Prodrugs of peptides and proteins for improved formulation and delivery

Annual Review of Pharmacology and Toxicology

Volumn 33, Issue , 1993, Pages 521-544

  Oliyai, Reza ^a   Stella, Valentino J ^a  

^a UNIVERSITY OF KANSAS   (United States)

Author keywords

Drug delivery; Peptide delivery; Permeability; Solubility; Stability

Indexed keywords

METENKEPHALIN DERIVATIVE; PEPTIDE DERIVATIVE; PRODRUG; PROTEIN DERIVATIVE; PROTIRELIN DERIVATIVE;

DRUG ADMINISTRATION; DRUG FORMULATION; DRUG METABOLISM; DRUG SOLUBILITY; DRUG STABILITY; DRUG TRANSPORT; HUMAN; MEMBRANE PERMEABILITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; REVIEW;

EID: 0027406209     PISSN: 00664251     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pa.33.040193.002513     Document Type: Review

References (121)

1. Sanders, L. M. 1990. Drug delivery system and routes of administration of peptide and protein drugs. Eur. J. Drug Metab. Pharmacokinet. 15:95-102
2. Davis, S. S. 1986. Advanced delivery systems for peptides and proteins-pharmaceutical considerations. In Delivery Systems for Peptide Drugs, ed. S. S. Davis, L. Illum, E. Tomlinson, pp. 1-21. New York: Plenum
3. Humphrey, M. J., Ringrose, P. S. 1986. Peptides and related drugs: A review of their absorption, metabolism and excretion. Drug Metab. Rev. 17: 283-310
4. Lee, V. H. L., Yamamoto, A. 1990. Penetration and enzymatic barriers to peptide and protein absorption. Adv. Drug Deliv. Rev. 4:171-207
5. Wiedhaup, K. 1981. The stability of small peptides in the gastrointestinal tract. In Topics in Pharmaceutical Sciences, ed. D. D. Breimer, P. Speiser, pp. 307-24. Amsterdam: Elsevier
6. Wang, Y. J., Pearlman, R., eds. 1992. Stability and characterization of protein and peptide drugs. Case histories. In Pharmaceutical Biotechnology, Vol. 5. New York/London: Plenum. In press
7. Zhou, X. H., Li Wan Po, A. 1991. Peptide and proteins drugs: II. Nonparenteral routes of delivery. Int. J. Pharm. 75:117-30
8. Su, K. S. E. 1986. Intranasal delivery of peptides and proteins. Pharm. Int. 7:8-11
9. Saffran, M., Bedra, C., Kumar, S., Neckers, D. C. 1988. Vasopressin: A model for the study of effects of additives on the oral and rectal administration of peptide drugs. J. Pharm. Sci. 77:33-38
10. Angust, B. J., Rogers, N. J., Shefter, E. 1988. Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of the a bile salt absorption promoter. J. Pharmacol. Exp. Ther. 244:23-27
11. Hussain, M. A., Shenvi, A. B., Rowe, S. M., Shefter, E. 1989. The use of α-aminoboronic acid derivatives to stabilize peptide drugs during their intranasal absorption. Pharm. Res. 6: 186-89
12. Lee, V. H. L. 1990. Protease inhibitors and penetration enhancers as approaches to modify peptide absorption. J. Control. Release 13:213-23
13. Ziv, E., Lior, O., Kidron, M. 1987. Absorption of protein via the intestinal wall. A quantitative model. Biochem. Pharmacol. 36:1035-39
14. Chiou, G. C. Y., Chuang, C. Y. 1989. Improvement of systemic absorption of insulin through eyes with absorption enhancers. J. Pharm. Sci. 78:815-18
15. Van Hoogdalem, E. J., Heijligers-Feijen, C. D., deBoer, A. G., Verhoef, J. C., Breimer, D. D. 1989. Rectal absorption enhancement of des-enkephalin-γ-endorphin (DEγE) by medium-chain glycerides and EDTA in conscious rats. Pharm. Res. 6:91-95
16. Hutchinson, F. G., Furr, B. J. A. 1990. Biodegradable polymer system for the sustained release of polypeptides. J. Control. Release 13:279-94
17. Damge, C., Michel, C., Aprahamian, M., Couvreur, P., Devissagute, J. P. 1990. Nanocapsules as carriers for oral peptide delivery. J. Control. Release 13:233-39
18. Plattner, J. J., Marcotte, P. A., Kleinert, H. D., Stein, H. H., Greer, J., et al. 1988. Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability. J. Med. Chem. 31:2277-88
19. Morley, J. S. 1980. Structure-activity relationships of enkephalin-like peptides. Annu. Rev. Pharmacol. Toxicol. 20:81-110
20. Higuchi, T., Stella, V. J. 1975. Prodrugs as Novel Drug Delivery Systems. Washington, DC: Am. Chem. Soc.
21. Bundgaard, H. 1985. Design of Prodrugs. New York: Elsevier
22. Young, S. D., Payne, L. S., Thompson, W. J., Gaffin, N., Lyle, T. A., et al. 1992. HIV-1 protease inhibitor based on hydroxyethylene dipeptide isosteres: An investigation into the role of the P1′ side chain on structure-activity. J. Med. Chem. 35:1702-9
23. Tucker, T. J., Lumma, W. C., Payne, L. S., Wai, J. M., de Solms, S. J., et al. 1992. Series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: Synthesis, enzyme inhibition, and antiviral activity. J. Med. Chem. 35:2525-33
24. Ismailos, G., Reppas, C., Dressman, J. B., Macheras, P. 1991. Unusual solubility behavior of cyclosporin A in aqueous media. J. Pharm. Pharmacol. 43:287-89
25. Ishikawa, K., Fukami, T., Nagase, T., Fujita, K., Hayama, T., et al. 1992. Cyclic pentapeptide endothelin antagonists with high ETA selectivity. Potency-and solubility-enhancing modifications. J. Med. Chem. 35:2139-42
26. Gordee, R. S., Zeckner, D. J., Howard, L. C., Alborn, W. E., Debono, M. 1988. Anti-candida activity and toxicology of LY121019, a novel semi-synthetic polypeptide antifungal antibiotic. Ann. NY Acad. Sci. 544:294-301
27. Balkovec, J. M., Black, R. M., Hammond, M. L., Heck, J. V., Zambias, R. A., et al. 1992. Synthesis, stability, and biological evaluation of water-soluble prodrugs of a new echinocandin lipopeptide. Discovery of a potential clinical agent for the treatment of systemic candidiasis and pneumocystis carinii pneumonia (PCP). J. Med. Chem. 35:194-98
28. Hajdu, R., Sundelof, J. G., Bartizal, K., Abruzzo, G., Trainor, C., et al. 1991. Comparative pharmacokinetics in four animal species of L-688,786 and its water-soluble prodrug L-693,989. Proc. ICAAC, 31st, Chicago, IL, Sept. 29-Oct. 2, Abstr. 209
29. Blaakmeer, J., Tijsse-Klasen, T., Tesser, G. I. 1991. Enhancement of solubility by temporary dimethoxybenzyl-substitution of peptide bonds. Int. J. Pept. Protein Res. 37:556-64
30. Fournié-Zaluski, M. C., Coric, P., Turcaud, S., Lucas, E., Nobel, F., et al. 1992. 'Mixed-inhibitor-prodrug' as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes. J. Med. Chem. 35:2473-81
31. Fournié-Zaluski, M. C., Coric, P., Turcaud, S., Bruetschy, L., Lucas, E., et al. 1992. Potent and systemically active aminopeptidase N inhibitors designed from active site investigation. J. Med. Chem. 35:1259-66
32. Swynnerton, N. F., McGovern, E. P., Mangold, D. J., Nino, J. A., Gouse, E. M., Fleckenstein, L. 1983. HPLC assay for S-2-(3-aminopropylamino) ethylphophorothioate (WR-2721. in plasma. J. Liq. Chromatogr. 6:1523-34
33. Manning, M. C., Patel, K., Borchardt, R. T. 1989. Stability of protein pharmaceuticals. Pharm. Res. 6:903-18
34. Ahern, T. J., Manning, M. C. eds. 1992. Stability of protein pharmaceuticals: Chemical and physical pathways of protein degradation. In Pharmaceutical Biotechnology, Vol. 2. New York/London: Plenum. In press
35. Alber, T. 1989. Mutational effects on protein stability. Annu. Rev. Biochem. 58:765-98
36. Alber, T., Wozniak, J. A. 1985. A genetic screen for mutations the increased the stability of phage T4 lysozyme. Proc. Natl. Acad. Sci. USA 82:747-50
37. Hampsey, D. M., Das, G., Sherman, F. 1988. Yeast iso-1-cytochrome c: Genetic analysis of structural requirements. FEBS Lett. 231:275-83
38. Friedman, D. I., Amidon, G. L. 1991. Oral absorption of peptides: Influence of pH and inhibitors on the intestinal hydrolysis of Leu-enkephalin and analogues. Pharm. Res. 8:93-96
39. Friedman, D. I., Amidon, G. L. 1989. Intestinal absorption mechanism of dipeptide angiotensin converting enzyme inhibitors of the lysyl-proline type: lisinopril and SQ 29,852. J. Pharm. Sci. 78:995-98
40. Matthews, D. M. 1975. Intestinal absorption of peptides. Physiol. Rev. 55: 537-607
41. Adibi, S. A. 1971. Intestinal transport of dipeptide in man: Relative importance of hydrolysis and intact absorption. J. Clin. Invest. 50:2266-75
42. Adibi, S. A., Morse, E. L. 1977. The number of glycine residues which limit intact absorption of glycine oligopeptides in human jejunum. J. Clin. Invest. 60:1008-16
43. Kenny, A. J., Maroux, S. 1982. Topology of microvillar membrane hydrolases of kidney and intestine. Physiol. Rev. 62:91-128
44. Ward, P. E., Sheridan, M. A. 1983. Immunoelectrophoretic analysis of renal and intestinal brush border converting enzyme. Biochem. Pharmacol. 32:265-74
45. Tobey, N., Haizers, W., Yeh, R., Huang, T.-I., Hoffner,C. 1985. Human intestinal brush border peptidases. Gastroenterology 88:913-26
46. Hussain, M. M. 1985. Reconstitution of purified dipeptidyl peptidase IV. A comparison with aminopeptidase N with respect to morphology and influence of anchoring peptide on function. Biochim. Biophys. Acta 815:306-12
47. Krieter, P. A., Olins, G. M., Verret, S. P., Durley, R. C. 1989. In vivo metabolism of atrial natriuretic peptide: Identification of plasma metabolites and enzyme responsible for their generation. J. Pharmacol. Exp. Ther. 249:411-17
48. Edgington, S. M. 1991. The anatomy of access: peptide drug delivery. Bio/Technology 9:1327-31
49. Amsberry, K. L., Borchardt, R. T. 1990. The lactonization of 2′-hydroxyhydrocinnamic acid amides: A potential prodrug for amines. J. Org. Chem. 55:5867-77
50. Amsberry, K. L., Borchardt, R. T. 1991. Amine prodrugs which utilize hydroxy amide lactonization. I. A potential redox-sensitive amide prodrug. Pharm. Res. 8:323-30
51. Amsberry, K. L., Gerstenberger, A. E., Borchardt, R. T. 1991. Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug. Pharm. Res. 8:455-61
52. Milstien, S., Cohen, L. A. 1972. Stereopopulation control. I. Rate enhancement in the lactonization of o-hydroxyhydrocinnamic acids. J. Am. Chem. Soc. 94:9158-65
53. Caswell, M., Schmir, G. L. 1980. Formation and hydrolysis of lactone of phenolic acids. J. Am. Chem. Soc. 102:4815-21
54. Rasmussen, G. J., Bundgaard, H. 1991. Prodrugs of peptides. 15. 4-Imidazolidinone prodrug derivatives of enkephalins to prevent aminopeptidase-catalyzed metabolism in plasma and absorptive mucosae. Int. J. Pharm. 76:113-22
55. Hanson, H. T., Smith, E. L. 1948. The application of peptides containing β-alanine to the study of the specificity of various peptidases. J. Biol. Chem. 175:833-48
56. Snoke, J. E., Neurath, H. 1949. Structural requirements of specific substrate for carboxypeptidases. J. Biol. Chem. 181:789-802
57. Bundgaard, H., Rasmussen, G. J. 1991. Prodrugs of peptides. 9. Bioreversible N-α-hydroxyalkylation of the peptide bond to effect protection against carboxypeptidases or other proteolytic enzymes. Pharm. Res. 8:313-22
58. Bundgaard, H., Rasmussen, G. J. 1991. Prodrugs of peptides. 11. Chemical and enzymatic hydrolysis kinetics of N-acyloxymethyl derivatives of a peptide-like bond. Pharm. Res. 8:1238-42
59. Bundgaard, H. 1992. Means to enhance penetration. (1) Prodrugs as means to improve the delivery of peptide drugs. Adv. Drug Deliv. Rev. 8:1-38
60. Steitz, T. A., Henderson, R., Blow, D. M. 1969. Structure of crystalline α-chymotrypsin. III. Crystallographic studies of substrates and inhibitors bound to the active site of α-chymotrypsin. J. Mol. Biol. 46:337-48
61. Bender, M. L., Killheffer, J. V. 1973. Chymotrypsins. Crit. Rev. Biochem. 1:149-99
62. Konno, S., Stammer, C. H. 1978. The synthesis of N-benzyloxycarbonyl-L-prolyl-dehydrophenylalanyl-LL-histidyl -L-leucine. Int. J. Pept. Protein Res. 12:222-31
63. Kahns, A. H., Bundgaard, H. 1991. Prodrugs of peptides. 14. Bioreversible derivatization of the tyrosine phenol group to effect protection of tyrosyl peptides against α-chymotrypsin. Int. J. Pharm. 76:99-112
64. Kundu, N., Roy, S., Maenza, F. 1972. Esterase activity of chymotrypsin on oxygen-substituted tyrosine substrate. Eur. J. Biochem. 28:311-15
65. Griffiths, E. C. 1987. Clinical application of thyrotropin-releasing hormone. Clin. Sci. 73:449-57
66. Hichens, M. 1983. A comparison of thyrotropin-releasing hormone with analogs: influence of disposition upon pharmacology. Drug Metab. Rev. 14: 77-98
67. Møss, J., Buur, A., Bundgaard, H. 1990. Prodrugs of peptides. 8. In vitro study of intestinal metabolism and penetration of thyrotropin-releasing hormone (TRH) and its prodrugs. Int. J. Pharm. 66:183-91
68. Møss, J., Bundgaard, H. 1990. Prodrugs of peptides 7. Transdermal delivery of thyrotropin-releasing hormone (TRH) via prodrugs. Int. J. Pharm. 66:39-45
69. Lundin, S., Møss, J., Bundgaard, H., Artursson, P. 1991. Absorption of thyrotropin-releasing hormone (TRH) and a TRH prodrug in human intestinal cell line (Caco-2). Int. J. Pharm. 76: R1-R4
70. Nellans, H. N. 1991. Mechanism of peptide and protein absorption. Paracellular intestinal transport: modulation of absorption. Adv. Drug Deliv. Rev. 7:339-64
71. Adibi, S. A., Kim, Y. S. 1981. Peptide absorption and hydrolysis. In Physiology of Gastrointestinal Tract, ed. L. R. Johnson, p. 1073. New York: Raven
72. Lein, E. J. 1981. Structure-activity relationships and drug disposition. Annu. Rev. Pharmacol. Tox. 21:31-61
73. Burton, P. S., Conradi, R. A., Hilgers, A. R. 1991. Transcellular mechanism of peptide and protein absorption: passive aspects. Adv. Drug. Deliv. Res. 7:365-86
74. Ho, N. F. H., Day, J. S., Barsuhn, C. L., Burton, P. S., Raub, T. J. 1990. Biophysical model approaches to mechanistic transepithelial studies of peptides. J. Control. Release 11:3-24
75. Conradi, R. A., Hilgers, A. R., Ho, N. F. H., Burton, P. S. 1991. The influence of peptide structure on the transport across Caco-2 cells. Pharm. Res. 8:1453-60
76. Stein, W. D. 1967. The molecular basis of diffusion across cell membranes. In The Movement of Molecules Across Cell Membranes, pp. 65-125. New York: Academic
77. Diamond, J. M., Wright, E. M. 1969. Molecular forces governing non-electrolyte permeation through cell membranes. Proc. R. Soc. London Ser. B 172:173-316
78. Conradi, R. A., Allen, R. H., Ho, N. F. H., Burton, P. S. 1992. The influence of peptide structure on transport across caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9: 435-39
79. Mason, R. P., Rhodes, D. G., Herbette, L. G. 1991. Reevaluating equilibrium and kinetic binding parameters for lipophilic drugs based on a structural model for drug interaction with biological membranes. J. Med. Chem. 34:869-77
80. Naringrekar, V. H., Stella, V. J. 1990. Mechanism of hydrolysis and structure-stability relationship of enaminones as potential prodrugs of model primary amines. J. Pharm. Sci. 79:138-46
81. Vida, J. A., Gordon, M. 1984. Conformationally directed drug design. ACS Symp. Ser. 251. Washington, DC: Am. Chem. Soc.
82. Kessler, H., Griesinger, C., Wagner, K. 1987. Peptide conformations. 42. Conformation of side chains in peptides using heteronuclear coupling constants obtained by two-dimensional NMR spectroscopy. J. Am. Chem. Soc. 109: 6927-33
83. Kim, Y., Prestegard, J. H. 1990. Demonstration of a conformational equilibrium in acyl carrier protein from spinach using rotating frame nuclear magnetic resonance spectroscopy. J. Am. Chem. Soc. 112:3707-9
84. Briggs, M. S., Cornell, D. G., Dluhy, R. A., Gierasch, L. M. 1986. Conformations of signal peptides induced by lipids suggest initial steps in protein export. Science 233:206-8
85. McKinght, C. J., Stradley, S. J., Jones, J. D., Gierasch, L. M. 1991. Conformational and membrane binding properties of signal sequence are largely unaltered by its adjacent mature region. Proc. Natl. Acad. Sci. USA 88:5799-803
86. Hoyt, D. W., Gierasch, L. M. 1991. Hydrophobic content and lipid interactions of wild-type and mutant OmpA signal peptides correlate with their in vivo function. Biochemistry 30:10155-63
87. Bruch, M. D., Gierasch, L. M. 1990. Comparison of helix stability in wild-type and mutant LamB signal sequences. J. Biol. Chem. 265:3851-58
88. Matthews, D. M., Payne, J. W. 1980. Transmembrane transport of small peptides. Curr. Top. Membr. Transp. 14: 331-425
89. Addison, J. M., Burston, D., Dalrymple, J. A., Matthews, D. M., Payne, J. W., et al. 1975. A common mechanism for transport of di- and tri-peptides by hamster jejunum in vitro. Clin. Sci. Mol. Med. 49:313-22
90. Addison, J. M., Burston, D., Payne, J. W., Wilkinson, S., Matthews, D. M. 1975. Evidence for active transport of tripeptides by hamster jejunum in vitro. Clin. Sci. Mol. Med. 49:305-12
91. Nakashima, E., Tsuji, A., Kagatani, S., Yamana, T. 1984. Intestinal absorption mechanism of amino-β-lactam antibiotics. III. Kinetics of carrier-mediated transport across the rat small intestine in situ. J. Pharm. Dyn. 7:452-64
92. Hu, M., Amidon, G. L. 1988. Passive and carrier-mediated intestinal absorption compenents of captopril. J. Pharm. Sci. 77:1007-11
93. Friedman, D. I., Amidon, G. L. 1989. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats: Enalapril and Fosinopril. Pharm. Res. 6:1043-47
94. Hu, M., Subramanian, P., Moseberg, H. I., Amidon, G. L. 1989. Use of the peptide carrier system to improve the intestinal absorption of L-α-methyldopa: Carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-α-methyldopa. Pharm. Res. 6:66-70
95. van Deurs, B., Hansen, S. H., Olsnes, S., Sandvig, K. 1993. Protein uptake and cytoplasmic acess in animal cells. Biological barrier to protein delivery. In Pharmaceutical Biotechnology, ed. K. L. Audus, T. J. Raub, Vol. 4. New York/London: Plenum Press. In press
96. Raub, T. J., Audus, K. L. 1990. Adsorptive endocyctosis amemberane recycling by cultured primary bovine brain microvessel endothelial cell monolayers. J. Cell. Sci. 97:127-38
97. Poznansky, M. J., Juliano, R. L. 1984. Biological approaches to the controlled delivery of drugs: A critical review. Pharmacol. Rev. 36:277-336
98. Gosling, J. P. 1990. A decade of development of immunoassay methodology. Clin. Chem. 36:1408-27
99. Gloff, C. A., Benet, L. Z. 1990. Pharmacokinetics and protein therapeutics. Adv. Drug Deliv. Rev. 4:359-86
100. Kuo, B.-S., Kusmik, W. F., Poole, J. C., Elsea, S. H., Chang, J., Hwang, K.-K. 1992. Pharmacokinetics evaluation of two human epidermal growth factors (hEGF51 and hEGF53) in rats. Drug Metab. Dispos. 20:23-30
101. Bartocci, A., Mastroginannis, A., Migliorati, G., Stockert, R. J., Wolkoff, A. W., Stanley, E. R. 1987. Macrophages specifically regulate the concentration of their own growth factor in the circulation. Proc. Natl. Acad. Sci. USA 84:6179-83
102. Blick, M., Sherwin, S. A., Rosenblum, M., Gutterman, J. 1987. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 47: 2986-89
103. Hilaire, R. J. S., Hradek, G. T., Jones, A. L. 1983. Hepatic sequestration and biliary secretion of epidermal growth factor: Evidence for a high capacity uptake system. Proc. Natl. Acad. Sci. USA 80:3791-801
104. Sugiyama, Y., Hanano, M. 1989. Receptor-mediated transport of peptide hormones and its importance in the overall hormone disposition in the body. Pharm. Res. 6:192-202
105. Baumann, G., Vance, M. L., Shaw, M. A., Thorner, M. O. 1990. Plasma transport of human growth hormone in vivo. Endocrinology 71:470-73
106. Schiff, J. M., Fisher, M. M., Jones, A. L., Underdown, B. J. 1986. Human IgA as a heterovalent ligand: Switching from the asialoglycoprotein receptor to secretory component during transport across the rat hepatocyte. J. Cell Biol. 102:920-31
107. Kim, D. C., Sugiyama, Y., Sawada, Y., Hanano, M. 1992. Renal tubular handling of p-aminohippurate and epidermal growth factor (EGF) in filtering and non-filtering perfused rat kidney. Pharm. Res. 9:271-75
108. Ishii, Y., Aramaki, Y., Hara, T., Tsuchiya, J., Fuwa, T. 1989. Preparation of EGF labeled liposomes and their uptake by hepatocytes. Biochem. Biophys. Res. Commun. 160:732-36
109. Pitt, C. G. 1990. The controlled parenteral delivery of polypeptides and proteins. Int. J. Pharm. 59:173-96
110. Knadker, M. P., Ackermann, J. E., Coutant, J. E., Hurst, G. H. 1992. Metabolism of the anticoagulant peptide, MDL 28,050, in rats. Drug. Metab. Dispos. 20:89-95
111. Ho, D. H., Brown, N. S., Yen, A., Holmes, R., Keating, M., et al. 1986. Clinical pharmacology of polyethylene glycol-L-asparaginase. Drug Metab. Dispos. 14:349-52
112. Rademacher, T. W., Parekh, R. B., Dwek, R. A. 1988. Glycobiology. Annu. Rev. Biochem. 57:785-838
113. Markwardt, F. 1989. Acyl-enzymes as prodrugs. Pharmazie 44:521-26
114. Duckert, F. 1979. Thrombolytic therapy in myocardial infarction. Prog. Cardiovasc. Dis. 21:342-50
115. Wiman, B., Collen, D. 1978. On the kinetics of the reaction between antiplasmin and plasmin. Eur. J. Biochem. 84:573-78
116. Christensen, U., Clemmensen, I. 1977. Kinetic properties of the primary inhibitor of plasmin from human plasma. Biochem. J. 163:389-91
117. Smith, R. A. G., Dupe, R. J., English, P. D., Green, J. 1981. Fibrinolysis with acyl-enzyme: a new approach to thrombolytic therapy. Nature 290:505-7
118. Stürzebecher, J., Kroneck, I., Klöcking, H.-P. 1986. Untersuchungen zur fibrinolytischen Aktivitat von Acyl-urokinase. Folia Haematol. (Leipzig) 113:137-43
119. Stürzebecher, J., Richter, M., Markwardt, F. 1987. Stable acyl-derivatives of tissue-type plasminogen activator. Thromb. Res. 47:699-703
120. Notari, R. E., Huang, M.-Y., Byron, P. R. 1978. Calculation of optimum pharmacokinetic drug supply rates for maximum duration during multiple dose therapy by prodrug administration. Int. J. Pharm. 1:233-47
121. Albert, A. 1965. Selective Toxicity. New York: Wiley. 3rd ed.