Iodixanol

Sutton AG, Finn P, Grech ED, et al Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. 

Use nonionic and either low or iso-osmolal products ° Example, iodixanol... 

Priebe et al. [7] have described the synthesis and purification of iodixanol and its physical and toxicological properties, and analytical and spectroscopic data. 

Priebe et al. [79] investigated the chemical stabiHty of iodixanol under accelerating cleavage of the central bridge under ultraviolet irradiation by a Norrish Type-II reaction. Basic conditions (pH 14) combined with heat (60 °C) initiated a cyclisation reaction. On the other hand, less than 1 % iodixanol decomposed in solution heated to 140 °C for 2 days or under both basic conditions (pH 11,20°C, 5 days) and acidic conditions (pH 0.4,80 °C, 5 days) or under an oxygen atmosphere (100°C,3 days). 

Jacobsen et al. described an HPLC/MS method for the determination and/ or identification of iodixanol and its metabolites in biological samples from animals [108]. 

The same authors also described an equivalent HPLC method for the determination of the non-ionic dimer, iofratol, in plasma and urine [111]. Andresen studied the analysis of iopentol by HPLC [112]. Iodixanol might be analysed according to Jacobsen [113,114]. 

Iodinated contrast agents with polyhydroxylated carbon side-chains contain a number of asymmetric carbon atoms yielding numerous optical isomers which relate to each other as enantiomers or diastereoisomers. Sterically hindered non-asymmetric carbon or nitrogen atoms might result in additional asymmetry centres while the partial double bond character of the acyl-carbon-nitrogen bond of amide functions can lead to cisitrans isomerism. Such isomers are labelled rotamers when heating in solution is able to modify their ratio. Isomerism of iodixanol has been described by Priebe et al. [122], Fossheim et al. [123] and by Molander et al. [115]. 

In the 1990s, to achieve iso-osmolality with plasma, various teams synthesized nonionic dimers, which resulted in the marketing of iotrolan and iodixanol. However, these compounds suffer from high levels of viscosity (at 20 °C and 320 mgl mL h iodixanol = 25.4 mPa.s vs 15.7 mPa.s for the ionic dimer sodium/ meglumine ioxaglate). 

A series of so-called compact dimers has also been described [4]. These compounds were characterized by an even three-dimensionally distributed hydrophilicity due to the perpendicular ring conformation, and stabiHzation of hydrophilicity by hydroxylated amido groups characterized by high energy rotational barriers for (E/Z) isomers. Furthermore, their viscosity was low, allowing injection at 350 mgl mL (at this concentration and at 20°C, their viscosities were found to be between 19 and 26 mPa.s vs 44.5 mPa.s for iodixanol) [4]. 

The pharmacokinetics of P840, another SCBPA, was investigated in rabbits, in comparison with the NS-CA iodixanol (Table 3). 

Table 3. Pharmacokinetic profile of P840 and the NS-CA iodixanol in rabbits...

In another study, the effects of intravenously-injected P840 (600 mgl kg ) and iodixanol (900 mgl kg ) on GFR (evaluated by inulin clearance) were evaluated in anesthetized euvolemic pigs (n = 10). 

Table 9. Effects of P840 and iodixanol on renal function in euvolemic pigs...

Neither P840 nor iodixanol had major deleterious consequences on the GFR up to 90 min following injection (Table 9). The selected doses were different for P840 and iodixanol since the expected clinical dose of the SCBPA is lower than that of a classic NS-CA. Since acute renal failure is defined as a rapid and sustained decrease in renal function and since renal function is best evaluated by measurement of the GFR [36], such a parameter appears to be of particular clinical interest. 

Leander et al. described ready-to-use liposomes that were effective and well tolerated in humans [61]. The iodinated contrast agent was the non-ionic dimer, iodixanol. The particle size of the liposomes was 350 nm with an iodine concentration of 70-80 mg mL encapsulated. They injected doses of 30, 70 or 100 mgl kg intravenously and found maximal enhancement values of 45 HU in the liver and 240 HU in the spleen. The uptake into these organs was not linealy correlated with the injected dose. No serious or unexpected adverse reactions were reported. Dose-dependent changes in leukocyte counts and body temperature were seen. 

The following three chapters describe different classes of X-ray contrast agents. The fourth chapter gives an overview on the chemistry of extracellular iodinated X-ray contrast agents starting with possible routes of synthesis. However, the main focus rests on analytical considerations with particular emphasis on the complex pattern of isomers. In particular dimeric compounds such as iodixanol and iotrolan exhibit a plethora of different types of isomers such as enantiomers, diastereoisomers, cis-trans isomers, and rotamers. In this chapter, the correlation of HPLC peaks with individual isomers is described in detail. 

Cells are lysed by three freeze/thaw cycles between dry ice-ethanol and 37 °C water baths. Benzonase (Sigma) is then added to the cell lysate (50 U/ml final concentration) and incubated for 30 min at 37 °C. The crude lysate is clarified by centrifugation at 4000 x g for 20 min and the vector-containing supernatant is divided between four iodixanol gradients. 

Discontinuous iodixanol step gradients are formed in quick seal tubes (25 x 89 mm, Beckman) by underlaying and displacing the less dense cell lysate (15 ml) with iodixanol (5,5 [(2-hydroxy-1-3-propanediyl)-bis(acetylamino)] bis [N,Ar,-bis(2,3dihydroxypro-pyl-2,4,6-triiodo-l,3-benzenecarboxamide]) prepared using a 60% (w/v) sterile solution of OptiPrep (Nycomed) and PBS-MK buffer (1 x PBS containing 1 mM MgCl2 and 2.5 mM KC1). Therefore,... 

For rAAVl and 5 vectors, a 5 ml HiTrap Q column (Pharmacia) is equilibrated at 5 ml/min with 5 column volumes (25 ml) of Buffer A (20 mM Tris, 15 mM NaCl, pH 8.5), then 25 ml Buffer B (20 mM Tris, 500 mM NaCl, pH 8.5), followed by 25 ml of Buffer A using a Pharmacia ATKA FPLC system. The 20 ml vector-containing iodixanol fraction is diluted 1 1 with Buffer A and applied to the column at a flow rate of 3-5 ml/min. After loading the sample, the column is washed with 10 column volumes (50 ml) of Buffer A. The vector is eluted with Buffer B and fractions are collected. 

Aspelin P Aubry R Fransson SG, et al. Cost-effectiveness of iodixanol in patients at high risk of contrast-induced nephropathy. Am Heart J 2005 149 298-303. 

Lancelot E, Idee J M, Couturier V et al. I nfluence of the viscosity of iodixanol on medullary and cortical blood flow in the rat kidney a potential cause of nephrotoxicity. J Appl Toxicol 1999 19 341-346. 

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