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Commentary |
1 Department of Radiology, Scott & White Clinic and Hospital, 2401 S 31st St., Temple, TX 76508.
Received December 14, 2007; accepted after revision December 18, 2007.
Periodically the American Journal of Roentgenology will republish
online one of the 100 most-cited articles from its first century. A
corresponding commentary in the journal by a contemporary radiologist will
provide a current perspective. For a full list of these articles, see
page 3 of the January 2006 issue of the
AJR or go to
www.ajronline.org.
Keywords: contrast media • DTPA • gadopentetate dimeglumine • MRI
The development of magnetic resonance imaging (MRI) provides a fascinating story, from its tentative early development to the award of the Nobel Prize, befitting the dominant role this modality serves today in clinical diagnosis. Key to the success of MRI was the development of safe, effective intra venous contrast media, the focus of this invited commentary. The article titled "Characteristics of Gadolinium-DTPA Complex: A Potential NMR Contrast Agent" [1], published in 1984, served not only as the first description of what was to become the dominant MRI contrast agent for 20 years, but also lay the groundwork for the entire field of gadolinium chelates. It should come as no surprise that this manuscript is the top-cited article published in the American Journal of Roentgenology (AJR) [2].
Hanns-Joachim Weinmann, first author of the article, led the development team at Schering (now Bayer HealthCare) responsible for gadopentetate dimeglumine (Magnevist) and all subsequent gadolinium chelates, such as gadolinium ethoxybenzyldiethylene triamine pentaacetic acid [3] and gadobutrol [4], under the direction of Ulrich Speck. Weinmann's work dated to 1981 and remained confidential until academia discovered the topic. My presentation at the 1982 meeting of the Radiological Society of North America detailed the potential of stable paramagnetic ion complexes as IV contrast agents [5]. That work was, however, less mature than that conducted at Schering in regard to specific choice of agent. It was my pleasure to meet Weinmann in early 1983, when he inquired about the status of my research, having attended, unbeknownst to me, the 1982 presentation. Given the state of development at Schering and my own knowledge of the field, I was easily convinced to focus on the preclinical evaluation of gadopentetate dimeglumine. This agent was an early obvious choice for development, if one knew the requirements and had sufficient foresight. The gadolinium ion is the most effective of the paramagnetic metals in terms of T1 relaxation and thus enhancement effect. The gadopentetate dimeglumine complex is extremely stable, and the chelate by itself (diethylenetriamine pentaacetic acid) was already commercially available in bulk quantity for human use.
The years 1983 and 1984 were busy ones for the field. A 1983 article in AJR [6] reviewed progress in the field, presenting primary findings and concluding "IV contrast agents may make possible the differentiation of tumor from surrounding edema in the brain, a problem that continues to confront NMR imaging." At the 1983 meeting of the Radiological Society of North America, Speck and Weinmann described the first use of gadopentetate dimeglumine in a healthy volunteer, an experiment performed at the clinical site of Professor Roland Felix in Berlin [7]. Uniform enhancement of the bladder had been visualized after a dose of only 0.8 mL. Clinical studies were begun at the Hammersmith Hospital in London at the end of 1983 [8], and Weinmann's seminal publication appeared in March 1984. Weinmann concluded, as subsequently confirmed in the 20 years of clinical experience with this agent, that "the combination of strong proton relaxation, in vivo stability, rapid urinary excretion, and high tolerance favors the further development and the potential clinical application of gadolinium-DTPA as a contrast enhancer in MRI" [1]. In June 1984, an oral presentation (published in 1985) described the in vivo use (in the same animal model that had been used for iodinated agents in CT for this purpose in 1979) and improved lesion sensitivity and specificity of MRI with gadopentetate dimeglumine [9]. Publications describing the pharmacokinetics in healthy volunteers [10] and injection in the first patient series [11] appeared by the end of 1984.
Gadopentetate dimeglumine was approved for clinical use in the United States, Germany, and Japan in 1988, after clinical trials that had been initiated in 1985. By 2007, more than 85 million doses had been administered, approximately 5 million applications annually. A 2006 review [12] of the spontaneous adverse event database confirmed the excellent safety profile of gadopentetate dimeglumine. The development of this agent was one of the fastest ever. Unfortunately, development in this time frame is unlikely to ever occur again. Successes like this have been slowed by bureaucracy within the business environment and the cost for approval by agencies such as the U.S. Food and Drug Administration [13]. The current cost of developing an agent for diagnostic imaging is $100 million to $200 million; gross annual sales of all gadolinium chelates in the United States are at most $400 million.
Beneath the tremendously successful pharmaceutical development lies the story of the quest for advancement and the roadblocks faced. Gadolinium chelates for MRI were developed during the time of rapid advancement in CT technology and the switch from ionic to nonionic iodinated contrast media. A question strongly voiced by CT advocates was whether there was any utility of a new technique such as MRI. In addition, the experts in the field of MRI at the time strongly criticized the suggestion that there would be any utility of contrast media. T1, T2, and proton density weighting were believed to provide more than sufficient tissue contrast. I for one was routinely booed off the podium (or at least felt that I was) in the 1980s for suggesting replacing a non invasive technique (MRI without IV contrast medium) with an invasive technique (gadolinium chelate injection). Weinmann deserves credit for making feasible a contrast agent containing a lanthanide metal (the lanthanide series is the first row of elements usually listed separately below the periodic table), the nonchelated gadolinium ion being poorly tolerated.
The year 2007 brought both good and bad news in the field of contrast agents for MRI. Nephrogenic systemic fibrosis emerged as a major adverse consequence of gadolinium chelate injection, although primarily involving weaker chelates of gadolinium that were later approved [14]. It is now known that nephrogenic systemic fibrosis occurs in only a very small subset of patients, those with stage 4 or 5 kidney failure, predominantly the latter end-stage renal disease. In respect for his work, it should be noted that the 1984 article by Weinmann et al. [1] credited the rapid renal excretion of the agent for its high in vivo tolerance. Regardless, 2007 brought further good news for this category of contrast media. It would have been hard to imagine in 1981, when Weinmann performed his first imaging experiments at 0.12 T, that 3 T would be considered the new benchmark and that contrast-enhanced MR angiography would be performed as a routine examination, replacing invasive diagnostic catheter angiography [15]. I greatly admire Weinmann and the many researchers who worked with him for their foresight and perseverance in what became a major field of diagnostic medicine.
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