Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

AAPS Journal

Volumn 7, Issue 4, 2005, Pages

  Bodor, Nicholas ^a   Buchwald, Peter ^b  

^a UNIVERSITY OF FLORIDA   (United States)

^b IVAX Research Inc   (United States)

Author keywords

Beta blockers; Corticosteroids; Eye targeted delivery; Glaucoma; Intraocular pressure; Oxime

Indexed keywords

ADAPROLOL; AGENTS ACTING ON THE EYE; ALPRENOLOL; ALPRENOXIME; ANTIGLAUCOMA AGENT; ANTIINFLAMMATORY AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BETAMETHASONE; BETAXOLOL; BETAXOXIME; BUDESONIDE; CARTEOLOL; CLOBETASONE; CORTICOSTEROID; DEXAMETHASONE; DIPIVEFRINE; ETIPREDNOL DICLOACETATE; HYDROCORTISONE; ISOPRENALINE; LATANOPROST; LOTEPREDNOL ETABONATE; METOPROLOL; OXIME DERIVATIVE; PLACEBO; PREDNISOLONE ACETATE; PROPRANOLOL; PROSTAGLANDIN F2 ALPHA DERIVATIVE; TIMOLOL; TRAVOPROST; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AMNESIA; ANXIETY DISORDER; BLOOD RETINA BARRIER; BRADYCARDIA; BRONCHOSPASM; CHEMICAL STRUCTURE; CLINICAL TRIAL; CONFUSION; CORNEA; DEPRESSION; DRUG ABSORPTION; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG ELIMINATION; DRUG PENETRATION; DRUG SOLUBILITY; DRUG TARGETING; DYSLIPIDEMIA; EYE BURNING; EYE DISEASE; EYE PAIN; EYE PROTECTION; EYE TOXICITY; EYELID; FOREIGN BODY REACTION; GLAUCOMA; HEART MUSCLE CONTRACTILITY; HUMAN; HYPOTENSION; INTRAOCULAR PRESSURE; MENTAL INSTABILITY; NEUROPROTECTION; NONHUMAN; PERMEABILITY BARRIER; REVIEW; SEXUAL DYSFUNCTION; SHELF LIFE; SLEEP DISORDER; SYSTEMATIC REVIEW; TEAR FLOW; CHEMISTRY; DRUG EFFECT; EYE; METABOLISM; METHODOLOGY;

ADRENAL CORTEX HORMONES; ADRENERGIC BETA-ANTAGONISTS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; EYE; HUMANS;

EID: 33747125838     PISSN: 15221059     EISSN: 15221059     Source Type: Journal    
DOI: 10.1208/aapsj070479     Document Type: Review

References (104)

1. Stewart PA, Tuor UI. Blood-eye barriers in the rat: correlation of ultrastructure with function. J Comp Neurol. 1994;340:566-576.
2. Schoenwald RD. Ocular drug delivery: pharmacokinetic considerations. Clin Pharmacokinet. 1990;18:255-269.
3. Mitra AK, Mikkelson TJ. Mechanism of transcorneal permeation of pilocarpine. J Pharm Sci. 1988;77:771-775.
4. Davies NM. Biopharmaceutical considerations in topical ocular drug delivery. Clin Exp Pharmacol Physiol. 2000;27:558-562.
5. Grass GM, Robinson JR. Mechanism of corneal penetration. I. In vivo and in vitro kinetics. J Pharm Sci. 1988;77:3-14.
6. Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjuctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87:1479-1488.
7. Edwards A, Prausnitz MR. Predicted permeability of the cornea to topical drugs. Pharm Res. 2001; 18:1497-1508.
8. Lee VH, Robinson JR. Topical ocular drug delivery: recent developments and future challenges. J Ocul Pharmacol. 1986;2:67-108.
9. Sasaki H, Yamamura K, Mukai T, et al. Enhancement of ocular drug penetration, Crit Rev Ther Drug Carrier Syst. 1999;16:85-146.
10. Bundgaard H, ed. Design of Prodrugs. Amsterdam, The Netherlands: Elsevier Science; 1985.
11. Bodor N, Kaminski JJ. Prodrugs and site-specific chemical delivery systems. Annu Rep Med Chem. 1987;22:303-313.
12. Wermuth CG, Gaignault J-C, Marchandeau C. Designing prodrugs and bioprecursors I: Carrier prodrugs. In: Wermuth CG, ed. The Practice of Medicinal Chemistry. London, UK: Academic Press; 1996:671-696.
13. Ettmayer P, Amidon GL, Clement B, Testa B. Lessons learned from marketed and investigational prodrugs. J Med Chem. 2004;47:2393-2404.
14. Bodor N. Drug targeting and retrometabolic drug design approaches. Adv Drug Deliv Rev. 1994;14:157-166.
15. Bodor N; Buchwald P. Drug targeting via retrometabolic approaches. Pharmacol Ther. 1997;76:1-27.
16. Bodor N, Buchwald P. Retrometabolism-based drug design and targeting. In: Abraham DJ, ed. Drug Discovery and Drug Development, Burger's Medicinal Chemistry and Drug Discovery. Vol 2. 6th ed. New York, NY: John Wiley and Sons; 2003:533-608.
17. Bodor N, El-Koussi A, Kano M, Nakamuro T. Improved delivery through biological membranes. 26. Design, synthesis, and pharmacological activity of a novel chemical delivery system for β-adrenergic blocking agents. J Med Chem. 1988;31:100-106.
18. El-Koussi A, Bodor N. Formation of propanolol in the iris-ciliary body from its propranolol ketoxime precursor - a potential antiglaucoma drug. Int J Pharm. 1989;53:189-194.
19. Bodor N, Prokai L. Site- and stereospecific ocular drug delivery by sequential enzymatic bioactivation. Pharm Res. 1990;7:723-725.
20. Bodor N, El-Koussi A. Improved delivery through biological membranes. LVI. Pharmacological evaluation of alprenoxime - a new potential antiglaucoma agent. Pharm Res. 1991;8:1389-1395.
21. Simay A, Prokai L, Bodor N. Oxidation of aryloxy-β-amino alcohols with activated dimethylsulfoxide: a novel C-N oxidation facilitated by neighboring group effect. Tetrahedron. 1989;45:4091-4102.
22. Simay A, Bodor N. Site- and stereospecific drug delivery to the eye. In: Sarel S, Mechoulam R, Agranat I, eds. Trends in Medicinal Chemistry '90. Oxford, UK: Blackwell Scientific Publications; 1992:361-368.
23. Bodor N. Retrometabolic drug design concepts in ophthalmic target-specific drug delivery. Adv Drug Deliv Rev. 1995;16:21-38.
24. Polgar P, Bodor N. Minimal cardiac electrophysiological activity of alprenoxime, a site-activated ocular β-blocker, in dogs: Life Sci. 1995;56:1207-1213.
25. Prokai L, Wu W-M, Somogyi G, Bodor N. Ocular delivery of the β-adrenergic antagonist alprenolol by sequential bioactivation of its methoxime analog. J Med Chem. 1995;38:2018-2020.
26. Bodor N, Farag HH, Somogyi G, Wu W-M, Barros MDC, Prokai L. Ocular-specific delivery of timolol by sequential bioactivation of its oxime and methoxime analogs. J Ocul Pharmacol. 1997;13:389-403.
27. Farag HH, Wu W-M, Barros MDC, Somogyi G, Prokai L, Bodor N. Ocular-specific chemical delivery system of betaxolol for safe local treatment of glaucoma. Drug Des Discov. 1997;15:117-130.
28. Nathanson JA. Stereospecificity of beta adrenergic antagonists: R-enantiomers show increased selectivity for beta-2 receptors in ciliary process. J Pharmacol Exp Ther. 1988;245:94-101.
29. Mehvar R, Brocks DR. Stereospecific pharmacokinetics and pharmacodynamics of beta-adrenergic blockers in humans. J Pharm Pharm Sci. 2001;4:185-200.
30. Sharif NA, Xu SX, Crider JY, McLaughlin M, Davis TL. Levobetaxolol (Betaxon) and other beta-adrenergic antagonists: preclinical pharmacology, IOP-lowering activity and sites of action in human eyes. J Ocul Pharmacol Ther. 2001;17:305-317.
31. Nandel FS, Dhaliwal RK, Singh B. Modeling, design, chiral aspects and role of para-substituents in aryloxypropranolamine based beta-blockers. Indian J Biochem Biophys. 1999;36:29-35.
32. Quigley H. How common is glaucoma worldwide? Int Glaucoma Rev [serial online]. 2002; Available at: http://www.glaucom,com/Meetings/3-3/worldwide.php. Accessed August 16, 2005.
33. Moroi SE. Lichter PR. Ocular pharmacology. In: Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill; 1996:1619-1645.
34. Alward WL. Biomedicine: a new angle on ocular development. Science. 2003;299:1527-1528.
35. Radius RL, Diamond GR, Pollack IP, Langham ME. Timolol: a new drug for management of chronic simple glaucoma. Arch Ophthalmol, 1978;96:1003-1008.
36. Sugrue MF. New approaches to antiglaucoma therapy. J Med Chem. 1997;40:2793-2809.
37. Stamper RL, Wigginton SA, Higginbotham EJ. Primary drug treatment for glaucoma: beta-blockers versus other medications. Surv Ophthalmol. 2002;47:63-73.
38. Taniguchi T, Kitazawa Y. The potential systemic effect of topically applied beta-blockers in glaucoma therapy. Curr Opin Ophthalmol. 1997;8:55-58.
39. Hayreh SS, Podhajsky P, Zimmerman MB. Beta-blocker eyedrops and nocturnal arterial hypotension. Am J Ophthalmol. 1999;128:301-309.
40. Nelson WL, Fraunfelder FT, Sills JM, Arrowsmith JB, Kuritsky JN. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978-1985. Am J Ophthalmol. 1986;102:606-611.
41. Lynch MG, Whitson JT, Brown RH, Nguyen H, Drake MM. Topical β-blocker therapy and central nervous system side effects: a preliminary study comparing betaxolol and timolol. Arch Ophthalmol. 1988; 106:908-911.
42. Fraunfelder FT, Meyer SM. Sexual dysfunction secondary to topical ophthalmic timolol. JAMA. 1985;253:3092-3093.
43. Sorensen SJ, Abel SR. Comparison of the ocular beta-blockers. Ann Pharmacother. 1996;30:43-54.
44. Schoene RB, Martin TR, Charan NB, French CL. Timolol-induced bronchospasm in asthmatic bronchitis. JAMA. 1981;245:1460-1461.
45. Van Buskirk EM, Weinreb RN, Berry DP, Lustgarten JS, Podos SM, Drake MM. Betaxolol in patients with glaucoma and asthma. Am J Ophthalmol. 1986;101:531-534.
46. Harris LS, Greenstein SH, Bloom AF. Respiratory difficulties with betaxololl. Am J Ophthalmol. 1986; 102:274-275.
47. Pfitzner KE, Moffat JG. Sulfoxide-carbodiimide reactions. I. A facile oxidation of alcohols. J Am Chem Soc. 1965;87:5661-5670.
48. Bodor N. The soft drug approach. Chemtech. 1984;14:28-38.
49. Bodor N, Buchwald P. Soft drug design: general principles and recent applications. Med Res Rev. 2000;20:58-101.
50. Bodor N. Designing safer ophthalmic drugs. In: Trends in Medicinal Chemistry '88: Proceedings of the Xth International Symposium on Medicinal Chemistry. Amsterdam, The Netherlands: Elsevier; 1989:145-164.
51. Bodor N. The use of retrometabolic drug design concepts in ophthalmic drug discovery. In: Reddy IK, ed. Ocular Therapeutics and Drug Delivery: A Multidisciplinary Approach. Lancaster, PA: Technomic; 1996:335-361.
52. Albert A. Selective Toxicity: The Physico-Chemical Basis of Therapy. London, UK: Chapman and Hall; 1985.
53. Gillette JR. Effects of induction of cytochrome P-450 enzymes on the concentration of foreign compounds and their metabolites and on the toxicological effects of these compounds. Drug Metab Rev. 1979;10:59-87.
54. Mannering GJ. Hepatic cytochrome P-450-linked drug-metabolizing systems. In: Testa B, Jenner P, eds. Concepts in Drug Metabolism. Part B. New York, NY: Marcel Dekker Inc; 1981:53-166.
55. 3H) in man, the dog and the rat. Acta Pharmacol Toxicol (Copenh). 1975;36:125-135.
56. Regardh CG, Johnsson G. Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet. 1980;5:557-569.
57. Benfield P, Clissold SP, Brogden RN. Metoprolol: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in hypertension, ischaemic heart disease and related cardiovascular disorders. Drugs. 1986;31:376-429.
58. Bodor N, Oshiro Y, Loftsson T, Katovich M, Caldwell W. Soft drugs. 6. The application of the inactive metabolite approach for design of soft β-blockers. Pharm Res. 1984;1:120-125.
59. Bodor N, El-Koussi A, Kano M, Khalifa MM. Soft drugs. 7. β-Blockers for systemic and ophthalmic use. J Med Chem. 1988;31:1651-1656.
60. Bodor N, El-Koussi A. Novel 'soft' β-blockers as potential safe antiglaucoma agents. Curr Eye Res. 1988;7:369-374.
61. Polgar P, Bodor N. Cardiac electrophysiologic effects of adaprolol maleate, a new β-blocker, in closed chest dogs. Life Sci. 1991;48:1519-1528.
62. Bodor N, El-Koussi A, Zuobi K, Kovacs P. Synthesis and pharmacological activity of adaprolol enantiomers: a new soft drug for treating glaucoma. J Ocul Pharmacol Ther. 1996;12:115-122.
63. McGhee CN, Dean S, Danesh-Meyer H. Locally administered ocular corticosteroids: benefits and risks. Drug Saf. 2002;25:33-55.
64. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001;33:289-294.
65. Raizman M. Corticosteroid therapy of eye disease: fifty years later. Arch Ophthalmol. 1996;114:1000-1001.
66. Dickerson JE Jr, Dotzel E, Clark AF. Steroid-induced cataract: new perspectives from in vitro and lens culture studies. Exp Eye Res. 1997;65:507-516.
67. Heyns K, Koch W. Über die bildung eines aminozuckers aus d-fruktose und ammoniak. Z Naturforsch [B]. 1952;7B:486-488.
68. Bucala R, Fishman J, Cerami A. Formation of covalent adducts between cortisol and 16α-hydroxyestrone and protein: possible role in the pathogenesis of cortisol toxicity and systemic lupus erythematosus. Proc Natl Acad Sci USA. 1982;79:3320-3324.
69. Manabe S, Bucala R, Cerami A. Nonenzymatic addition of glucocorticoids to lens proteins in steroid-induced cataracts. J Clin Invest. 1984;74:1803-1810.
70. Bucala R, Gallati M, Manabe S, Cotlier E, Cerami A. Glucocorticoid-lens protein adducts in experimentally induced steroid cataracts. Exp Eye Res. 1985;40:853-863.
71. Urban RC, Jr, Cotlier E. Corticosteroid-induced cataracts. Surv Ophthalmol. 1986;31:102-110.
72. Noble S, Goa KL. Loteprednol etabonate: clinical potential in the management of ocular inflammation. BioDrugs. 1998;10:329-339.
73. Howes JF. Loteprednol etabonate: a review of ophthalmic clinical studies. Pharmazie. 2000;55:178-183.
74. Bodor N, Buchwald P. Design and development of a soft corticosteroid, loteprednol etabonate. In: Schleimer RP, O'Byrne PM, Szefler SJ, Brattsand R, eds. Inhaled Steroids in Asthma. Optimizing Effects in the Airways. New York, NY: Marcel Dekker; 2002:541-564.
75. Bodor N, inventor. Stéroïds doux exerçant une activité anti-inflammatoire (Steroids having antiinflammatory activity). Belgian patent BE889,563 (Internat Classif C07J/A61K). November 3, 1981.
76. Bodor N, Varga M. Effect of a novel soft steroid on the wound healing of rabbit cornea. Exp Eye Res. 1990;50:183-187.
77. Druzgala P, Hochhaus G, Bodor N. Soft drugs. 10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate. J Steroid Biochem. 1991;38:149-154.
78. Bodor N, Loftsson T, Wu W-M. Metabolism, distribution, and transdermal permeability of a soft corticosteroid, loteprednol etabonate. Pharm Res. 1992;9:1275-1278.
79. Hochhaus G, Chen L-S, Ratka A, et al. Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs. J Pharm Sci. 1992;81:1210-1215.
80. Bodor N, Murakami T, Wu W-M. Soft drugs. 18. Oral and rectal delivery of loteprednol etabonate, a novel soft corticosteroid, in rats - for safer treatment of gastrointestinal inflammation. Pharm Res. 1995;12:869-874.
81. Bodor N, Wu W-M, Murakami T, Engel S. Soft drugs. 19. Pharmacokinetics, metabolism and excretion of a novel soft corticosteroid, loteprednol etabonate, in rats. Pharm Res. 1995; 12:875-879.
82. Monder C, Bradlow HL. Cortoic acids: explorations at the frontier of corticosteroid metabolism. Recent Prog Horm Res. 1980;36:345-400.
83. Bodor N. Novel approaches for the design of membrane transport properties of drugs. In: Roche EB, ed. Design of Biopharmaceutical Properties Through Prodrugs and Analogs. Washington, DC: Academy of Pharmaceutical Sciences; 1977:98-135.
84. Bodor N. Designing safer drugs based on the soft drug approach. Trends Pharmacol Sci. 1982;3:53-56.
85. Bodor N. Soft drugs: strategies for design of safer drugs, Metabolisme et Conception Medicaments: Quo Vadis? Proceedings of Symposium at Montpellier, France; November 26-27, 1981; Montpellier, France: CLIN MIDY; 1983. 217-251.
86. Druzgala P, Bodor N. Regioselective O-alkylation of cortienic acid and synthesis of a new class of glucocorticoids containing a 17α-alkoxy, a 17α-(1′-alkoxyethyloxy), a 17α-alkoxymethyloxy, or a 17α-methylthiomethyloxy function. Steroids. 1991;56:490-494.
87. Bodor N. The application of soft drug approaches to the design of safer corticosteroids. In: Christophers E, Kligman AM, Schöpf E, Stoughton RB, eds. Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs. New York, NY: Raven Press Ltd; 1988:13-25.
88. Buchwald P, Bodor N. Soft glucocorticoid design: structural elements and physicochemical parameters determining receptor-binding affinity, Pharmazie. 2004;59:396-404.
89. Buchwald P. General linearized biexponential model for QSAR data showing bilinear-type distribution. J Pharm Sci. 2005;94:2355-2379.
90. Druzgala P, Wu W-M, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res. 1991;10:933-937.
91. Bodor N, Bodor N, Wu W-M. A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits. Curr Eye Res. 1992; 11:525-530.
92. Novack GD, Howes J, Crockett RS, Sherwood MB. Change in intraocular pressure during long-term use of loteprednol etabonate. J Glaucoma. 1998;7:266-269.
93. Howes J, Novack GD. Failure to detect systemic levels and effects of loteprednol etabonate and its metabolite, PJ-91, following chronic ocular administration. J Ocul Pharmacol Ther. 1998;14:153-158.
94. Lotemax (Loteprednol Etabonate Ophthalmic Suspension 0.5%) [product monograph]. Rochester, NY: Bausch & Lomb Pharmaceuticals. 1998.
95. Ilyas H, Slonim CB, Braswell GR, Favetta JR, Schulman M. Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye Contact Lens. 2004;30:10-13.
96. Szelenyi I, Hermann R, Petzold U, Pahl A, Hochhaus G. Possibilities in improvement of glucocorticoid treatments in asthma with special reference to loteprednol etabonate. Pharmazie. 2004;59:409-411.
97. Szelenyi I, Hochhaus G, Heer S, et al. Loteprednol etabonate: a soft steroid for the treatment of allergic diseases of the airways. Drugs Today (Barc). 2000;36:313-320.
98. Bodor N, inventor. Androstene derivatives. US patent 5 981 517. November 9, 1999.
99. Barton P, Laws AP, Page MI. Structure-activity relationships in the esterase-catalysed hydrolysis and transesterification of esters and lactones. J Chem Soc, Perkin Trans 2. 1994;2021-2029.
100. Miklós A, Magyar Z, Kiss É, et al. 28-Day oral toxicity study with soft corticosteroid BNP-166 in rats and dogs, followed by a 14-day recovery period. Pharmazie. 2002;57:142-146.
101. Kurucz I, Tóth S, Németh K, et al. Potency and specificity of the pharmacological action of a new, antiasthmatic, topically administered soft steroid, etiprednol dicloacetate (BNP-166). J Pharmacol Exp Ther. 2003;307:83-92.
102. Kurucz I, Németh K, Mészáros S, et al. Anti-inflammatory effect and soft properties of etiprednol dicloacetate (BNP-166), a new, anti-asthmatic steroid. Pharmazie. 2004;59:412-416.
103. Jaffuel D, Demoly P, Gougat C, et al. Transcriptional potencies of inhaled glucocorticoids. Am J Respir Crit Care Med. 2000;162:57-63.
104. Bhalay G, Sandham DA. Recent advances in corticosteroids for the treatment of asthma. Curr Opin Investig Drugs. 2002;3:1149-1156.