(CA) Contrast agents are used to change the imaging characteristics, resulting in additional information about anatomy, morphology or physiology of the human body. Radiocontrast agents (also called photon-based imaging agents) are used to improve the visibility of internal body structures in x-ray and CT procedures. Contrast agents are also used to increase the contrast between different tissues in MRI (magnetic resonance imaging) and ultrasound imaging. The ideal imaging agent provides enhanced contrast with little biological interaction.
First investigations with radiopaque materials are done shortly after the discovery of x-rays. These positive contrast agents attenuate x-rays more than body soft tissues due to their high atomic weight. Iodine and barium have been identified as suitable materials with high radiodensity and are used until today in x-ray and CT contrast agents. Iodine-based contrast agents are water-soluble and the solutions are used nearly anywhere in the body. Iodinated contrast materials are most administered intravenous, but can also be introduced intraarterial, intrathecal, oral, rectal, intravesical, or installed in body cavities. Barium sulfate is only used for opacification of the gastrointestinal tract. Negative contrast agents attenuate x-rays less than body soft tissues, for example gas.

Iodinated contrast media are differentiated in;

Intravascular iodinated contrast agents are required for a large number of x-ray and CT studies to enhance vessels and organs dependent on the blood supply. Injectable contrast agents are diluted in the bloodstream and rapidly distributed throughout the extracellular fluid. The main route of excretion is through the kidneys, related to the poor binding of the agent to serum albumin. The liver (gall bladder) and small intestine provide alternate routes of elimination particularly in patients with severe renal impairment. The use of special biliary contrast agents is suitable for gallbladder CT and cholecystograms because they are concentrated by the liver to be detectable in the hepatic bile.
The introduction of fast multi-detector row CT technology, has led to the development of optimized contrast injection techniques. The amount of contrast enhancement depends on the contrast agent characteristics, such as iodine concentration, osmolality, viscosity, and the injection protocol, such as iodine flux and iodine dose. Adverse reactions are rare and have decreased with the introduction of nonionic contrast agents.
See also Contrast Enhanced Computed Tomography, Abdomen CT, Contrast Media Injector, Single-Head CT Power Injector, Multi-Head Contrast Media Injector, Syringeless CT Power Injector, CT Power Injector.

Contrast-induced nephropathy is a serious complication of intravascular x-ray contrast agents. The osmolality of the contrast medium is an important fact in contrast-induced nephropathy and should ideally be iso-osmolar to blood. Today, nonionic contrast agents are state of the art for vascular use, the ionic contrast agents caused more adverse reactions.
Signs of contrast-induced nephropathy after the application of vascular contrast agents are a serum creatinine increase of 0.5 mg/dL (In the United States, creatinine is typically reported in mg/dL, while in Canada and Europe µmol/L may be used. 1 mg/dL of creatinine is 88.4 µmol/L) or an increase of serum creatinine greater than 25%.

A higher risk of contrast-induced nephropathy is associated with:
The use of a nonionic contrast agent, iso-osmolar to blood and a low dose reduces the risk for contrast-induced nephropathy.

Different stages of the drug development and approval process in the USA, lead from preclinical trials (testing in animals), first application in humans through limited and broad clinical tests, to postmarketing studies.

	Years	Test Population	Purpose	Success Rate
Preclinical Testing	3.5	Laboratory and animal studies	Assess safety and biological activity	5,000 compounds evaluated
File IND at FDA
Phase I	1	20 to 80 healthy volunteers	Determine safety and dosage	5 enter trials
Phase II	2	100 to 300 patient volunteers	Evaluate effectiveness, look for side effects
Phase III	3	1000 to 3000 patient volunteers	Verify effectiveness, monitor adverse reactions from long-term use
File NDA at FDA
FDA	2.5	Review process / Approval		1 approved
	12 Total
Phase IV	Additional Post marketing testing required by FDA

By Dale E. Wierenga, Ph.D. and C. Robert Eaton
Office of Research and Development
Pharmaceutical Manufacturers Association

'In reviewing this report, it is important to keep in mind the realities of the drug discovery and development process. The U.S. system of new drug approvals is perhaps the most rigorous in the world. On average, it costs a company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 report by the Congressional Office of Technology Assessment.'

See also Phase 1 2 3 4 Drug Trials, Clinical Trial, Food and Drug Administration, and European Medicines Agency.

Patents can unintended respond with an idiosyncratic reaction to the application of contrast media. Idiosyncratic reactions to contrast agents start usually within 20 minutes after injection and occur more frequently in patients 20 to 40 years old.
Idiosyncratic reactions may or may not be dependent on the amount of dose injected, the speed of injection, the mode of injection and the radiographic procedure.


See also Adverse Reaction and Anaphylactoid Reaction.

The first-generation contrast agents were all ionic monomers, consisting of a tri-iodinated benzene ring with 2 organic side chains and a carboxyl group. Diatrizoate or iothalamate are common iodinated anions, conjugated with a cation, sodium or meglumine. The ionization at the carboxyl-cation bond makes the agent water soluble.
Ionic monomers have the highest osmolality (high-osmolar contrast media (HOCM) possess an osmolality seven to eight times higher than plasma) of the different groups of contrast agents (CM ratio=1.5) and the lowest viscosity. The osmolality in solutions of ionic monomers ranges from 600 to 2100 mOsm/kg (human plasma = 290 mOsm/kg). These high osmolality is related to some of the adverse reactions. HOCM's have been widely replaced by newer contrast agents with improved tolerability and safety profiles.
Examples of HOCM's are Renografin®-60, Hypaque 76, Hypaque Meglumine, Hypaque Sodium and Conray®.

See also Ionic Contrast Agents.