Designing safe drugs: What to consider?

Expert Opinion on Drug Discovery

Volumn 3, Issue 7, 2008, Pages 707-713

  Kramer, Jeffrey A ^a  

^a LEXICON PHARMACEUTICALS INC   (United States)

Author keywords

Preclinical drug development; Toxicity

Indexed keywords

ANDROGEN RECEPTOR; ANTICOAGULANT AGENT; CIPROFIBRATE; CLOFIBRATE; CYTOCHROME P450; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DRUG METABOLITE; EPLERENONE; FENOFIBRATE; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; PROGESTERONE RECEPTOR; RALOXIFENE; SMALL INTERFERING RNA; SPIRONOLACTONE;

ABSENCE OF SIDE EFFECTS; BIOINFORMATICS; DOSE RESPONSE; DRUG APPROVAL; DRUG COST; DRUG DESIGN; DRUG EFFECT; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; EDITORIAL; ENZYME ASSAY; ENZYME INACTIVATION; ENZYME INHIBITION; GENE TARGETING; GENETIC MODEL; GYNECOMASTIA; HEART FAILURE; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; MEDICAL TECHNOLOGY; MICROARRAY ANALYSIS; NONHUMAN; PHARMACOLOGICAL PARAMETERS; PREDICTION; PRIORITY JOURNAL; PROTEIN TARGETING; RISK REDUCTION; RNA INTERFERENCE; STANDARDIZATION; STRUCTURE ACTIVITY RELATION;

EID: 48049112010     PISSN: 17460441     EISSN: None     Source Type: Journal    
DOI: 10.1517/17460441.3.7.707     Document Type: Editorial

References (30)

1. International Centre for Medicines Research, "The CMR International 2004 R&D Factbook." 2004
2. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3(8):711-5
3. Kramer JA, Sagartz JE, Morris DL. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat Rev Drug Discov 2007;6(8):636-49
4. Fielden MR, Kolaja KL. The role of early in vivo toxicity testing in drug discovery toxicology. Expert Opin Drug Saf 2008;7(2):107-10
5. Helvig C, et al. Suicide inactivation of cytochrome P450 by midchain and terminal acetylenes. A mechanistic study of inactivation of a plant lauric acid omega-hydroxylase. J Biol Chem 1997;272(1):414-21
6. Nakajima M, et al. Isoform selective inhibition and inactivation of human cytochrome P450s by methylenedioxyphenyl compounds. Xenobiotica 1999;29(12):1191-202
7. Bencz Z, Ivan E, Cholnoky E. Analysis of cataract and keratotic damage induced by 4-diethylaminoethoxy-alpha-ethyl-benzhydrol (RGH-6201) in rats. Arch Toxicol Suppl 1985;8:476-9
8. Menard J. The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol 2004;217(1-2):45-52
9. Barnes BJ, Howard PA. Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure. Ann Pharmacother 2005;39(1):68-76
10. Lee SS, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 1995;15(6):3012-22
11. Adgey AA. Bleeding complications with new antithrombotics used in ischaemic heart disease. Haemostasis 1996;26(5):237-46
12. Tabacova S. Mode of action: angiotensin-converting enzyme inhibition - developmental effects associated with exposure to ACE inhibitors. Crit Rev Toxicol 2005;35(8-9):747-55
13. Hilgers KF, et al. Aberrant renal vascular morphology and renin expression in mutant mice lacking angiotensin-converting enzyme. Hypertension 1997;29(1 Pt 2):216-21
14. Zambrowicz BP, Turner CA, Sands AT. Predicting drug efficacy: knockouts model pipeline drugs of the pharmaceutical industry. Curr Opin Pharmacol 2003;3(5):563-70
15. Rudmann DG, Durham SK. Utilization of genetically altered animals in the pharmaceutical industry. Toxicol Pathol 1999;27(1):111-4
16. Martin M, Reidhaar-Olson JF, Rondinone CM. Genetic association meets RNA interference: large-scale genomic screens for causation and mechanism of complex diseases. Pharmacogenomics 2007;8(5):455-64
17. Berg AL, Bohlooly YM. The program for phenotyping of genetically modified animals at AstraZeneca. Exp Toxicol Pathol 2006;57(5-6):383-4
18. Foster WR, et al. A retrospective analysis of toxicogenomics in the safety assessment of drug candidates. Toxicol Pathol 2007;35(5):621-35
19. Nomanbhoy TK, et al. Inhibitor focusing: direct selection of drug targets from proteomes using activity-based probes. Assay Drug Dev Technol 2003;1(1 Pt 2):137-46
20. Olson H, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000;32(1):56-67
21. Tateno C, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol 2004;165(3):901-12
22. Dieckhaus CM, et al. Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 2005;18(4):630-8
23. Vickers AE, et al. Kidney slices of human and rat to characterize cisplatin-induced injury on cellular pathways and morphology. Toxicol Pathol 2004;32(5):577-90
24. Luyendyk JP, et al. Unique gene expression and hepatocellular injury in the lipopolysaccharide-ranitidine drug idiosyncrasy rat model: comparison with famotidine. Toxicol Sci 2006;90(2):569-85
25. Roth RA, Ganey PE. Successes and frustrations in developing animal models of idiosyncratic drug reactions. Chem Biol Interact 2005;152(2-3):165; author reply 167-8
26. Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol 1998;11(9):969-88
27. Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 2005;35(4):325-61
28. Mitchell MD, et al. Peptide-based in vitro assay for the detection of reactive metabolites. Chem Res Toxicol 2008;21(4):859-68
29. Pharmaceutical Research and Manufacturers of America, Pharmaceutical Industry Profile. Washington DC: PhRMA, 2007
30. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003;22(2):151-85