1997;1-27.
64. N. Bodor, M.E. Brewster, Chemical delivery systems, in: R.L. Juliano (Ed.), Handbook of Experimental Pharmacology, Vol. 100, Targeted Drug Delivery, Springer, Berlin, 1991, pp. 231-284.
65. Bodor N., Roller R.G., Selk S.J. Elimination of a quaternary pyridinium salt delivered as its dihydropyridine derivative from brain of mice. J. Pharm. Sci. 67:1978;685-687.
66. Palomino E., Kessel D., Horwitz J.P. A dihydropyridine carrier system for sustained delivery of 1′,3′-dideoxynucleosides to the brain. J. Med. Chem. 32:1989;622-625.
67. Bodor N., Farag H.H., Brewster M.E. Site-specific, sustained release of drugs to the brain. Science. 214:1981;1370-1372.
68. Bodor N., Farag H.H. Improved delivery through biological membranes. 11. A redox chemical drug-delivery system and its use for brain specific delivery of phenylethylamine. J. Med. Chem. 26:1983;313-318.
69. Bodor N., Farag H.H. Improved delivery through biological membranes. XIV: brain-specific, sustained delivery of testosterone using a redox chemical delivery system. J. Pharm. Sci. 73:1984;385-389.
70. Brewster M.E., Estes K.S., Bodor N. Improved delivery through biological membranes. XXIV. Synthesis, in vitro studies, and in vivo characterization of brain-specific and sustained progestin delivery systems. Pharm. Res. 3:1986;278-285.
71. Anderson W.R., Simpkins J.W., Brewster M.E., Bodor N. Evidence of prolonged suppression of stress-induced release of adrenocortopic hormone and corticosterone with a brain-enhanced dexamethasone-redox delivery system. Neuroendocrinology. 50:1989;9-16.
72. Siegal T., Soti F., Biegon A., Pop E., Brewster M.E. Effect of a chemical delivery system for dexamethasone (Dex-CDS) on peritumoral edema in an experimental brain tumor model. Pharm. Res. 14:1997;672-675.
73. Brewster M.E., Deyrup M., Czako K., Bodor N. Extension of a redox-based chemical delivery system to α,β-unsaturated ketones. J. Med. Chem. 33:1990;2063-2065.
74. Bodor N., McCornack J., Brewster M.E. Improved delivery through biological membranes. XXII. Synthesis and distribution of brain-selective estrogen delivery systems. Int. J. Pharm. 35:1987;47-59.
75. Brewster M.E., Estes K.S., Bodor N. Improved delivery through biological membranes. XXXII. Synthesis and biological activity of brain-targeted delivery systems for various estradiol derivatives. J. Med. Chem. 31:1988;244-249.
76. Mullersman G., Derendorf H., Brewster M.E., Estes K.S., Bodor N. High performance liquid chromatographic assay of a central nervous system (CNS)-directed estradiol chemical delivery system and its application after intravenous administration in rats. Pharm. Res. 5:1988;172-177.
77. Estes K.S., Brewster M.E., Bodor N. Evaluation of an estradiol chemical delivery system (CDS) designed to provide enhanced and sustained hormone levels in the brain. Adv. Drug Deliv. Rev. 14:1994;167-175.
78. Simpkins J.W., Rajakumar G., Zhang Y.-Q., Simpkins C.E., Greenwald D., Yu C.J., Bodor N., Day A.L. Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J. Neurosurg. 87:1997;724-730.
79. Rabbani O., Panickar K.S., Rajakumar G., King M.A., Bodor N., Meyer E.M., Simpkins J.W. 17 β-estradiol attenuates fimbrial lesion-induced decline of ChAT-immunoreactive neurons in the rat medial septum. Exp. Neurol. 146:1997;179-186.
80. Pop E., Wu W.-M., Shek E., Bodor N. Brain-specific chemical delivery systems for β-lactam antibiotics. Synthesis and properties of some dihydropyridine and dihydroisoquinoline derivatives of benzylpenicillin. J. Med. Chem. 32:1989;1774-1781.
81. Pop E., Wu W.-M., Bodor N. Chemical delivery systems for some penicillinase-resistant semisynthetic penicillins. J. Med. Chem. 32:1989;1789-1795.
82. Wu W.-M., Pop E., Shek E., Bodor N. Brain-specific chemical delivery systems for β-lactam antibiotics. In vitro and in vivo studies of some dihydropyridine and dihydroisoquinoline derivatives of benzylpenicillin in rats. J. Med. Chem. 32:1989;1782-1788.
83. Wu W.-M., Pop E., Shek E., Clemmons R., Bodor N. Brain and CSF specific chemical delivery systems for β-lactam antibiotics. Study of two dihydropyridine derivatives of benzylpenicillin in rabbits and dogs. Drug Des. Deliv. 7:1990;33-43.
84. Venkatraghavan V., Shek E., Perchalski R., Bodor N. Brain-specific chemical delivery systems for acyclovir (abstract). Pharmacologist. 28:1986;145.
85. Rand K., Bodor N., El-Koussi A., Raad I., Miyake A., Houck H., Gildersleeve N. Potential treatment of herpes simplex virus encephalitis by brain-specific delivery of trifluorothymidine using a dihydropyridine-pyridinium salt redox delivery system. J. Med. Virol. 20:1986;1-8.
86. El-Koussi A., Bodor N. Improved delivery through biological membranes. XXV. Enhanced and sustained delivery of trifluorothymidine to the brain using a dihydropyridine-pyridinium salt type redox delivery system. Drug Des. Deliv. 1:1987;275-283.
87. Canonico P.G., Kende M., Gabrielsen B. Carrier-mediated delivery of antiviral agents. Adv. Virus Res. 35:1988;271-312.
88. Bhagrath M., Sidwell R., Czako K., Seyda K., Anderson W., Bodor N., Brewster M.E. Improved delivery through biological membranes. Synthesis, characterization and antiviral activity of a series of ribavirin chemical delivery systems: 5′ and carboxamide derivatives. Antiviral Chem. Chemother. 2:1991;265-286.
89. Deyrup M., Sidwell R., Little R., Druzgala P., Bodor N., Brewster M.E. Improved delivery through biological membranes. Synthesis and antiviral activity of a series of ribavirin chemical delivery systems: 2′ and 3′ derivatives. Antiviral Chem. Chemother. 2:1991;337-355.
90. Morin K.W., Wiebe L.I., Knaus E.E. Synthesis of brain-targeted 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-(E)-5-(2-iodovinyl)uracil coupled to a dihydropyridine-pyridinium salt redox chemical-delivery system. Carbohydr. Res. 249:1993;109-116.
91. Morin K.W., Knaus E.E., Wiebe L.I. Site-directed design and synthesis of a brain-targeted radioiodinated nucleoside for diagnosis of herpes simplex encephalitis. J. Label. Compd. Radiopharm. 35:1994;205-207.
92. Balzarini J., Morin K.W., Knaus E.E., Wiebe L.I., De Clercq E. Novel (E)-5-(2-iodovinyl)-2′-deoxyuridine derivatives as potential cytostatic agents against herpes-simplex virus thymidine kinase gene transfected tumors. Gene Ther. 2:1995;317-322.
93. Pop E., Anderson W., Vlasak J., Brewster M.E., Bodor N. Enhanced brain delivery of 2′-fluoro-5-methylarabinosyluracil. Int. J. Pharm. 84:1992;39-48.
94. Brewster M.E., Little R., Venkatraghavan V., Bodor N. Brain-enhanced delivery of antiviral agents (abstract). Antiviral Res. 9:1988;127.
95. Little R., Bailey D., Brewster M.E., Estes K.S., Clemmons R.M., Saab A., Bodor N. Improved delivery through biological membranes. XXXIII. Brain enhanced delivery of azidothymidine (AZT). J. Biopharm. Sci. 1:1990;1-18.
96. Brewster M.E., Anderson W., Bodor N. Brain, blood, and cerebrospinal fluid distribution of a zidovudine chemical delivery system in rabbits. J. Pharm. Sci. 80:1991;843-845.
97. Mizrachi Y., Rubinstein A., Harish Z., Biegon A., Anderson W.R., Brewster M.E. Improved delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system. AIDS. 9:1995;153-158.
98. Brewster M.E., Anderson W.R., Webb A.I., Pablo L.M., Meinsma D., Moreno D., Derendorf H., Bodor N., Pop E. Evaluation of a brain-targeting zidovudine chemical delivery system in dogs. Antimicrob. Agents Chemother. 41:1997;122-128.
99. Torrence P.T., Kinjo J., Lesiak K., Balzarini J., DeClerq E. AIDS dementia: synthesis and properties of a derivative of 3′-azido-3′-deoxythimidine (AZT) that may become 'locked' in the central nervous system. FEBS Lett. 234:1988;135-140.
100. Gogu S.R., Aggarwal S.K., Rangan S.R.S., Agrawal K.C. A prodrug of zidovudine with enhanced efficacy against human immunodeficiency virus. Biochem. Biophys. Res. Commun. 160:1989;656-661.
101. Aggarwal S.K., Gogu S.R., Rangan S.R.S., Agrawal K.C. Synthesis and biological evaluation of prodrugs of zidovudine. J. Med. Chem. 33:1990;1505-1510.
102. Lupia R.H., Ferencz N., Aggarwal S.K., Agrawal K.C., Lertora J.J.L. Plasma (P), cerebrospinal fluid (C) and brain (B) pharmacokinetics of two novel prodrugs of zidovudine (Z) (abstract). Clin. Res. 38:1990;15A.
103. Lupia R.H., Ferencz N., Lertora J.J.L., Aggarwal S.K., George W.J., Agrawal K.C. Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue. Antimicrob. Agents Chemother. 37:1993;818-824.
104. Gallo J., Boubinot F., Doshi D., Etse J., Bhandti V., Schinazi R., Chu C.K. Evaluation of brain targeting of anti-HIV nucleosides delivered via dihydropyridine prodrugs (abstract). Pharm. Res. 6:1989;S161.
105. Chu C.K., Bhadti V.S., Doshi K.J., Etse J.T., Gallo J.M., Boudinot F.D., Schinazi R.F. Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3′-azido-2′,3′-dideoxyuridine and 3′-azido-3′-deoxythimidine. J. Med. Chem. 33:1990;2188-2192.
106. Gallo J.M., Etse J.T., Doshi K.J., Boudinot F.D., Chu C.K. Hybrid pharmacokinetic models to describe anti-HIV nucleoside brain disposition following parent and prodrug administration in mice. Pharm. Res. 8:1991;247-253.
107. Brewster M.E., Raghavan K., Pop E., Bodor N. Enhanced delivery of ganciclovir to the brain through the use of redox targeting. Antimicrob. Agents Chemother. 38:1994;817-823.
108. Camplo M., Charvet Faury A.S., Borel C., Turin F., Hantz O., Trabaud C., Niddam V., Mourier N., Graciet J.C., Chermann J.C., Kraus J.L. Synthesis and antiviral activity of N-4′-dihydropyridinyl and dihydroquinolinylcarbonyl-2-hydroxymethyl-5-cytosin-1′-yl-1,3-oxathiolane derivatives against human immunodeficiency virus and duck hepatitis B virus. Eur. J. Med. Chem. 31:1996;539-546.
109. Raghavan K., Shek E., Bodor N. Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1,4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU. Anticancer Drug Des. 2:1987;25-36.
110. Raghavan K., Loftsson T., Brewster M.E., Bodor N. Improved delivery through biological membranes. XLV. Synthesis, physical-chemical evaluation, and brain uptake studies of 2-chloroethyl nitrosourea delivery system. Pharm. Res. 9:1992;743-749.
111. Bodor N., Venkatraghavan V., Winwood D., Estes K., Brewster M.E. Improved delivery through biological membranes. XLI. Brain-enhanced delivery of chlorambucil. Int. J. Pharm. 53:1989;195-208.
112. Bodor N., Simpkins J.W. Redox delivery system for brain-specific, sustained release of dopamine. Science. 221:1983;65-67.
113. Bodor N., Farag H.H. Improved delivery through biological membranes. 13. Brain-specific delivery of dopamine with a dihydropyridine-pyridinium salt type redox delivery system. J. Med. Chem. 26:1983;528-534.
114. Omar F.A., Farag H.H., Bodor N. Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester. J. Drug Targeting. 2:1994;309-316.
115. Carelli V., Liberatore F., Scipione L., Impicciatore M., Barocelli E., Cardellini M., Giorgioni G. New systems for the specific delivery and sustained release of dopamine to the brain. J. Control. Release. 42:1996;209-216.
116. Anderson W.R., Simpkins J.W., Woodard P.A., Winwood D., Stern W.C., Bodor N. Anxiolytic activity of a brain delivery system for GABA. Psychopharmacology. 92:1987;157-163.
117. Woodard P.A., Winwood D., Brewster M.E., Estes K.S., Bodor N. Improved delivery through biological membranes. XXI. Brain-targeted anti-convulsive agents. Drug Des. Deliv. 6:1990;15-28.
118. Kourounakis A., Bodor N., Simpkins J. Synthesis and evaluation of a brain-targeted catechol derivative as a potential NGF-inducer. Int. J. Pharm. 141:1996;239-250.
119. Kourounakis A., Bodor N., Simpkins J. Synthesis and evaluation of a brain-targeted chemical delivery system for the neurotrophomodulator 4-methylcatechol. J. Pharm. Pharmacol. 49:1997;1-9.
120. Shek E., Murakami T., Nath C., Pop E., Bodor N.S. Improved anticonvulsant activity of phenytoin by a redox brain delivery system. III. Brain uptake and pharmacological effects. J. Pharm. Sci. 78:1989;837-843.
121. Boddy A.V., Zhang K., Lepage F., Tombret F., Slatter J.G., Baillie T.A., Levy R.H. In vitro and in vivo investigations of dihydropyridine-based chemical delivery systems for anticonvulsants. Pharm. Res. 8:1991;690-697.
122. Yiu S.H., Knaus E.E. Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine-pyridinium salt redox chemical delivery system. J. Med. Chem. 39:1996;4576-4582.
123. Prókai-Tátrai K., Pop E., Anderson W., Lin J.-L., Brewster M.E., Bodor N. Redox derivatives of tranylcypromine: synthesis, properties, and monoamine oxidase inhibitor activity of some chemical delivery systems. J. Pharm. Sci. 80:1991;255-261.
124. Pop E., Prókai-Tátrai K., Scott J.D., Brewster M.E., Bodor N. Application of a brain-targeting chemical delivery system to 9-amino-1,2,3,4-tetrahydroacridine. Pharm. Res. 7:1990;658-664.
125. Pop E., Soti F., Anderson W.R., Panetta J.A., Estes K.S., Bodor N.S., Brewster M.E. Redox targeting of LY231617, an antioxidant with potential use in the treatment of brain damage. Int. J. Pharm. 140:1996;33-44.
126. Phelan M.J., Bodor N. Improved delivery through biological membranes. XXXVII. Synthesis and stability of novel redox derivatives of naproxen and indomethacin. Pharm. Res. 6:1989;667-676.
127. Pop E., Anderson W., Prókai-Tátrai K., Vlasak J., Brewster M.E., Bodor N. Synthesis and preliminary pharmacological evaluation of some chemical delivery systems of 2,6-diisopropylphenol (propofol). Med. Chem. Res. 2:1992;16-21.
128. Anderson W., Pop E., Lee S.-K., Bodor N., Brewster M. Brain-targeting chemical delivery systems for adenosine depresses locomotor behavior in rats. Med. Chem. Res. 1:1991;74-79.
129. Pop E., Anderson W., Prókai-Tátrai K., Brewster M.E., Fregly M., Bodor N. Antihypertensive activity of redox derivatives of tryptophan. J. Med. Chem. 33:1990;2216-2221.
130. Bodor N., Prokai L., Wu W.-M., Farag H.H., Jonnalagadda S., Kawamura M., Simpkins J. A strategy for delivering peptides into the central nervous system by sequential metabolism. Science. 257:1992;1698-1700.
131. Prokai-Tatrai K., Prokai L., Bodor N. Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design. J. Med. Chem. 39:1996;4775-4782.
132. Prokai L., Ouyang X.-D., Wu W.-M., Bodor N. Chemical delivery system to transport a pyroglutamyl peptide to the central nervous system. J. Am. Chem. Soc. 116:1994;2643-2644.
133. Bodor N., Buchwald P. All in the mind. Chem. Br. 34(1):1998;36-40.
134. Chen P., Bodor N., Wu W.-M., Prokai L. Strategies to target kyotorphin analogues to the brain. J. Med. Chem. 41:1998;3773-3781.
135. Somogyi G., Nishitani S., Nomi D., Buchwald P., Prokai L., Bodor N. Targeted drug delivery to the brain via phosphonate derivatives. I. Design, synthesis, and evaluation of an anionic chemical delivery system for testosterone. Int. J. Pharm. 166:1998;15-26.
136. Somogyi G., Buchwald P., Nomi D., Prokai L., Bodor N. Targeted drug delivery to the brain via phosphonate derivatives. II. Anionic chemical delivery system for zidovudine (AZT). Int. J. Pharm. 166:1998;27-35.
137. Bodor N., Buchwald P. Molecular size based approach to estimate partition properties for organic solutes. J. Phys. Chem. B. 101:1997;3404-3412.
138. Buchwald P., Bodor N. Octanol-water partition of nonzwitterionic peptides: predictive power of a molecular size based model. Proteins. 30:1998;86-99.
139. Buchwald P., Bodor N. Molecular size-based model to describe simple organic liquids. J. Phys. Chem. B. 102:1998;5715-5726.
140. Bodor N., Buchwald P., Huang M.-J. Computer assisted design of new drugs based on retrometabolic concepts. SAR QSAR Environ. Res. 8:1998;41-92.
141. Pop E. Optimization of the properties of brain specific chemical delivery systems by structural modifications. Curr. Med. Chem. 4:1997;279-294.
142. Kaplan N.M. Cardiovascular complications of oral contraceptives. Annu. Rev. Med. 29:1978;31-40.
143. Fotherby K. Oral contraceptives, lipids and cardiovascular disease. Contraception. 31:1985;367-394.
144. Upton G.V. Therapeutic considerations in the management of the climacteric. J. Reprod. Med. 29:1984;71-79.
145. Maggi A., Perez J. Role of female gonadal hormones in the CNS: clinical and experimental aspects. Life Sci. 37:1985;893-906.
146. Janocko L., Lamer J.M., Hochberg R.B. The interaction of C-17 esters of estradiol with the estrogen receptor. Endocrinology. 114:1984;1180-1186.
147. Simpkins J.W., McCornack J., Estes K.S., Brewster M.E., Shek E., Bodor N. Sustained brain-specific delivery of estradiol causes long-term suppression of luteinizing hormone secretion. J. Med. Chem. 29:1986;1809-1812.
148. Estes K.S., Brewster M.E., Simpkins J.W., Bodor N. A novel redox system for CNS-directed delivery of estradiol causes sustained LH suppression in castrate rats. Life Sci. 40:1987;1327-1334.
149. J. Szejtli, Cyclodextrins and their Inclusion Complexes, Akadémiai Kiadó, Budapest, 1982.
150. Szejtli J. Medicinal applications of cyclodextrins. Med. Res. Rev. 14:1994;353-386.
151. Brewster M.E., Estes K.E., Loftsson T., Perchalski R., Derendorf H., Mullersman G., Bodor N. Improved delivery through biological membranes. XXXI. Solubilization and stabilization of an estradiol chemical delivery system by modified β-cyclodextrins. J. Pharm. Sci. 77:1988;981-985.
152. Pitha J., Pitha J. Amorphous water-soluble derivatives of cyclodextrins: nontoxic dissolution enhancing excipients. J. Pharm. Sci. 74:1985;987-990.
153. Pop E., Loftsson T., Bodor N. Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-β-cyclodextrin. Pharm. Res. 8:1991;1044-1049.
154. A.J. Kastin, R.H. Ehrensing, W.A. Banks, J.E. Zadina, Possible therapeutic implications of the effects of some peptides on the brain, in: E.R. de Kloet, V.M. Wiegant, D. de Wied (Eds.), Progress in Brain Research, Vol. 72, Neuropeptides and Brain Function, Elsevier, Amsterdam, 1987, pp. 223-234.
155. C.B.E. Nemeroff, Neuropeptides in Psychiatric and Neurological Disorders, John Hopkins University Press, Baltimore, 1988.
156. C.H.V. Hoyle, Neuropeptides. Essential Data, Wiley, Chichester, 1996.
157. N. Bodor, L. Prokai, Molecular packaging: peptide delivery to the central nervous system by sequential metabolism, in: M. Taylor, G. Amidon (Eds.), Peptide-Based Drug Design: Controlling Transport and Metabolism, American Chemical Society, Washington, DC, 1995, pp. 317-337.
158. Hughes J., Smith T.V., Kosterlitz H.W., Fothergill L., Morgan B.A., Morris H.R. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 258:1975;577-579.
159. Thomas P. Top ten advances of 1992. Harvard Health Lett. 18:1993;1-4.
160. Takagi H., Shiomi H., Ueda H., Amano H. A novel analgesic dipeptide from bovine brain is a possible Met-enkephalin releaser. Nature. 282:1979;410-412.
161. Buchwald P., Bodor N. Octanol-water partition searching for predictive models. Curr. Med. Chem. 5:1998;353-380.