<<

Acta Scientific MEDICAL SCIENCES (ISSN: 2582-0931) Volume 5 Issue 6 June 2021 Review Article

Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy Alain L Fymat* Received: March 20, 2021 Institute Professor, International Institute of Medicine and Science, California, USA Published: May 11, 2021 *Corresponding Author: Alain L Fymat, Institute Professor, International Institute © All rights are reserved by Alain L Fymat. of Medicine and Science, California, USA.

Abstract This article addresses important issues regarding the use of certain MRI contrast agents (linear and macrocylic -based,

or repeated use in patients with certain medical conditions. non-gadolinium-based, iron-based, others). Specific attention is devoted to their corresponding safety and efficacy, and to their use

Keywords: Imaging Agents; Linear Gadolinium-based; Macrocyclic Gadolinium-based; Non-gadolinium Based; Iron-based; Safety;

Efficacy

Abbreviations • The stability constant (or formation constant, or binding con- stant) is an equilibrium constant in the formation of a com- BBB: Blood-brain Barrier; CA: Contrast Agents; DTPA (or Pen- plex and a measure of the solution’s cohesion. It also tetic Acid): Diethylenetriaminepentaacetic acid; EMA: European informs on the solutes’ concentrations. It is found in many ap- Medicines Agency; FDA: (U.S.) Food and Drug Administration; plications including chelation therapy, poisoning treatment, GBCA: Gadolinium-based Contrast Agents; Gd: Gadolinium; GDD: and plutonium poisoning by DTPA (pentetic acid or diethyl- Gd Deposition Disease; IBMCA: Iron-based MRI Contrast Agents; enetriaminepentaacetic acid) of interest in MRI’s GBCA. On LD: Lethal Dose; MEMRI: Manganese-enhanced MRI; MRI: Mag- the other hand, the macrocyclic effect is a phenomenon that netic Resonance Imaging; MRA: Magnetic Resonance Angiography; takes place when the stability of the complex solution is much NFD: Nephrogenic Fibrosing Dermopathy; NGBCA: Non-Gadolin- greater than expected, involving both an entropy (a measure ium-based Contrast Agents; NSF: Nephrogenic Systemic Fibrosis; of randomness) and an enthalpy (a thermodynamic state func- PMCA: Paramagnetic Contrast Agents; SIOP: Superparamagnetic tion). factor. Iron Oxide Particles; SIPP: Superparamagnetic Iron Platinum Par- ticles; WHO: World Health Organization Now, macrocyclic vs linear is an important dichotomy between macrocyclic ligands and open-chain (chelating) ligands in that they Gadolinium-based contrast agents have selectivity for metal ions (a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose).

- Gadolinium-based contrast agents (GBCA) come in two flavors: - bility constant and the macrocyclic effect: trast agents; six for blood pool agents, one for hepatobiliary (liver) linear and macrocyclic. For clarity, let me first define what is a sta As shown in table 1, there are eight extra-cellular fluid con agents, and nine agents approved for human use.

Citation: Alain L Fymat. Acta Scientific Medical Sciences 5.6 (2021): 28-33. “Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy". Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy

29

Extra-cellular Gadoderate (Dotarem, clariscan) Type Components/ Applications (Omniscan) properties Gadobenate (MultiHance) Gd chelates T1 enhancement GI tract fluid Gadopentetate (Magnevist) Mn chelates (ProHance) Fe salts (OptiMARK) Natural products with (Gadovist: EMA; Gadavist: FDA) high Mn concentration dimeglumine (Magnetol) (blueberry, green tea) Blood pool agents Albumin-binding Gd complexes SPIO T2 lowering (Ablavar, formerly Vasovist) Gadocoletic acid Iron salts Polymeric Gd complexes Air Gadomelitol Clay Gadomer Reduces number Pediatric GI Hepatobilary (Primovist: EMA; Eovist: of H ions in body (liver) agents FDA) [50% excreted by liver; 50% excreted cavity (appears by kidneys] dark in images) Agents approved Gadoterate (Dotarem; Clariscan in Europe): for human use EMA; FDA Table 2: (EMA=European Gadodiamide (Omniscan): EMA; FDA Classification of non-gadolinium based contrast agents. Medicines Agency Gadobenate (MultiHance): EMA; FDA Paramagnetic contrast agents FDA= (U.S.) Gadpentetate (Magnevist: EMA; Food and Drug Magnegita, Gado-MRT ratiopharm: FDA) Paramagnetic contrast agents (PMCA) make us of manganese Administration) Gadoteridol (Prohance): EMA; FDA o and its ions. They enhance the T1-relaxation time and are used to Gadofosveset (Ablavar, formerly Vasovist): detect liver and brain lesions, and also in animal studies (See table EMA, FDA 3). The MEMRI (manganese-enhanced MRI) procedure that was in Gadoversetamide (OptiMARK): EMA; FDA its early developmental stage is now more fully established. Gadoxetate (Eovist: EMA; Primovist: FDA) Gadobutrol (Gadovist): EMA, FDA Type Components/ Applications properties Table 1: Various contrast agents and approval for human use. Manganese ions Enhance T1 Detection of Mn2+ Chelates dissociate liver lesions Non-gadolinium-based contrast agents Chelates Mn- in vivo into Mn that is Functional DPDP absorbed intra-cellularly brain imaging There is quite a variety of non-gadolinium-based contrast Early and excreted in bile; and Animal studies - developmental DPDP that is eliminated cording to their types, properties, and applications. In particular, agents (NGBCA) as charted in table 2, which classifies them ac stage (aka MEMRI:Mn- Mn2+ enters cells through via kidney filtration the first four have the characteristic property of enhancing the T1- enhanced MRI) calcium Ca2+ channels last one reduces the number of hydrogen ions in the body cavity. relaxation time, the next five lower the T2-relaxation time, and the Table 3: Paramagnetic contrast agents properties and applications.

Citation: Alain L Fymat. Acta Scientific Medical Sciences 5.6 (2021): 28-33. “Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy". Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy

30

Iron-based MRI contrast agents Particle type Components/ Applications properties Iron-based MRI contrast agents (IBMCA) are superparamag- SIOP Suspended colloids Liver tumor netic. To clarify this property, paramagnetism and diamagnetism Feridex IV (aka Endorem of iron oxide enhancement need first to be clarified as concepts. Paramagnetism is a weak or ferumoxides form of parallel magnetism induced in nanoparticles under the in- => Discontinued in 2008 They Reduce T2 of by AMAG Pharma absorbing tissues fluence of an external magnetic field. By contrast, in diamagnetism, Resovist (aka Cliavist): needed contrast amounts to visualize certain organs and tissues the induced magnetic field is anti-parallel. Table 4 summarizes the => Abandoned in 2009 and the importance of the state of the blood-brain barrier (BBB) in Sinerem (aka Combidex): the case of brain lesions and tumors. => Marketing authoriza- tion application with- Organ or Needed contrast Blood-brain barrier drawn in 2007 tissue amount effects Lumirem (aka Gastro- Aorta As low as 0.1 mmol/kg Not applicable mark): Fine Higher than 0.1 mmol. Not applicable vasculature kg => Discontinued in 2012 Clariscan (aka PEG-fero, Lesions and Being hydrophilic, tumors: Gd(III) chelates* do Feruglose, NC100150): A not pass the intact macrocyclic extracellular In brain BBB, but are useful Gd containing gado- where the BBB is In rest of the compromised and teric acid and gadoterade body GdIII leaks out meglumine:

Initially Gd(III) => Discontinued by remains in GE Healthcare in early circulation but then 2000s due to safety con- distributes into cerns interstitial space or is eliminated by the SIPP Better T2 relaxivity Tumor spe- kidneys (investigational) than SIOP Encapsulated with prostate Table 4: Tissue and organ visualization and effects of the blood- cific: human phospholipids to cancer cells brain barrier. create multifunc- tional SIPP stealth Now, there are two types of iron-based contrast agents: immunomicelles • Superparamagnetic iron oxide particles (SIOP): Their Synthesized and sizes range from small to ultra-small. They have all been conjugated to discontinued because of concerns about their safety. a monoclonal antibody against • Superparamagnetic iron platinum particles (SIPP): These are still investigational. membrane antigen prostate-specific

Table 5 sets forth the various particulars of the SIOPs: Table 5:

Classification of superparamagnetic iron particles.

Citation: Alain L Fymat. Acta Scientific Medical Sciences 5.6 (2021): 28-33. “Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy". Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy

31 Other contrast agents amino-acids to bind with Gd. The enzyme-activity agents affect the Other contrast agents include protein-based, enzyme-activated, T1 and T2 relaxation times and, importantly, in contrast with other and calcium-ion dependent activation. These are shown in table 6. MRI modalities that give only anatomical information, they make In particular, the protein-activated agents utilize the ability of some molecular processes visible.

Type Variety Components/properties Applications Protein-based Abilities of some amino-acids to bind with Gd Enzyme-activated T1, T2 affected by paramagnetic iron component when In vivo assays of (+ other possible enzyme-related reaction takes place enzyme activity Β-galactosidase-activated enzymes) Compounds cause detectable change in image intensity when in presence of active form of a certain enzyme Distinguish from current contrast agents that give only ana- tomical information => make molecular processes visible Ca2+ dependent activation

Table 6: Other contrast agents.

Safety and efficacy of linear vs. macrocyclic GBCAs • Longer term adverse health effects of Gadolinium deposits in the body, the brain, and other tissues are unknown. Reg- vs. microcyclic gadolinium- ulatory agencies have therefore issued several cautionary based contrast agents devolve from the following factors: The safety and efficacy of linear notices in this regard. Thus, the FDA issued a revision of its class warnings for all Gd-based contrast media, particularly in • Chelating carrier molecules, whether ionic or not, are ei- their retention characteristics, dosages, patient types (preg- ther macrocyclic or linear. The former are the least likely to - release very toxic Gd(III) compounds and are, consequent- tory conditions) without necessarily avoiding or deferring the ly, the safest. About a dozen of them have been approved nant women, pediatric patients, and patients with inflamma studies. Particular attention was given to: minimizing repeat worldwide. While toxic, Gd(III) is generally regarded as or/and closely spaced studies, associated risks of stillbirths or safe when chelated with a toxicity comparable to the iodin- neonatal deaths, and patient education. ated contrast agents used in X-ray and CT imaging. • As with the FDA, the European Medicines Agency (EMA) has • In persons with kidney disease, even several months after revised its conduct of the safety review of MRI contrast agents GBCA administration, Gd(III) can lead to the rare but se- and implemented a change in its market authorization for all vere complication of the systemic disease known as neph- linear chelated Gd-based media. nephrogenic sys- (NSF). Dialysis patients are more at risk than • Gd(III) ions in -soluble salts are toxic to mammals. As rogenic fibrosing dermopathy (NFD) or patients with chronic kidney disease. free ions, they are highly toxic. However, there is low or no tox- temic fibrosis icity for low dose ions. Chelated Gd(III) are far less toxic and • The World Health Organization (WHO) had issued the fol- are generally considered as safe enough for use in most cases. lowing restriction: “... high-risk gadolinium-containing con- The process of chelation improves and decreases trast agents (Optimark, Omniscan, Magnevist, Magnegita, toxicity (a factor of 100 or more), its strength determining its and Gado-MRT ratiopharm) are contraindicated in patients clinical toxicity. Anaphylactoid reactions are rare, occurring in with severe kidney problems, in patients who are sched- about 0.03 - 0.1% of cases. uled for or have recently received a liver transplant, and in newborn babies up to four weeks of age” (November 2009). • that may occur months after a GBCA MRI in the case of renal Nephrogenic systemic fibrosis is a rare but serious disease

Citation: Alain L Fymat. Acta Scientific Medical Sciences 5.6 (2021): 28-33. “Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy". Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy

32 impairment or severe kidney failure requiring dialysis. A simi- lar but presenting different symptoms is Gadolinium deposi- particles that are being developed specifically for prostate cancer tion disease (GDD) that may also develop in normal or near- based contrast agents devolve from the following factors. Unlikely cells. The safety and efficacy of linear vs microcyclic gadolinium- normal renal function within hours to 2 months thereafter. to release Gd(III)-ions, cyclical ionic Gd(III) compounds are least likely to release the Gd(III) ion and, hence, are the safest with rare • GBCA-nanotubes are more effective than GBCAs (a factor of anaphylactoid reactions. are rare. In their chelated form, they are generally considered as safe. However, in persons with kidney dis- a more accurate diagnosis of abnormal growths and tumors. approximately 40), yielding a crisper contrast and permitting dermopathy (aka ) may occur. Also, • Current guidelines for the use of GBCA recommend for dialy- ease, the rare but serious complication of nephrogenic fibrosing chronic kidney disease patients are less at risk of complications sis patients: considering gadolinium retention in selecting a nephrogenic systemic fibrosis than dialysis patients. Cautionary notices have been issued by the GBCA, avoiding high-risk agents, performing the exam as near FDA and the EMA regarding these agents. dialysis time as possible, administering an after-exam dialy- sis., and be particularly attentive to - Bibliography tory conditions or who may require multiple lifetime doses, patients with inflamma pregnant women, and children. 1. Centers for Disease Control and Prevention (CDC). “Nephro- - Summary and Conclusion olinium-containing contrast agents”. MMWR. Morbidity and genic fibrosing dermopathy associated with exposure to gad Mortality Weekly Report an important dichotomy between macrocyclic ligands and open- GBCAs come in two flavors: Linear and macrocyclic. There is 2. “EMA recommendations 56.7 on (2007):Gadolinium-containing 137-141. contrast chain (chelating) ligands in that they have selectivity for metal ions. agents”. ema.europa.eu. Retrieved 2018-07-12. “Information on Gadolinium-Containing Contrast Agents”. Fda.gov. pool agents, one for hepatobiliary (liver) agents, and nine agents There are eight extra-cellular fluid contrast agents; six for blood approved for human use. In MRI/MRA, Gadolinium nanotubes are 3. “FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings” (PDF). safetr than iodinated contrast agents [1-17]. 40 times more effective and more contrasting. They are usually United States Food and Drug Administration. 2017-12-19.

There are ten different varieties of non-Gadolinium based con- Fymat AL. “Magnetic Resonance Imaging with Nanocontrast- trast agents. They have been developed for GI imaging. The tenth - 4. nual Congress in Nanomedicine, Shuzou, China, June 2013 ing Materials”, Invited Address presented at the BIT’s 4th An these agents the T1-relaxation time, others the T2-relaxation time, agent (Perflubron) is more specialized for pediatric GI. Some of (2013). and still another one reduces the number of hydrogen ions in the body cavity. 5. Fymat. “Magnetic Resonance Imaging Modalities with Nano- contrasting Materials”. Journal of Current Trends in Clinical and Paramagnetic contrast agents are based on manganese and its ions. They enhance the T1-relaxation time and are used to detect 1.1 (2017): 1-4. liver and brain lesions, and also in animal studies. 6. - ties of contrast agents for magnetic resonance imaging”. Con- Geraldes CFGC and Laurent S. “Classification and basic proper trast Media and Molecular Imaging type made-up of superparamagnetic oxide particles was developed There are two types of iron-based MRI contrast agents. The first 4.1 (2009): 1-23. for liver tumor enhancement. It includes six different contrast 7. - agents that over the years have all been discontinued for safety rea- Grobner T. “Gadolinium - a specific trigger for the develop sons. The second type is made up of superparamagnetic platinum Nephrology Dialysis Transplantation ment of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?”. 21.4 (2005): 1104-1108.

Citation: Alain L Fymat. Acta Scientific Medical Sciences 5.6 (2021): 28-33. “Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy". Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy

33 8. Kanal E., et al. “ACR Guidance Document for Safe MR Practices: 2007”. American Journal of Roentgenology Assets from publication with us • Prompt Acknowledgement after receiving the article 188.6 (2007): 1447- • Thorough Double blinded peer review 9. Koretsky1474. Alan P and Silva Afonso C. ““Manganese-enhanced • Rapid Publication magnetic resonance imaging (MEMRI)”. NMR in Biomedicine •

• High visibility of your Published work Issue of Publication Certificate 10. Marckmann17.8 (2004): P., 527-531. et al. “Nephrogenic Systemic Fibrosis: Suspect- Website: ed Causative Role of Gadodiamide Used for Contrast-Enhanced Submit Article: www.actascientific.com/ Magnetic Resonance Imaging”. Email us: Journal of the American Society www.actascientific.com/submission.php 17.9 (2006): 2359-2362. Contact us: of Nephrology [email protected] +91 9182824667 11. Murphy KJ., et al. “Adverse reactions to gadolinium contrast media: A 1996 review of 36 cases”. American Journal of Roent- genology

12. Qiao Jingjuan., 167.4 et (1996): al. “Molecular 847-849. imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents”. Journal of Biologi- cal Inorganic Chemistry

13. Rinck PA. “Chapter 13 - Contrast19.2 (2014): Agents”. 259-270. Magnetic Resonance in Medicine (11th ed.). European Magnetic Resonance Forum. Retrieved 2020-07-31 (2017).

Sudarshana DM., et al. “Manganese-Enhanced MRI of the Brain in Healthy Volunteers”. American Journal of Neuroradiology 14.

15. Xue40.8 Shenghui., (2019): 1309-1316. et al. “Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecu- lar imaging of cancer biomarkers”. Wiley Interdisciplinary Re- views: Nanomedicine and Nanobiotechnology 5.2 (2013): 163- 179.

16. Xue Shenghui., et al. “Design of ProCAs (Protein-Based Gd3+ - ity for Molecular Imaging of Cancer Biomarkers”. Medicinal MRI Contrast Agents) with High Dose Efficiency and Capabil Research Reviews

17. Zhen Zipeng and 34.5Xie J(2014): . “Development 1070-1099. of Manganese-Based Nanoparticles as Contrast Probes for Magnetic Resonance Im- aging”. Theranostics

2.1 (2012): 45-54.

Citation: Alain L Fymat. Acta Scientific Medical Sciences 5.6 (2021): 28-33. “Magnetic Resonance Imaging Contrast Agents - Issues of Concern, Safety, and Efficacy".