Conception of the first magnetic resonance imaging contrast agents: a brief history.

About 20 years ago, a technological innovation process started that eventually led to the affirmation of magnetic resonance imaging (MRI) contrast agents, which are used today in about 25% of all MRI procedures, as medical diagnostic tools. The process began with exploration of various technical possibilities and the conception in the years 1981 to 1982 of two types of agents (soluble paramagnetic chelates and protection colloid-stabilized colloidal particle solutions of magnetite) that eventually found embodiments in commercially available products. The pioneering products that eventually reached the market were gadopentetate dimeglumine (Magnevist, Schering AG) and the ferumoxides (Endorem, Guerbet SA; or Ferridex , Berlex Laboratories Inc.). The history of the conception phase of the technology is reconstructed here, focusing on the social dynamics rather than on technological aspects. In the period 1981 to 1982, a number of independent inventors from industry and academia conceived of water-soluble paramagnetic chelates and protection colloid-stabilized colloidal solutions of small particles of magnetite, both of acceptable tolerability, as contrast agents for MRI. Priorities on patents conditioned the further course of events. The analyzed history helps in understanding the typical roles of different institutions in technological innovation. The foundation of MRI contrast agent technology in basic science clearly was laid in academia. During the conception of practical products, industry assumed a dominant role. Beginning with the radiological evaluation of candidate products, the collaboration between industry and academia became essential.

Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) as contrast agent for magnetic resonance imaging of the liver: mechanistic studies in animals.

Mechanistic studies regarding the action of gadobenate dimeglumine (Gd-BOPTA/Dimeg; MultiHance) in animals are presented, and the relevance of the results to protocols for MR imaging of the liver are discussed. Gd-BOPTA/Dimeg maintains all the characteristics of an extracellular contrast agent, but owing to a weak affinity for serum albumin, provides in these applications stronger signal intensities than contrast agents without such affinity at the same dose. This property can be taken advantage of for dynamic liver imaging. A unique property of Gd-BOPTA/Dimeg is that the contrast effective ion, Gd-BOPTA2-, enters hepatocytes selectively and reversibly through the sinusoidal plasma membrane using transport mechanisms other than the organic anion transport polypeptide. In a rate-limiting step, the ion is excreted by the multispecific organic anion transporter into the bile. The increase in liver distribution space of Gd-BOPTA2-, as compared to that of purely extracellular contrast agents, is identified as the principal mechanism of normal parenchymal signal enhancement. Microviscosity effects inside hepatocytes add to the relaxation effectiveness of Gd-BOPTA2-, while its presence in the bile and an affinity for intracellular macromolecules play subordinate roles only. Gd-BOPTA2- persists in hepatocytes beyond the times characteristic of dynamic imaging, providing delayed-phase contrast between normal hepatocytes and tumor cells. As a result, the conspicuity of small focal lesions and thus their detection is improved. Additionally, Gd-BOPTA/Dimeg allows sites of abscesses and systemically damaged tissue to be distinguished from healthy liver. Taken together these mechanistically-supported properties qualify the product as a versatile general MR contrast agent with added merits in liver imaging.

Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) pharmaceutical formulation and physicochemical properties of a new magnetic resonance imaging contrast medium.

OBJECTIVE: To characterize the proton-magnetic relaxation properties and complexation equilibria of gadobenate dimeglumine and to develop a pharmaceutical formulation for injection. METHODS: Proton-magnetic relaxivities were determined at 20 MHz and 39 degrees C. Metal complexation was studied potentiometrically. Degradation pathways were identified through prolonged exposure to elevated temperature. RESULTS: Because of its size and very weak interaction with serum albumin, gadobenate dimeglumine has proton-magnetic relaxivities that are larger than those of gadopentetate dimeglumine in both water and biological fluids. With regard to metal complexation, the two products are indistinguishable. The metal complexation behavior and thermal stability of the product allowed a pharmaceutical formulation for injection containing 0.5 M gadobenate dimeglumine without excipients. The physicochemical properties of the formulated product were determined. CONCLUSION: Gadobenate dimeglumine has an elevated T1-relaxivity, especially in blood plasma. The high stability of the complex guarantees a negligible release of gadolinium ion. Gadobenate dimeglumine 0.5 M solution for injection has a shelf life of three years.

Pharmacokinetics and tissue distribution in animals of gadobenate ion, the magnetic resonance imaging contrast enhancing component of gadobenate dimeglumine 0.5 M solution for injection (MultiHance).

OBJECTIVE: Evaluation of the pharmacokinetic behavior of gadobenate dimeglumine, a new multipurpose parenteral contrast agent for magnetic resonance imaging. METHODS: The pharmacokinetics were evaluated in rats, rabbits, dogs and monkeys after intravenous injections of non-labelled gadobenate dimeglumine and, for biodistribution studies, 153Gd-labelled gadobenate dimeglumine. Assays were performed by high performance liquid chromatography, X-ray fluorescence and gamma spectrometry. The binding of gadobenate ion to animal and human serum albumin was studied by equilibrium dialysis. RESULTS: After intravenous injection gadobenate dimeglumine distributes into plasma and extracellular fluid as well as into the intrahepatocytic space. Gadobenate ion is cleared from plasma by renal and biliary excretion. It does not accumulate in specific tissues, except temporarily in tissues related to its elimination. Gadobenate ion is not metabolized. Its binding to plasma proteins is too weak to be detected by equilibrium dialysis. CONCLUSIONS: Gadobenate dimeglumine combines the properties of an extracellular-fluid agent with those of a hepatobiliary agent. Its complete elimination and biological stability satisfy the requirements for its safe use in humans.

Toxicological safety evaluation of gadobenate dimeglumine 0.5 M solution for injection (MultiHance), a new magnetic resonance imaging contrast medium.

OBJECTIVE: To support the clinical use of gadobenate dimeglumine for injection as an intravascular magnetic resonance imaging contrast medium through an extensive battery of toxicological safety studies. METHODS: Single and multiple dose toxicity, reproduction and mutagenicity assessments were carried out in rodents and non-rodents. RESULTS: Initial adverse clinical signs in monkeys were associated with a systemic exposure 34 times higher than that found in humans after 0.1 mmol/kg gadobenate dimeglumine. Good systemic tolerance was observed in repeated dose toxicity studies. Reproductive performance and physical and behavioral development of offspring were unaffected at doses corresponding to 20 times the human dose. Mutagenicity tests excluded any genotoxic potential of gadobenate dimeglumine. CONCLUSION: Based on the wide margins of safety demonstrated in different species, particularly in primates, gadobenate dimeglumine can be considered as safe in the range of clinical doses recommended for magnetic resonance imaging.

General pharmacology in experimental animals of gadobenate dimeglumine (MultiHance), a new magnetic resonance imaging contrast agent.

OBJECTIVES: To assess in animals the pharmacological tolerability for intravascular gadobenate dimeglumine. RESULTS: Cardiovascular effects: In healthy animals no relevant effects were observed apart from slight and transient increases in cardiac output and decreases in systemic vascular resistance. In pigs with myocardial ischemia: doses up to 3.0 mmol/kg caused dose-dependent decreases in heart rate, systemic vascular resistance and mean arterial blood pressure along with transient increases in cardiac output. In vitro: Myocardial contractility was slightly depressed after direct exposure to a 30 mM solution. Respiratory effects in healthy pigs: no effects after 1.0 mmol/kg i.v. Effects on the central nervous system: In healthy animals: gadobenate dimeglumine, 1.0 mmol/kg i.v, did not penetrate nor impair the blood-brain barrier in rats and did not affect behavior, motor coordination or EEG. In pathological models: even in the presence of an osmotically disrupted blood-brain barrier, brain penetration of gadobenate was poor and no signs of epileptogenic potential were evident. Effects on blood: No hemolytic potential was observed. Plasma coagulation was slightly affected in vitro but not in vivo. Effects on kidney and liver function: Transient increases in diuresis, without effects on blood and urine enzymes were observed at doses of 1.25 and 2.5 mmol/kg. CONCLUSIONS: The clinical use of gadobenate dimeglumine as an intravascular magnetic resonance imaging contrast agent is strongly supported by the good tolerability of the product in healthy and pathological animal models.

The haemodynamic effects of iodinated water soluble radiographic contrast media: a review.

All classes of iodinated water-soluble radiographic contrast media (RCM) are vasoactive with the iso-osmolar dimers inducing the least changes in the vascular tone. The mechanisms responsible for RCM-induced changes in the vascular tone are not fully understood and could be multifactorial. A direct effect on the vascular smooth muscle cells causing alterations in the ion exchanges across the cell membrane is thought to be an important factor in RCM-induced vasodilatation. The release of the endogenous vasoactive mediators adenosine and endothelin may also play a crucial role in the haemodynamic effects of RCM particularly in the kidney. In addition, the effects of RCM on blood rheology can cause a reduction in the blood flow in the microcirculation. The purpose of this review is to discuss the pathophysiology of the haemodynamic effects of RCM and to offer some insight into the biology of the endothelium and vascular smooth muscle cells as well as the pharmacology of the important vasoactive mediators endothelin and adenosine.

Inhibition of in vitro growth of enteropathogens by new Lactobacillus isolates of human intestinal origin.

Three human Lactobacillus strains, coded B21060, B21070 and B21190, have recently been isolated. The strains show a series of features (acid and bile resistance, adhesion to various types of mucosal cell) which make them particularly promising for the preparation of probiotic products. In the present study, the ability of the strains to inhibit the growth of pathogens in coculture was investigated. Lactobacilli were incubated simultaneously or after one overnight growth with enterotoxigenic Escherichia coli, Salmonella enteritidis or Vibrio cholerae. After 24 and 48 h, bacterial counts of the pathogens and of the lactobacilli were performed. The results showed that these Lactobacillus strains inhibited the in vitro growth of E. coli and S. enteritidis under both conditions. Moreover, a cumulative effect was observed for mixtures of lactobacilli. In contrast, no significant inhibition of Vibrio cholerae growth was observed, provided that the pH of the medium was kept constant. The presence of the pathogens did not affect the growth of the Lactobacillus strains. Moreover, each of the Lactobacillus strains showed coaggregation ability with two pathogenic E. coli strains, namely ATCC 25922 and ATCC 35401.

Brain penetration and neurological effects of gadobenate dimeglumine in the rat.

PURPOSE: The study aimed at measuring the amount of the gadobenate ion that crosses an experimentally disrupted blood-brain barrier (BBB) in rats following i.v. administration of gadobenate dimeglumine (GD). The intention was also to compare this amount with the minimally effective intrathecal dose that alters the cerebral function. METHODS: Sprague Dawley rats with an osmotically disrupted BBB received 0.3 mmol/kg of (153Gd) GD, i.v. Radioactivity was measured in plasma and brain parenchyma. The effect on the cerebral function was evaluated by means of a standard motor coordination test (Rota-rod test). RESULTS: Brain levels of the gadobenate ion were approximately 60 nmol/g tissue after i.v. injection of GD. In rats with an intact BBB, the lowest dose of GD able to slightly impair motor coordination was 0.01 mmol/kg following intracisternal injection. CONCLUSION: I.v. administration of GD to rats with a disrupted BBB results in brain levels of the gadobenate ion that are more than 20 times lower than those reached following intrathecal administration of the minimal effective dose, as determined by the Rota-rod test.

Hepatocyte-directed MR contrast agents. Can we take advantage of bile acids?

A series of gadolinium complexes conjugated to bile acids was prepared and investigated as possible hepatospecific MR imaging contrast agents. In the design of such compounds, features such as the nature of the bile acid, the site of conjugation on the bile acid skeleton, and the global charge of the conjugate were taken into account. Relaxivity measurements carried out in human serum indicate interaction of the conjugates with human serum proteins; even small structural variations significantly affect relaxivity in human serum. Pharmacokinetic data (biliary elimination in the range of 18.4-45.6%) show that bile acids can be used as address moieties to transport gadolinium complexes through hepatocytes. For a homogeneous series of compounds, differing only in the bile acid residue conjugated, it was unexpectedly found that cholic acid is twice as efficient an address moiety as cholylglycine or cholyltaurine. Preliminary results show that none of the conjugates is transported through the basolateral membrane of hepatocytes by the Na+/taurocholate carrier.

Neurotolerability of nonionic X-ray contrast media. The role of chemotoxicity.

RATIONALE AND OBJECTIVES: Because small quantities of x-ray contrast agents can cross the blood-brain barrier, the authors evaluate the properties that contribute to neurotoxicity. METHODS: The acute toxicity of various monomer and dimer contrast media was assessed after intracerebroventricular (ICV) injection to mice and intracisternal (ICI) injection to rats. RESULTS: In mice, median lethal dose (LD50) values for monomer contrast media apart from iohexol were higher than those for dimer contrast media. In rats, iopentol and iopromide were more neurotoxic than all other contrast media. The signs of toxicity for all contrast media included convulsions, dyspnea, hypoactivity, and sedation. Hypertonic D-mannitol solution was tolerated as well as artificial cerebrospinal fluid. Neither the hydrophilicity of the molecules nor the physicochemical properties of their solutions explain the toxicities satisfactorily. CONCLUSIONS: Neurotoxicity of monomer or dimer contrast media depends more on chemical structure characteristics other than hydrophilicity than on the physicochemical characteristics of their solutions.

Conditioned taste aversion in rats following intrathecal administration of contrast media.

PURPOSE: The occurrence of side-effects such as visceral malaise after intrathecal administration of the non-ionic radiography contrast media iomeprol, iopamidol, and iotrolan was assessed in rats by the conditioned tasted aversion procedure. METHODS: Reduced preference towards a saccharose solution compared with normal water following intraventricular administration of a contrast medium was used as a measure of the aversive response. RESULTS: At a dose of 100 mg I/kg none of the tested contrast media induced aversion. At 200 and 300 mg I/kg, both iopamidol and iomeprol induced significant aversive responses with respect to control, although the response of the iomeprol group appeared milder than that of the iopamidol group at a dose of 200 mg I/kg. Iotrolan could be tested only at the lowest dose since the high doses caused excessive mortality. CONCLUSION: Intrathecally administered iomeprol appeared to be well tolerated in rats at doses higher than those suggested for clinical use.

Effects of iodinated contrast media on pulmonary airway resistance in anesthetized guinea pigs.

RATIONALE AND OBJECTIVES: Bronchospasm is occasionally observed following iodinated X-ray contrast medium administration. We performed an in vivo study in guinea pigs to investigate the effects of a number of iodinated contrast media on pulmonary airway resistance and the mechanisms underlying the potential bronchoconstrictor effect. METHODS: The contrast media studied were the pharmaceutical formulations of iomeprol (400 mg I/ml), iopamidol (370 mg I/ml), and iohexol (350 mg I/ml), which are nonionic, triiodinated contrast media; diatrizoate (370 mg I/ml), an ionic, triiodinated contrast medium; iotrolan (300 mg I/ml), a nonionic, hexaiodinated contrast medium; and iocarmate (280 mg I/ml) and ioxaglate (320 mg I/ml), which are both hexaiodinated and ionic contrast media. Each contrast medium was administered intravenously at 2 g I/kg. Changes in pulmonary airway resistance were evaluated by measuring intratracheal pressure at the moment of maximum insufflation, or maximal insufflation pressure (MIP), in anesthetized guinea pigs submitted to forced ventilation. RESULTS: All contrast media except ioxaglate caused mean increases of MIP of no more than 20%. By contrast, ioxaglate caused a marked bronchoconstrictor effect, increasing MIP by 242% +/- 46%. Of the drugs tested for antagonistic action on this increase in MIP, salbutamol inhibited almost completely the increase in MIP for the first 40 min posttreatment. Similarly, lysine acetylsalicylate and indomethacin consistently reduced MIP after contrast media administration to levels only 30% and 14% above those of baseline precontrast media, respectively. Promethazine had only a minor inhibitory effect, and the response to prednisolone varied. CONCLUSION: There was no apparent relationship between the size of the increase in airway resistance and the charge or molecular weight of the contrast agent molecule or the pharmaceutical formulation. The increase induced by ioxaglate must be attributed to inherent molecular toxicity mediated through a direct action on the production of bradykinin and/or the prostanoid products of the cyclooxygenase pathway, rather than through a direct action on the release of histamine.

Hepatic transport of the magnetic resonance imaging contrast agent gadobenate dimeglumine in the rat.

RATIONALE AND OBJECTIVES: Gadobenate dimeglumine is a new octadentate gadolinium (III) complex salified with meglumine. The compound is currently under evaluation as an intravenously administered paramagnetic contrast agent for magnetic resonance (MR) imaging. We investigated the mechanisms involved in the biliary excretion of gadobenate ion, the contrast-effective ion in gadobenate dimeglumine. METHODS: Biliary and urinary excretion of gadobenate ion injected intravenously to rats at 0.25 mmol/kg was studied following pretreatment with bromosulfophthalein (BSP) disodium salt, sodium taurocholate (TC), or oxyphenonium bromide (OP) and at various times after common bile duct ligation. Gadobenate ion was assayed by high-pressure liquid chromatography in bile and urine. Plasma bilirubin levels after duct ligation were measured by colorimetric assay. RESULTS: The 90-min excretion of gadobenate ion into bile accounted for 35.5 +/- 3.7% and excretion into urine for 45.7 +/- 3.5% of the injected dose (mean +/- SD). Pretreatment with BSP reduced recovery of the compound in bile to less than 1% and increased urinary excretion to 65.6 +/- 4.7%. Gadobenate dimeglumine had a substantial choleretic effect that was completely abolished by pretreatment with BSP. Pretreatment with TC and OP did not change the biliary or urinary excretion of gadobenate ion. Surgical cholestasis led to a massive increase in plasma bilirubin levels from 3.9 +/- 2.2 (day of surgery) to 129 +/- 37 mumol/L (4 days after common bile duct ligature) and decreased 6-hr cumulative biliary excretion of gadobenate ion from 45 +/- 16% to 5.3 +/- 4.2% of the injected dose. Urinary excretion increased correspondingly from 49 +/- 15% to 83 +/- 12%. CONCLUSION: The transport of gadobenate ion from plasma to bile occurs in the rat mainly through the BSP/bilirubin transport systems.

The chemistry of iomeprol and physico-chemical properties of its aqueous solutions and pharmaceutical formulations.

The synthesis and the chemical characterization of iomeprol, a new triiodinated nonionic radiographic contrast agent, are reported. The physico-chemical properties both of aqueous solutions of the pure compound and of its pharmaceutical formulations are presented and these last data are compared with those of other contrast media. The pharmaceutical development of the product is described. Iomeprol is obtained via a synthesis which is particularly friendly to the environment. The compound shows an unusually high solubility which allows the formulation of contrast media with the lowest osmolalities and viscosities as compared with corresponding contrast media of the same category. In view of these favourable characteristics and of the remarkably high stability of its solutions, iomeprol for injection is formulated also at 400 mgI/ml, the highest concentration so far available on the market for non-ionic contrast media.