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Division of Gastroenterology and Hepatology Northwestern University Medical School 676 North St Clair Street Suite 880 Chicago, IL 60611 E-mail: a-buchman{at}northwestern.edu
Dear Sir:
Contrary to Cynober's statements, many glutamine studies have serious flaws in their hypothesis, design, methods, and data analysis. In my paper, I did not state that a study had flaws without describing the flaws in detail. I discussed the inadequacies of both well-designed and poorly designed studies and reported both positive and negative findings. Cynober stated that I excluded studies that did not support my conclusions but cited no example of a glutamine study in humans that was excluded. I did exclude many animal studies at the request of the Journal's reviewers, who wanted the review limited to studies of humans. Nevertheless, I tried to point out the differences between animal and human data. It is important that the results of rodent studies not be generalized to humans. Animal studies confirm in vitro investigations and must be confirmed in humans.
Parenteral and enteral glutamine studies were discussed together because the bioavailability of both is similar (1) and the results of both types of studies are similar. Nevertheless, my review was not meant to be a meta-analysis; the results of each study were discussed independently.
Cynober stated that one could conclude from my review that enteral nutrition is not better than parenteral nutrition, perioperative nutrition is of no value, early enteral nutrition is not efficacious, and fiber is worthless. Arguments for and against each of these conclusions can be made, just as with glutamine (2,3). My intention was to review glutamine only.
I described some positive results of glutamine studies and indicated which of the studies appeared to be valid and which did not, providing well-documented criticism for each. Cynober made his conjectures without any data or references and failed to describe how any of my specific critiques of the glutamine studies were inaccurate. Glutamine has somewhat of a cult following. One should not allow this behavior to interfere with proper data analysis and interpretation. My hope is that physicians and investigators will now consider both sides of the glutamine story for the first time.
Cynober suggested that I inappropriately excluded human studies of ornithine -ketoglutarate in my review; however, my review was intended to be solely about glutamine. Nevertheless, in a small, open-labeled study with a crossover design that I was involved in, ornithine -ketoglutarate was shown to be important in the linear growth of children dependent on total parenteral nutrition (4). However, rather than via glutamine, the effects of ornithine -ketoglutarate were probably mediated via growth hormone, insulin-like growth factor 1, or both (5).
Cynober cited 3 studies in burn patients, one of which he was involved in (6–8). De Bandt et al (6) reported that plasma glutamine increased in association with ornithine -ketoglutarate supplementation (similar to the findings of my previous study; 4) on days 10 and 13 but not on days 2, 4, 7, or 21. It is difficult to make sense of these data; however, one cannot assume that ornithine -ketoglutarate's effects were mediated via glutamine when ornithine -ketoglutarate supplementation results in increased plasma arginine, ornithine, proline, polyamine, growth hormone, and insulin-like growth factor 1 concentrations. Cynober suggested that the positive effects of ornithine -ketoglutarate supplementation on burn wound healing in a well-designed, double-blinded, placebo-controlled trial were probably mediated via increased proline, arginine, ornithine, growth hormone, or insulin-like growth factor 1; glutamine was never mentioned in his discussion (7). Cynober's own study contradicts his argument about my review. Donati et al (8) describe that wound healing was improved with ornithine -ketoglutarate supplementation, but they used an unvalidated technique of assessment. In addition, nitrogen intake differed between the experimental and control groups because the goal was for the diets to be isoenergetic. These investigators also failed to show that ornithine -ketoglutarate's effects were mediated via glutamine.
It is unclear what Cynober meant when he stated that I combined "the results of studies of the effects of enteral and parenteral nutrition even though the differences in glutamine's effects with the route of administration were emphasized in a remarkable analysis." The analysis to which he refers is a review article in which Alpers (9) concluded, similarly to my conclusion, that "its [glutamine's] clinical effects, if indeed unique and consistent, may result from actions other than as a fuel for the intestine," so the route of administration should not matter. Furthermore, Alpers concluded that "In interpreting the literature...one should make cautious applications of experimental results in small rodents and isolated cells, for example to clinical situations in intact humans." That is exactly my argument.
Cynober asked what was meant by "commercially essential" and further suggests that companies are free to market any available product because they reinvest the profits in research. He is correct in his first assumption. In the United States, companies are free to market any nutritional supplement without having to seek approval from the Food and Drug Administration (FDA), which would ordinarily require the efficacy and safety of glutamine to be proven. Because of the 1994 Dietary Supplement Health and Education Act, the burden of proof is now on the FDA to prove that an enteral supplement is unsafe rather than on the manufacturer to prove that it is safe; efficacy does not even enter into the equation (10). FDA review and approval of marketing claims that enteral glutamine helps maintain normal bodily functions is not required; only specific medical claims require approval. Marketing a product that has superior claims over a competitor is key to marketing success. As such, to gain market share, those manufacturers whose products contain glutamine have been touting their products as superior to their competitors. That makes glutamine commercially essential. Parenteral glutamine is regulated by the FDA and is not specifically approved for use in total parenteral nutrition or for any other purpose.
I am unaware of any data proving that manufacturers and hawkers of glutamine use their profits from this product to conduct research in humans, as Cynober stated. Perhaps if as much money were spent on glutamine research as is spent on marketing it, there would be better data from which one could make more appropriate conclusions.
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