Advertisement

Magnetic Resonance Imaging in Pharmaceutical Safety Assessment

  • Paul D. Hockings
Reference work entry

Abstract

The high rate of attrition of drug projects through the pharmaceutical pipeline is a significant contributor to the increasing R&D costs seen in recent years. In 2004, the FDA released a report entitled “Innovation or Stagnation, Challenge and Opportunity on the Critical Path to New Medical Products” in which the alarm was raised that only 8% of the molecules that enter clinical development were successfully registered (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html). Recent data suggests that this figure had fallen to 4% by 2010 (Bunnage 2011). Many more fail in the preclinical stages of development. There is an urgent need for new tools to improve drug development, and the critical path document specifically highlights imaging as one of the new technologies that have a potential to contribute. One quote from the report is particularly telling, “Often, developers are forced to use the tools of the last century to evaluate this century’s advances.”

Keywords

Magnetic Resonance Spectroscopy Hepatic Steatosis Liver Volume Good Laboratory Practice Lumen Volume 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

  1. Bambach GA, Penney DG, Negendank WG (1991) In situ assessment of the rat heart during chronic carbon monoxide exposure using nuclear magnetic resonance imaging. J Appl Toxicol 11:43–49PubMedCrossRefGoogle Scholar
  2. Beckmann N, Laurent D, Tigani B, Panizzutti R, Rudin M (2004) Magnetic resonance imaging in drug discovery: lessons from disease areas. Drug Discov Today 9:35–42PubMedCrossRefGoogle Scholar
  3. Beckmann N, Kneuer R, Gremlich HU et al (2007) In vivo mouse imaging and spectroscopy in drug discovery. NMR Biomed 20:154–185PubMedCrossRefGoogle Scholar
  4. Bottomley PA (1987) Spatial localization in NMR spectroscopy in vivo. Annal N Y Acad Sci 508:333–348CrossRefGoogle Scholar
  5. Brown H, Prescott R (1999) Applied mixed models in medicine. Wiley, ChichesterGoogle Scholar
  6. Bunnage ME (2011) Getting pharmaceutical R&D back on target. Nat Chem Biol 7:335–339PubMedCrossRefGoogle Scholar
  7. Chandra S, Muir C, Silva M et al (2005) Imaging biomarkers in drug development: an overview of opportunities and open issues. J Proteome Res 4:1134–1137PubMedCrossRefGoogle Scholar
  8. Clark JM, Brancati FL, Diehl AM (2002) Nonalcoholic fatty liver disease. Gastroenterology 122:1649–1657PubMedCrossRefGoogle Scholar
  9. Coatney RW (2001) Ultrasound imaging: principles and applications in rodent research. ILAR J 42:233–247PubMedGoogle Scholar
  10. Cockman MD, Hayes DA, Kuzmak BR (1993) Motion suppression improves quantification of rat liver volume in vivo by magnetic resonance imaging. Magn Reson Med 30:355–360PubMedCrossRefGoogle Scholar
  11. Collins KA, Korcarz CE, Lang RM (2003) Use of echocardiography for the phenotypic assessment of genetically altered mice. Physiol Genomics 13:227–239PubMedGoogle Scholar
  12. Cuchel M, Bloedon LT, Szapary PO et al (2007) Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 356:148–156PubMedCrossRefGoogle Scholar
  13. Daubioul C, Rousseau N, Demeure R, Gallez B, Taper H, Declerck B, Delzenne N (2002) Dietary fructans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats. J Nutr 132:967–973PubMedGoogle Scholar
  14. de Simone G, Wallerson DC, Volpe M, Devereux RB (1990) Echocardiographic measurement of left ventricular mass and volume in normotensive and hypertensive rats. Necropsy validation. Am J Hypertens 3:688–696PubMedCrossRefGoogle Scholar
  15. Diehl AM (1999) Nonalcoholic steatohepatitis. Semin Liver Dis 19:221–229PubMedCrossRefGoogle Scholar
  16. Ettlin RA, Kuroda J, Plassmann S et al (2010) Successful drug development despite adverse preclinical findings part 1: processes to address issues and most important findings. J Toxicol Pathol 23:189–211PubMedCrossRefGoogle Scholar
  17. Garbow JR, Kataoka M, Flye MW (2004a) MRI measurement of liver regeneration in mice following partial hepatectomy. Magn Reson Med 52:177–180PubMedCrossRefGoogle Scholar
  18. Garbow JR, Lin X, Sakata N, Chen Z, Koh D, Schonfeld G (2004b) In vivo MRS measurement of liver lipid levels in mice. J Lipid Res 45:1364–1371PubMedCrossRefGoogle Scholar
  19. Grothues F, Smith GC, Moon JCC et al (2002) Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 90:29–34PubMedCrossRefGoogle Scholar
  20. Hajnal JV, Saeed N, Soar EJ, Oatridge A, Young IR, Bydder GM (1995) A registration and interpolation procedure for subvoxel matching of serially acquired MR images. J Comput Assist Tomogr 19:289–296PubMedCrossRefGoogle Scholar
  21. Hazle JD, Narayana PA, Dunsford HA (1991) In vivo NMR, biochemical, and histologic evaluation of alcohol-induced fatty liver in rat and a comparison with CCl4 hepatotoxicity. Magn Reson Med 19:124–135PubMedCrossRefGoogle Scholar
  22. Hockings PD, Roberts T, Campbell SP, Reid DG, Greenhill RW, Polley SR, Nelson P, Bertram TA, Kramer K (2002) Longitudinal magnetic resonance imaging quantitation of rat liver regeneration after partial hepatectomy. Toxicol Pathol 30:606–610PubMedCrossRefGoogle Scholar
  23. Hockings PD, Changani KK, Saeed N, Reid DG, Birmingham J, O'Brien P, Osborne J, Toseland CN, Buckingham RE (2003a) Rapid reversal of hepatic steatosis, and reduction of muscle triglyceride, by rosiglitazone: MRI/S studies in Zucker fatty rats. Diabetes Obes Metab 5:234–243PubMedCrossRefGoogle Scholar
  24. Hockings PD, Busza AL, Byrne J, Patel B, Smart SC, Reid DG, Lloyd HL, White A, Pointing K, Farnfield BA, Criado-Gonzalez A, Whelan GA, Taylor GL, Birmingham JM, Slaughter MR, Osborne JA, Krebs-Brown A, Templeton D (2003b) Validation of MRI measurement of cardiac output in the dog: the effects of dobutamine and minoxidil. Toxicol Mech Methods 13:39–43PubMedCrossRefGoogle Scholar
  25. Hoffmann U, Globits S, Stefenelli T, Loewe C, Kostner K, Frank H (2001) The effects of ACE inhibitor therapy on left ventricular myocardial mass and diastolic filling in previously untreated hypertensive patients: a cine MRI study. J Magn Reson Imaging 14:16–22PubMedCrossRefGoogle Scholar
  26. Koretsky AP, Williams DS (1992) Application of localized in vivo NMR to whole organ physiology in the animal. Annu Rev Physiol 54:799–826PubMedCrossRefGoogle Scholar
  27. Kuhlmann J, Neumann-Haefelin C, Belz U, Kalisch J, Juretschke HP, Stein M, Kleinschmidt E, Kramer W, Herling AW (2003) Intramyocellular lipid and insulin resistance: a longitudinal in vivo 1 H-spectroscopic study in Zucker diabetic fatty rats. Diabetes 52:138–144PubMedCrossRefGoogle Scholar
  28. Latour MG, Brault A, Huet PM, Lavoie JM (1999) Effects of acute physical exercise on hepatocyte volume and function in rat. Am J Physiol 276:R1258–1264PubMedGoogle Scholar
  29. Lee JK, Dixon WT, Ling D, Levitt RG, Murphy WA Jr (1984) Fatty infiltration of the liver: demonstration by proton spectroscopic imaging. Preliminary observations. Radiology 153:195–201PubMedGoogle Scholar
  30. Ling M, Brauer M (1992) Ethanol-induced fatty liver in the rat examined by in vivo 1 H chemical shift selective magnetic resonance imaging and localized spectroscopic methods. Magn Reson Imaging 10:663–677PubMedCrossRefGoogle Scholar
  31. Longo R, Ricci C, Masutti F, Vidimari R, Croce LS, Bercich L, Tiribelli C, Dalla Palma L (1993) Fatty infiltration of the liver. Quantification by 1 H localized magnetic resonance spectroscopy and comparison with computed tomography. Invest Radiol 28:297–302PubMedCrossRefGoogle Scholar
  32. Markiewicz W, Sechtem U, Kirby R, Derugin N, Caputo GC, Higgins CB (1987) Measurement of ventricular volumes in the dog by nuclear magnetic resonance imaging. J Am Coll Cardiol 10:170–177PubMedCrossRefGoogle Scholar
  33. Maronpot RR, Sills RC, Johnson GA (2004) Applications of magnetic resonance microscopy. Toxicol Pathol 32(Suppl 2):42–48PubMedCrossRefGoogle Scholar
  34. Ou YC, Conolly RB, Thomas RS, Xu Y, Andersen ME, Chubb LS, Pitot HC, Yang RS (2001) A clonal growth model: time-course simulations of liver foci growth following penta- or hexachlorobenzene treatment in a medium-term bioassay. Cancer Res 61:1879–1889PubMedGoogle Scholar
  35. Pien HH, Fischman AJ, Thrall JH et al (2005) Using imaging biomarkers to accelerate drug development and clinical trials. Drug Discov Today 10:259–266PubMedCrossRefGoogle Scholar
  36. Rudin M, Pedersen B, Umemura K, Zierhut W (1991) Determination of rat heart morphology and function in vivo in two models of cardiac hypertrophy by means of magnetic resonance imaging. Basic Res Cardiol 86:165–174PubMedCrossRefGoogle Scholar
  37. Schwarz AJ, Leach MO (2000) Implications of respiratory motion for the quantification of 2D MR spectroscopic imaging data in the abdomen. Phys Med Biol 45:2105–2116PubMedCrossRefGoogle Scholar
  38. Shapiro EP, Rogers WJ, Beyar R, Soulen RL, Zerhouni EA, Lima JA, Weiss JL (1989) Determination of left ventricular mass by magnetic resonance imaging in hearts deformed by acute infarction. Circulation 79:706–711PubMedCrossRefGoogle Scholar
  39. Shoda T, Mitsumori K, Onodera H, Toyoda K, Uneyama C, Takada K, Hirose M (2000) Liver tumor-promoting effect of beta-naphthoflavone, a strong CYP 1A1/2 inducer, and the relationship between CYP 1A1/2 induction and Cx32 decrease in its hepatocarcinogenesis in the rat. Toxicol Pathol 28:540–547PubMedCrossRefGoogle Scholar
  40. Siren AL, Feuerstein G (1990) Cardiovascular effects of anatoxin-A in the conscious rat. Toxicol Appl Pharmacol 102:91–100PubMedCrossRefGoogle Scholar
  41. Siri FM, Jelicks LA, Leinwand LA, Gardin JM (1997) Gated magnetic resonance imaging of normal and hypertrophied murine hearts. Am J Physiol 272:H2394–2402PubMedGoogle Scholar
  42. Slawson SE, Roman BB, Williams DS, Koretsky AP (1998) Cardiac MRI of the normal and hypertrophied mouse heart. Magn Reson Med 39:980–987PubMedCrossRefGoogle Scholar
  43. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT (1999) Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol 276:E977–989PubMedGoogle Scholar
  44. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–468PubMedCrossRefGoogle Scholar
  45. Tang H, Vasselli JR, Wu EX, Boozer CN, Gallagher D (2002) High-resolution magnetic resonance imaging tracks changes in organ and tissue mass in obese and aging rats. Am J Physiol Regul Integr Comp Physiol 282:R890–899PubMedGoogle Scholar
  46. Visser ME, Akdim F, Tribble DL et al (2010) Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J Lipid Res 51:1057–1062PubMedCrossRefGoogle Scholar
  47. Wehling M (2006) Translational science in medicine: implications for the pharmaceutical industry. Int J Pharm Med 20:303–310CrossRefGoogle Scholar
  48. Wilson SJ, Brereton IM, Hockings P, Roffmann W, Doddrell DM (1993) Respiratory triggered imaging with an optical displacement sensor. Magn Reson Imaging 11:1027–1032PubMedCrossRefGoogle Scholar
  49. Zhang X, Tengowski M, Fasulo L, Botts S, Suddarth SA, Johnson GA (2004) Measurement of fat/water ratios in rat liver using 3D three-point Dixon MRI. Magn Reson Med 51:697–702PubMedCrossRefGoogle Scholar
  50. Zhou YQ, Foster FS, Nieman BJ, Davidson L, Chen XJ, Henkelman RM (2004) Comprehensive transthoracic cardiac imaging in mice using ultrasound biomicroscopy with anatomical confirmation by magnetic resonance imaging. Physiol Genomics 18:232–244PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.PHB Imaging AstraZenecaMölndalSweden

Personalised recommendations