Abstract
Antisense oligonucleotides represent a promising, rational, and seductive approach to drug discovery and development. Several early attempts to develop therapeutic agents using this technology targeted clinical conditions which could be treated by local administration of the oligonucleotide, thereby avoiding their systemic use. However, in order for antisense oligonucleotides to reach their full potential as therapeutic entities across a wide variety of disease applications, systemic use is likely to be necessary; identifying and solving any problems associated with systemically administered oligonucleotides is therefore of major importance.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Agrawal S, Tang JY (1992) GEM 91 — an antisense oligonucleotide phosphorothioate as a therapeutic agent for AIDS. Antisense Res Dev 2:261–266
Bayever E, Iversen PL, Bishop MR, Sharp JG, Tewary HK, Arneson MA, Pirruccello SJ, Ruddon RW, Kessinger A, Zon G, Armitage JO (1993) Systemic administration of a phosphorothioate oligonucleotide with a sequence complementary to p53 for acute myelogenous leukemia and myelodysplastic syndrome: initial results of a phase I trial. Antisense Res Dev 3:383–390
Bishop MR, Iversen PL, Bayever E, Sharp JG, Greiner TC, Copple BL, Ruddon R, Zon G, Spinolo J, Arneson M, Armitage JO, Kessinger A (1996) Phase I trial of an antisense oligonucleotide OL(1) p53 in hematologic malignancies. J Clin Oncol 14:320–1326
Black LE, Farrelly JG, Cavagnaro JA, Ahn C-H, DeGeorge JJ, Taylor AS, DeFelice AF, Jordan A (1994) Regulatory considerations for oligonucleotide drugs: update recommendations for pharmacology and toxicology studies. Antisense Res Dev 4:299–301
Bock LC, Griffin LC, Latham JA, Vermaas EH, Toole JJ (1992) Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 355:564–566
Cornish KG, Iversen P, Smith L, Arneson M, Bayever E (1993) Cardiovascular effects of a phosphorothioate oligonucleotide with sequence antisense to p53 in the conscious Rhesus monkey. Pharmacol Commun 3:239–247
Dukes GE, Sanders SW, Russo J, Swenson E, Burnakis TG, Saffle JR, Warden GD (1984) Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 100:646–650
Field AK, Goodchild J (1995) Antisense oligonucleotides: rational drug design for genetic pharmacology. Exp Opin Invest Drugs 4:799–821
Flexner C, Barditch-Crovo PA, Kornhauser DM, Farazadegan H, Nerhood LJ, Chaisson RE, Bell KM, Lorentsen KJ, Hendrix CW, Petty BG, Lietman PS (1991) Pharmacokinetics, toxicity and activity of intravenous dextran sulfate in human immunodeficiency virus infection. Antimicrob Agents Chemother 35: 2544–2550
Galbraith WM, Hobson WC, Giclas PC, Schechter PI, Agrawal S (1994) Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res Dev 4:201–206
Gordon M, Guralnik M, Kaneko Y, Mimura T, Baker M, Lang W (1994) A phase I study of curdlan sulfate — an HIV inhibitor. Tolerance, pharmacokinetics and effects on coagulation and CD4 lymphocytes. J Med 25:163–180
Hjort P, Stormorken H (1957) A study of the vivo effects of a synthetic heparin-like anticoagulant: dextran sulphate. Scand J Clin Lab Invest 9:6–81
King DJ, Kelton JG (1984) Heparin-associated thrombocytopenia. Ann Intern Med 100:535–540
Lisziewicz J, Sun D, Wiechold FF, Thierry AR, Lusso P, Tang J, Gallo RC, Agrawal S (1994) Antisense oligodeoxynucleotide phosporothioate complementary to gag mRNA blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells. Proc Natl Acad Sci U S A 91:7942–7946
Monreal M, Lafoz E, Salvador R, Roncales J, Navarro A (1989) Adverse effects of three different forms of heparin therapy: thrombocytopenia, increased transaminases and hyperkalemia. Eur J Clin Pharmacol 37:415–418
Nakashima H, Inazawa K, Iciyama K, Ito M, Ikushima N, Shoji T, Katsuraya K, Uryu T, Yamamoto N, Juodawikis AS, Schinazi RF (1995) Sulfated alkyl oligosaccharides inhibit human immunodeficiency virus in vitro and provide sustained drug levels in mammals. Antiviral Chem Chemother 6:271–280
Nelson JC, Lerner RG, Goldstein R, Cagin NA (1978) Heparin-induced thrombocytopenia. Arch Intern Med 138:548–552
Olsson R, Korsan-Bengstein BM, Korsan-Bengstein K, Lennartsson J, Waldestrom J (1978) Serum aminotransferases after low-dose heparin treatment. Acta Med Scand 204:229–230
Powers PJ, Kelton JG, Carter CJ (1984) Studies on the frequency of heparin-associated thrombocytopenia. Thromb Res 33:439–443
Sarmiento UM, Perez JR, Becker JM, Narayanan R (1994) In vivo toxicological effects of rel A antisense phosphorothioates in CD-1 mice. Antisense Res Dev 4:99–107
Sereni D, Katlama C, Gouyette A, Re M, Lascoux C, Tubiana R, Tournerie C (1994) Open-label safety and pharmacokinetic study of single intravenous or subcutaneous ascending doses of GEM 91 in untreated, adult, HIV positive, asymptomatic human volunteer patients. In: Proceedings of the 34th interscience conference on antimicrobial agents and chemotherapy, Orlando, 4–7 October 1994, p 217
Sereni D, Katlama C, Vilde JL, Bouvet E, Brun-Vezinet F, Gouyette A, Tournerie C (1995) An open-label, multiple-dose safety, pharmacokinetic and preliminary antiviral activity study of GEM 91 administered by intermittent intravenous infusion in HIV-positive adults. In: Proceedings of the 35th interscience conference on antimicrobial agents and chemotherapy, San Francisco, 17–20 September 1995, p 236
Shanahan W, Glover J, Mant T, Amin D, Leeds J, Zuckerman J, Levin A (1996) Phase I study of an ICAM-1 antisense oligonucleotide (ISIS 2302). Clin Pharmacol Ther 59:208
Srinivasan SK, Iversen P (1995) Review of vivo pharmacokinetics and toxicology of phosphorothioate oligonucleotides. J Clin Lab Anal 9:129–137
Toulon P, Ankri A, Tournerie C, Sereni D (1995) Effect of GEM 91, a phosphorothioate on the coagulation system. Results of ex vivo and vitro studies. Blood 86:889a
Wallace TL, Bazemore SA, Kornbrust DJ, Cossum PA (1996) Single-dose hemodynamic toxicity and pharmacokinetics of a partial phosphorothioate anti-HIV oligonucleotide (AR177) after intravenous infusion to cynomolgus monkeys. J Pharmacol Exp Ther 59:208
Zhang RW, Diasio RB, Lu ZH, Liu TP, Jiang ZW, Galbraith WM, Agrawal S (1995a) Pharmacokinetics and tissue distribution in rats of an oligodeoxynucleotide phosphorothioate (GEM 91) developed as a therapeutic agent for human immunodeficiency virus type 1. Biochem Pharmacol 49:929–939
Zhang RW, Lu ZH, Zhang XS, Zhao H, Diasio RB, Lui TP, Jiang ZW, Agrawal S (1995b) In vivo stability and disposition of a self-stabilized oligodeoxynucleotide phosphorothioate in rats. Clin Chem 41:836–843
Zhang R, Yan J, Shahinian H, Amin G, Lu Z, Liu T, Saag MS, Jiang Z, Temsamani J, Martin RR, Schechter PJ, Agrawal S, Diasio RB (1995c) Pharmacokinetics of an anti-human immunodeficiency virus antisense oligodeoxynucleotide phosphorothioate (GEM 91) in HIV-infected subjects. Clin Pharmacol Ther 58:44–53
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Schechter, P.J., Martin, R.R. (1998). Safety and Tolerance of Phosphorothioates in Humans. In: Crooke, S.T. (eds) Antisense Research and Application. Handbook of Experimental Pharmacology, vol 131. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-58785-6_7
Download citation
DOI: https://doi.org/10.1007/978-3-642-58785-6_7
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-63730-8
Online ISBN: 978-3-642-58785-6
eBook Packages: Springer Book Archive