Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review

Nephrogenic systemic fibrosis (NSF) has been associated with the administration of gadolinium‐based contrast agents in patients with severely impaired renal function (SIRF), endstage renal disease (ESRD), or acute renal failure (ARF). Since the vast majority of these patients do not get NSF, it is highly likely that patient factors play a role in its development. Although “free” or dechelated gadolinium is thought by some to be the only trigger of NSF, recent evidence suggests that chelated gadolinium may be important. Chelated gadolinium such as Omniscan (gadodiamide) and Magnevist (gadopentetate) can directly stimulate macrophages and monocytes in vitro to release profibrotic cytokines and growth factors capable of initiating and supporting the tissue fibrosis that is characteristic of NSF. In addition, an effect of chelated gadolinium on fibroblasts has also been demonstrated. Chelated gadolinium in the form of Omniscan, Magnevist, MultiHance, and ProHance increased proliferation of human dermal fibroblasts. Indeed, increased numbers of macrophages, together with activated fibroblasts and fibrocytes, are essential cells in the fibrotic process and are present in NSF skin. Accordingly, it is important that chelated gadolinium, in combination with patient cofactors, is considered in the etiology of NSF associated with enhanced scans. J. Magn. Reson. Imaging 2009;30:1277–1283. © 2009 Wiley‐Liss, Inc.

Section: The Phagocytosis Of Gd Triggers Inflammatorymentioning

confidence: 99%

Mechanism of NSF: New evidence challenging the prevailing theory

Newton¹,

Jimenez

2009

“…This represents 96% of the 163 unconfounded cases where documentation showed that a single type of gadolinium-chelate was given to the patient before the onset of NSF; excluding cases where the type of agent was unknown, multiple types of agents were given, or there was no documentation of gadolinium-chelate administration. Gadodiamide (Omniscan) has relatively lower conditional stability (35,36). Normal half-life is approximately 90 min, but this can be prolonged to greater than 50 hours in the setting of renal failure.…”

Section: Gadolinium Agent Utilization and Safetymentioning

confidence: 99%

Kidney transplantation: Structural and functional evaluation using MR Nephro‐Urography

Kalb

Martín

Salman

et al. 2008

End-stage-renal disease (ESRD) is a major health issue in the United States, and the Medicare costs of ESRD totaled nearly $21 billion in 2005. Renal transplantation has emerged as the treatment of choice in this patient population, providing improved quality of life and lower healthcare costs compared with other treatment options. Imaging evaluation of a graft kidney plays a critical role in the postoperative care of the renal transplant patient. In the past, diagnostic evaluation of the transplant kidney has depended upon a combination of ultrasonography, computed tomography, MRI, and biopsy, used in conjunction with the patient's clinical presentation. However, new and developing advances in MR technology has lead to the development of MR Nephro-Urography (MRNU), which provides both anatomic and functional evaluation of the kidney in a single examination. It is expected that the increasing use of MRNU will have a significant impact on the management of renal transplant patients. This review describes MRNU methodology, examines known posttransplant complications, and highlights the utility of MRNU as a comprehensive imaging examination to diagnose both surgical and medical complications of the transplant kidney.

“…Furthermore, GC can be either nonionic (in which the number of carboxyl groups are reduced to three, which neutralize the three positive charges of Gd 3þ ) (strictly speaking, such GC are ''neutral'' rather than ''nonionic'') or ionic (in which the remaining carboxyl groups are salified with meglumine or sodium) (9,10,23,24) (Fig. 1).…”

Section: Chemistry and Pharmacology Of Gadolinium Chelatesmentioning

confidence: 99%

“…Such excipients are intended to ensure the absence of free Gd 3þ cations in pharmaceutical solutions for the duration of their shelf lives (23,24). According to the law of mass action (Eqs.…”

Section: Chemistry and Pharmacology Of Gadolinium Chelatesmentioning

confidence: 99%

“…[1] and [2], below), an excess in free ligand reduces the concentration of free Gd 3þ . The least stable agents (Gd-DTPA-BMA and Gd-DTPA-BMEA) each have considerably larger amounts of excess chelate (25 and 50 mmol/L, ie, 5% and 10% of the GC concentration, respectively) than the most stable agents (23,24). There is no excess ligand in the approved formulations of Gd-DOTA and Gd-BOPTA (Table 1).…”

Section: Chemistry and Pharmacology Of Gadolinium Chelatesmentioning

confidence: 99%

See 1 more Smart Citation

Role of thermodynamic and kinetic parameters in gadolinium chelate stability

Idée

Port

Robic

et al. 2009

Self Cite

164

In recent years there has been a renewed interest in the physicochemical properties of gadolinium chelates (GC). The aim of this review is to discuss the physicochemical properties of marketed GC with regard to possible biological consequences. GC can be classified according to three key molecular features: 1) the nature of the chelating moiety: either macrocyclic molecules in which Gd 3þ is caged in the preorganized cavity of the ligand, or linear, openchain molecules; 2) ionicity: the ionicity of the molecule varies from neutral to tri-anionic agents; and 3) the presence or absence of an aromatic lipophilic moiety, which has a profound impact on the biodistribution of the GC. These parameters can also explain why GC differ considerably with regard to their thermodynamic stability constants and kinetic stability, as demonstrated by numerous studies. The concept of thermodynamic and kinetic stability is critically discussed, as it remains somewhat controversial, especially in predicting the amount of free gadolinium that may result from decomplexation of chelates in physiologic or pathologic situations. This review examines the possibility that the high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) can minimize the amount of free Gd 3þ released in the body.