P. Fürst

Glutamine Dipeptides in Clinical Nutrition

Glutamine is a conditional indispensable amino acid during stress. However, limited solubility and instability of glutamine prevent its addition to presently available nutritional preparations. To overcome these drawbacks, we propose the dipeptide concept by which stable and highly soluble synthetic glutamine containing dipeptides are used. The synthetic dipeptides fulfill all chemical/physical properties to be considered as parenteral substrates. Numerous experimental studies show rapid clearance of parenteral supplied glutamine containing dipeptides without accumulation in tissues; the loss via the urine being inconsequential. Differences related to the dipeptide structure are not observed. There is overwhelming evidence existent that a nutritional support with supplemental glutamine dipeptide positively influences nitrogen excretion, immune status, gut integrity, morbidity, rehabilitation and outcome. Consequently, omission of glutamine from conventional TPN and its subsequent administration should be considered as a replacement of a deficiency rather than a supplementation. It might thus be conceivable that the beneficial effects observed with glutamine nutrition are simply a correction of disadvantages produced by an inadequacy of conventional amino acid solutions. The availability of stable glutamine containing preparations will certainly facilitate an adequate amino acid nutrition in routine clinical setting during episodes of stress and malnutrition.

Glutamine-containing dipeptides in parenteral nutrition.

Of the total pool of muscle free intracellular amino acids, glutamine represents about 60%. During catabolic stress, a marked reduction (50%) of this pool occurs; the depletion is not reversible by therapeutic efforts or conventional nutritional means. If maintenance of the intracellular glutamine pool promotes conservation of muscle protein, there is a theoretical case for use of glutamine supplements in the parenteral nutrition of patients with injury and infection. Glutamine is too unstable and poorly soluble for addition to existing preparations in its native form, but this drawback can be overcome by the use of synthetic stable and highly soluble glutamine-containing dipeptides. In vivo studies in humans and animals provide firm evidence that a synthetic glutamine-containing dipeptide, L-alanyl-L-glutamine (Ala-Gln), is readily hydrolyzed following its intravenous administration. The results also indicate a safe and efficient use of Ala-Gln as a source of free glutamine in parenteral nutrition. In clinical studies, nitrogen balance was more positive in catabolic patients receiving a peptide-supplemented solution than in control patients given isonitrogenous, isoenergetic total parenteral nutrition. Muscle glutamine concentrations were markedly decreased in the control groups. The intracellular concentrations were not influenced following severe injury, but were maintained in postoperative trauma. It is inferred that the increased intestinal requirement and cellular demand for metabolic fuel during catabolic stress is matched by an enhanced demand on muscle glutamine, resulting in intracellular glutamine depletion. Thus, the delivery of adequate amounts of glutamine is essential to maintain the integrity of intestinal mucosa and rapidly proliferating cells, to preserve the muscle glutamine pool, and to improve overall nitrogen economy during conditions of stress.

New Developments in Glutamine Delivery

Numerous studies demonstrate that free glutamine can be added to commercially available crystalline amino acid-based preparations before their administration. Instability during heat sterilization and prolonged storage and limited solubility (35 g/L at 20 degrees C) hamper the use of free glutamine in the routine clinical setting. Indeed, there are many well-controlled and valuable trials with free glutamine, yet its use is restricted to clinical research. The obvious limitations of using free glutamine initiated an intensive search for alternative substrates. Synthetic glutamine dipeptides are stable under heat sterilization and highly soluble; these properties qualify the dipeptides as suitable constituents of nutritional preparations. Industrial production of these dipeptides at a reasonable price is an essential prerequisite for implications of dipeptide-containing solutions in clinical practice. Recent development of novel synthesis procedures allows increased capacity in industrial-scale production. Basic studies with synthetic glutamine-containing short-chain peptides provide convincing evidence that these new substrates are cleared rapidly from plasma after parenteral administration, without being accumulated in tissues and with negligible loss in urine. The presence of membrane-bound as well as tissue-free extracellular hydrolase activity facilitates a prompt and quantitative peptide hydrolysis, the liberated amino acids being available for protein synthesis and/or generation of energy. In the clinical setting, glutamine dipeptide nutrition beneficially influences outcome (nitrogen balance, immunity, gut integrity, hospital stay, morbidity and mortality). The provision of conditionally indispensable glutamine should be considered a necessary replacement of a deficiency rather than a supplementation. The beneficial effects observed with glutamine dipeptide nutrition should be seen simply as a correction of disadvantages produced by the inadequacy of conventional clinical nutrition. The availability of stable dipeptide preparations certainly facilitates, for the first time, adequate amino acid nutrition of critically ill, malnourished or stressed patients in the routine clinical setting and, thus, represents a new dimension in artificial nutrition.

Nitrogen sparing effect of ornicetil® in the immediate post-operative state—Plasma and muscle amino-acids

Abstract In an earlier report we demonstrated that parenteral nutrition (TPN) with addition of 1(+)ornithine alpha-ketoglutarate (Ornicetil®) markedly improved nitrogen economy in the immediate post-operative period compared to controls given isocaloric and isonitrogenous TPN but without Ornicetil®. In the present study, plasma and intracellular muscle free amino-acid concentrations were measured in 13 patients before and 3 days after major elective abdominal surgery; seven patients without and six with Ornicetil® supplementation. The pre-operative values for plasma and muscle free amino-acids did not differ from those derived from age matched health subjects. The direction of post-operative alterations in plasma amino-acid concentrations were similar in both groups, consistent with the earlier reported post-operative pattern, although the elevations of BCAA, proline and ornithine were much more accentuated in the Ornicetil® group. After surgery the majority of the commonly observed intracellular changes were abolished or minimised in patients receiving Ornicetil®, while the intracellular depletion of glutamine persisted and the levels of ornithine and proline were markedly elevated as a consequence of Ornicetil® supply. A tentative explanation for the biochemical action of Ornicetil® is given.

The European View of Hospital Undernutrition

Disease-related undernutrition is significant in European hospitals but is seldom treated or prevented. In 1999, the Council of Europe decided to collect information regarding nutrition programs in hospitals, and for this purpose, a network consisting of national experts from 12 of the Partial Agreement member states was established. The aim was to review the current practices in Europe regarding hospital food provision, to highlight deficiencies, and to issue recommendations to improve the nutritional care and support of hospitalized patients. Five major common problems were identified: 1) lack of clearly defined responsibilities, 2) lack of sufficient education, 3) lack of influence and knowledge of the patients, 4) lack of cooperation between different staff groups, and 5) lack of involvement from the hospital management. To solve the problems highlighted, a combined timely and concerted effort is required from national authorities and hospital staff, including managers, to ensure appropriate nutritional care and support.