The structure of current water-soluble radiocontrast media (RCM) is based on fully substituted benzoic acid with three iodines at positions 2, 4, and 6 on the benzene ring (Hong SJ, Wong JT 2002 Allergy Asthma Proc; Pasternak JJ and Williamson EE 2012 Mayo Clin Proc; Szebeni J 2004 Curr Allergy Asthma Rep). The ionic monomers are sodium or meglumine salts of the anionic triiodinated benzene ring and they render with high osmolarity (>1400 mOsm/kg). The dimerized derivatives already have lower osmolarity (eg, 600 mOsm/kg), and further derivatization with hydroxyl groups or other hydrophilic conjugates results in even lower-osmolarity (500–700 mOsm/kg) or isoosmolarity (Hong SJ, Wong JT 2002 Allergy Asthma Proc) resulting in a lack of ionization as shown in table 22.214.171.124.
Although intravenous use of RCMs is routine medical practice today (Szebeni J 2004 Curr Allergy Asthma Rep), they still carry a significant risk for hypersensitivity reactions (HSRs), also referred to as “RCM reactions”(Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2005 Toxicology; Szebeni J 2001 Crit Rev Ther Drug Carrier Syst). It has been proposed in several studies that nonionic, low-osmolarity RCMs (LO-RCM) are safer than ionic, high osmolarity agents (HO-RCM) (Hong SJ, Wong JT 2002 Allergy Asthma Proc; Henry DA, Evans DB 1991 Med J Aust; Westhoff-Bleck M, Bleck JS 1991 Drug Saf; Katayama H, et al. 2001 Invest Radiol; Barrett BJ, et al. 1992 N Engl J Med).
Mast cells and basophils are in the centre of RCM reactions (Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2005 Toxicology; Szebeni J 2001 Crit Rev Ther Drug Carrier Syst). They can be triggered by RCM molecules directly, through intracellular interactions and/or extracellular physical effects (for example, osmotic stress), or indirectly, via cell membrane receptors (e.g. C5aR and C3aR, FcɛRI) (Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2005 Toxicology). Among these, anaphylatoxin receptors (C5aR and C3aR) seem to have the highest impact since complement activation has been shown as an underlying cause of RMC reactions in several experimental studies (Lasser EC, Sovak M 1976 Radiology; Lang JH, Lasser EC 1976 Invest Radiol) and in clinical observations (Lasser EC, et al. 1980 Invest Radiol; Vandenplas O, et al. 1990 Acta Clin Belg; Lieberman P 1991 Clin Rev Allergy; Small P, et al. 1982 Clin Allergy; Westaby S, et al. 1985 Cardiovasc Res), suggesting that CARPA is a good terminology in the majority of HSRs.
Both the classical and the alternative pathways of the complement system can be activated during the RCM reaction (Lieberman P 1991 Clin Rev Allergy; Napolov Iu K, Bolotova EN 1998 Eksp Klin Farmakol) via physical effects (charge, viscosity, iodine number, hydrophilicity and osmotic pressure) (Lieberman P 1991 Clin Rev Allergy; Napolov Iu K, Bolotova EN 1998 Eksp Klin Farmakol; Vik H, et al. 1995 Acta Radiol Suppl); via uncommon mechanisms, such as non-localized, nonsequential cleavage of C proteins (Kolb WP, Lang JH 1978 J Immunol); via suppression of complement inhibitor factors (Factors H and I) (Lieberman P 1991 Clin Rev Allergy); and via direct action on the thioester bonds of C4 and C3 (Vik H, et al. 1995 Acta Radiol Suppl). Positive feedback can be also provided by co-activation of the coagulation and kinin-kallikrein systems, leading to crossover activation of the complement cascade with depletion of C1INH (Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2001 Crit Rev Ther Drug Carrier Syst; Fattori R, et al. 1994 Eur J Radiol). This means that the in vitro investigations of complement system (link) has a prominent role in the immune toxicity research of RCMs.
As it was mentioned, complement activation exerts its effects mainly in the effector arm of the immune response by mast cells and basophil granulocytes, which provoke the clinical symptoms via releasing secondary mediators, including histamine, tryptase, PAF, LTB2, LTB4, LTC4, LTD4, LTE4, TXA2, PGD2 and TXD4 (Westhoff-Bleck M, Bleck JS 1991 Drug Saf; Lieberman P 1991 Clin Rev Allergy; Greenberger PA 1984 J Allergy Clin Immunol). SeroScience offers the measurements of some of these mediators’ derivatives (link), and also offer tests for the investigation of basophil functions both in vitro (link) and in vivo (link). It must be noted that the secretory response of mast cells and basophils to RCM is dependent on the localization of these cells. For example, mast cells from the skin might not respond to certain RCM, whereas pulmonary and cardiac mast cells are triggered for strong release of inflammatory mediators (Genovese A, et al. 1996 Int J Clin Lab Res) by the same RCM.
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