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University of Hohenheim, Institute for Biological Chemistry and Nutrition, Stuttgart, Germany
2To whom correspondence should be addressed. E-mail: b-c-nutr{at}uni-hohenheim.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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KEY WORDS: • glutamine dipeptides • ornithine 
-ketoglutarate • acetylated amino acids • short chain protein hydrolysates • catabolic stress
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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, Fürst et al. 2000a, Griffiths 1999
). However, two unfavorable physical
chemical properties prevent the inclusion of free glutamine in
commercially available amino acid preparations; the quantitative
decomposition of aqueous glutamine to the cyclic product associated
with ammonia liberation (Fürst et al. 1990
) and
its limited solubility in water (35 g/L H2O at
20°C). Therefore, glutamine-containing TPN solutions must be
prepared freshly under strict aseptic conditions and stored at
4°C. To diminish the risk of precipitation, the glutamine
concentration in such solution should not exceed 2.5%. This means that
provision of adequate amounts of glutamine to injured or critically ill
patients represents a severe burden, especially in
volume-restricted situations. Consequently, parenteral use of free
glutamine is reserved for controlled clinical trials and only in
countries allowing nonheat-sterilized solutions.
Controlled clinical studies with free glutamine showed improved
nitrogen balance and rate of protein synthesis (Griffiths 1999
, Hammarqvist et al. 1989
, Ziegler et al. 1992
, Li et al. 1997
) compared with control
groups. Post-bone marrow transplantation morbidity was reduced with
supplemental glutamine; the incidence of clinical infection, total and
site-specific microbial colonization and the length of hospital
stay were reduced compared with control groups (Hammarqvist et al. 1989
, Schloerb and Amare 1993
). A recent
clinical study demonstrated reduced 6-mo mortality in critically ill
patients with a decrease in treatment costs, comparing
glutamine-enriched parenteral nutrition with isonitrogenous
isocaloric controls (Griffiths et al. 1997
).
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Dipeptide concept |
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TOPABSTRACTINTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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The dipeptides with glutamine at the C-terminal position, fulfill all chemical and physical criteria needed for approval by the authorities for composition of parenteral solutions.
Synthesis and characterization of dipeptides with special reference to glutamine containing dipeptides.
In the early 1980s, dipeptides were not commercially available. Thus,
the first task was to synthesize suitable dipeptides on a laboratory
scale and attempt a purity of >99%, high water solubility, stability
during heat sterilization and storage. In early trials, we used a
modified N-carboxy anhydride method for the synthesis of a
great variety of peptides in acceptable yields (Stehle et al. 1982
). Confirmation of the structure of the purified peptides
was achieved via mass spectroscopy and nuclear magnetic resonance
spectroscopy. Great efforts were made to obtain reliable data
concerning peptide purity. We established a novel free-flow
electrophoretic technology (analytical isotachophoresis) enabling
simultaneous determination of organic and inorganic impurities in the
purified peptide material (Stehle et al. 1986
). The
combined use of this highly specific method with reverse-phase HPLC
techniques showed purity degrees > 99% for the synthetic
peptides. Interestingly, the peptides synthesized revealed solubilities
in aqueous solutions 20- to 2000-fold higher than the corresponding
free amino acids (Table 1). Heat stability under strictly controlled conditions at 121°C over
30 min was confirmed by heat stability of glutamine and
tyrosine peptides (Stehle et al.1982
). Under these
conditions, the cystine-containing peptides showed less stability,
yet still retained sufficient stability during sterile filtration to be
considered parenteral substrates.
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,
Jakubke et al. 1985
). The obvious advantages of an
enzyme-catalyzed peptide synthesis are the (stereo)-specificity of
the reaction, the possibility to minimize protection of functional
groups and the feasibility to use free amino acids as nucleophiles. The
principle of the kinetic approach using serine or sulfhydryl proteases
in aqueous medium is schematically shown in Figure 1
. These enzymes exhibit both hydrolase and esterase activities. In
alkaline aqueous solutions, the N-protected amino acid
esters (electrophiles) rapidly form the intermediate acyl-enzyme
complex. This complex is attacked by nucleophiles, either by water
(hydrolysis) or by an amine (aminolysis, e.g., a free amino acid). If
k4 (H2N-R) is higher than
k3 (H2O), the corresponding
N-protected dipeptide is accumulated in the reaction medium.
Besides the nucleophile concentration, the ratio aminolysis/hydrolysis
additionally can be influenced by pH in the medium reaction temperature
and the ratio of nucleophile to electrophile.
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; Stehle et al. 1990
, Monter et al. 1991
).
The use of selectively cleavable N-protecting group (e.g.,
carbobenzoxy-, formyl-, maleyl-) facilitates an easy and effective
liberation of the desired unprotected dipeptide, e.g., simply by
acidification of the reaction mixture. After deprotection, the desired
dipeptide could be almost quantitatively isolated in high purity
(Monter et al. 1991
).
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). The flow diagram of
the experimental system is shown in Figure 2
. The native enzyme is retained in the reactor using an ultrafiltration
membrane. Substrate solution 1 (0.2 mol/L Gln, 8 mmol/L EDTA, pH 9.2)
was continuously pumped (5–10 mL, residence time: 90 min)
through a sterile filter into the thermostatic (30°C) reactor. Before
entering the reactor, the glutamine solution was adjusted to pH
9.3–9.5 to maintain an effluent pH of 9.2. Substrate solution 2 (1
mmol/L of the electrophile Cbz-Ala-Ome in EtOH) was periodically added
to the reaction mixture every 3 h for 60 min (flow rate: 0.5
mL/h). The reaction was started by adding 100 mg ficin dissolved in
water; loss of enzyme activity over time was compensated by periodic
addition of 100-mg portions of the enzyme. The mean process time was 60
± 25 h. At this time, the product yields an average of 45%
of theory, which is not yet sufficient to compete with traditional
industrial procedures. The results are sufficiently encouraging to
justify additional biotechnological approaches for chemical dipeptide
synthesis.
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Glutamine dipeptides: a new dimension in clinical nutrition |
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TOPABSTRACTINTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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The glutamine containing dipeptides
L-alanyl-L-glutamine (Ala-Gln) and
glycyl-L-glutamine are available products and today are an
integral part of routine clinical practice. These preparations,
Dipeptiven and Glamin (Fresenius Kabi, Uppsala, Sweden), are
innovative products; the result of many years of intensive research in
the field of clinical nutrition. Dipeptiven is a 20% solution of the
glutamine-containing dipeptide
N(2)-L-alanyl-L-glutamine
(Ala-Gln). It is stable during heat sterilization and storage, and it
is highly soluble (568 g/L; Table 1
). Glamin is a complete,
well-balanced amino acid solution containing 30.27 g/L stable
glycyl-L-glutamine (Gly-Gln). Basic studies in
humans and animals provide firm evidence that both glutamine dipeptides
are readily used. Importantly, infusion of Dipeptiven or Glamin is well
tolerated and not accompanied by any side effects or complaints. The
dipeptide concept is based upon the premise that improvement in the
quality of available amino acid solutions, currently lacking glutamine,
is a major step in resolving the problem of how to formulate and
prepare a complete, well-balanced amino acid solution.
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Implications for glutamine dipeptide therapy |
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TOPABSTRACTINTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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Biochemical indications.
Generally, poor nutritional status as assessed by body weight, body mass index, anthropometric measures and low plasma albumin, and severe loss of nitrogen and functional tissue, is a useful indication for glutamine dipeptide therapy. Poor immune status is always a strong signal of glutamine deprivation. Decreased body cell mass, in combination with decreased intracellular and increased extracellular water (easily measured via bioimpedance spectroscopy), favor glutamine dipeptide administration. Please note that plasma-free glutamine concentrations do not always reflect body glutamine status. A normal plasma glutamine level might be associated with severe intracellular glutamine depletion.
Patients.
Glutamine (dipeptide) nutrition is an important therapeutic measure in
a number of clinical situations. Table 3
suggests patient categories that may benefit from glutamine dipeptide
therapy.
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Administration of glutamine by the intravenous route is the most
reliable method of achieving a prolonged constant elevation of the free
glutamine pool of the body. Supplemental intravenous glutamine
dipeptides exert numerous beneficial effects as summarized in
Table 4
. Glutamine dipeptides should be provided immediately after the
catabolic insult to initially support the attenuated tissues with
glutamine.
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). In many
available studies no convincing biologic or clinical results were
obtained from traumatized or intensive care unit
(ICU)3
patients despite considerable supply of glutamine (15–35 g/d;
Table 5
).
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).
It is notable that enteral glutamine nutrition, which initially did not
raise the blood glutamine concentration, has been shown to improve the
outcome in premature infants; for example, the frequency of sepsis
decreased and immunity increased after 0.3 g/kg body enteral
supplementation of glutamine (Neu et al. 1997
). These
beneficial effects presumably reflect increased bowel maturation,
indicating that enteral glutamine can act on the gastrointestinal tract
without exerting direct systemic effects (Wilmore and Shabert 1998
). In adult patients, glutamine has been shown to have a
beneficial effect on intestinal barrier function when given orally (30
g/d) for several weeks after high dose chemotherapy or radiotherapy for
esophageal cancer (Yoshida et al. 1998
).
Another confirmation that enteral glutamine is effective in preventing
infective complications has been recently reported in 60 patients with
severe multiple trauma (Houdijk et al. 1998
). There was
a significant reduction (
50%) in the 15-d incidence of pneumonia,
bacteremia and severe sepsis. The strengths of this study are in the
relatively homogeneous population of patients studied and the fact that
the study did not suffer from the confounding factors present in
multicenter studies. The results of this fascinating study require
confirmation.
There is some evidence that the body glutamine pool is slower to
recover when the same dose of glutamine is given enterally (orally) as
opposed to parenterally (Fish et al. 1997
). The enteral
route may be ideal when given early to the noninfected patient to
improve gut-associated lymphoid tissue function and immune defense
against infection, but for already severely stressed or infected ICU
patients, enteral supplements alone may be inadequate, and parallel
parenteral support is likely to be required. It has been clearly shown
that during intensive care parenteral supplementation of enteral
nutrition with glutamine does not increase the risk to the patients and
may ensure a better overall outcome (Bauer et al. 1998
).
It should, however, be borne in mind that enteral supplementation with
glutamine is a potential hazard because such formulations may form a
vigorous cultural medium for microorganisms if strict care is not taken
(Griffiths 1999
).
Dosing of glutamine dipeptides.
It is generally accepted that a 60- to 70-kg patient after major
injury, uncomplicated elective surgery, with gastrointestinal
malfunctions or cachexia, should be given 18–30 g glutamine dipeptides
(13–20 g glutamine/d). A severely injured patient with multiple
injury, burns, sepsis, systemic inflammatory response syndrome,
serious immune deficiency, as well as after bone marrow transplant, may
require higher doses of glutamine dipeptide (Wilmore and Shabert 1998
, Griffiths 1999
, Wilmore 1997
, Wilmore et al. 1999
, Fürst et al. 2000b
).
Indeed, lack of glutamine from conventional TPN and its subsequent
supplementation should be considered as a correction of a deficiency
rather than as supplementation (Griffiths 1999
,
Fürst et al. 1997b
) and as a novel therapeutical
measure using glutamine as a pharmacon (pharmacological nutrition).
Thus, it is conceivable that the beneficial effects observed with
glutamine dipeptide nutrition are simply a correction of disadvantages
produced by inadequacies of conventional amino acid solutions. The
availability of stable glutamine-dipeptide-containing preparations
(Dipeptiven and Glamin) now facilitates glutamine nutrition in routine
clinical settings.
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Alternative nitrogen-containing substrates |
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TOPABSTRACTINTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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The implication of N-acetylated amino acids was an early
suggestion to facilitate parenteral provision of cysteine, tyrosine and
glutamine. Early studies in experimental rats undergoing long-term
TPN clearly have shown that highly soluble and stable
N-acetylated amino acids, acetylcysteine, acetyltyrosine and
acetylglutamine, are rapidly taken up and are subsequently hydrolyzed
by acylases after their parenteral administration
(Neuhäuser et al. 1985
, 1986
,
1988
). In a subsequent study in dogs, Abumrad et al.
(1989
) observed only poor use of parenterally supplied
acetylglutamine associated with a large urinary excretion (38% of the
amount infused). Among the organs studied, only the kidney cleared
acetylglutamine to a measurable extent. This was confirmed in healthy
humans because continuous infusion of acetylglutamine (Magnusson et al. 1989a
), acetyltyrosine or acetylcysteine
(Magnusson et al. 1989b
) resulted in an accumulation of
the respective compound in plasma in which levels of the corresponding
free amino acids were not, or only slightly, increased (Fig. 3
). The urinary excretion rate of the acetylated amino acids approached
40–50% of the amount given. After bolus injection of acetyltyrosine,
Druml et al. (1991
) observed little if any hydrolysis of
the acetylated amino acid. Pharmacokinetic evaluation after intravenous
supply of acetyl-cysteine in humans exhibited an elimination
half-life of 2.3 h, a value which is indeed 40-fold higher
than values observed for cystine-containing peptides (Stehle et al. 1988
).
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Short-chain protein hydrolysates.
Purified short-chain protein hydrolysates (>67% di- and
tripeptides, >10% free amino acids) have been discussed as a low
osmolality alternative to free amino acid solutions and synthetic
dipeptides for peripheral parenteral nutrition (Grimble and Silk 1989
, Grimble et al. 1992
). In an enzymatically
prepared short-chain casein hydrolysate, < 10% of those amino
acids that are themselves relatively insoluble or unstable (tyrosine,
cysteine, glutamine, tryptophan) were found to exist in free form
(Grimble et al. 1987
).
During intravenous infusion of a short-chain ovalbumin hydrolysate
in healthy human subjects, excess peptide excretion suggested that a
large proportion of the hydrolysate was metabolized (Grimble et al. 1988
). Marked differences between infused and excreted
peptide profiles indicated that use of peptides from the hydrolysate
was sequence-specific.
Ornithine -ketoglutarate (OKG).
The salt OKG might exert a synergistic effect on both its constituents.
Recent investigations suggest that after enteral OKG administration gut
morphology and function improve, trauma-induced immune dysfunction
is alleviated and there are anabolic/anticatabolic actions on protein
metabolism (Cynober 1995
, 1999
). Because
the majority of these studies were performed in various experimental
models, it is necessary to confirm the postulated benefits in
controlled clinical trials. Theoretically, the properties of OKG should
counteract the catabolic response that occurs during episodes of
infection and after trauma and injury. Enteral administration has been
proposed in various catabolic situations (Cynober 1999
).
Favorable effects on muscle protein synthesis have been observed in
trauma and burned patients after enteral administration (Cynober 1999
, Le Bricon et al. 1997
), and improved
N-balance and protein synthesis have been found after
intravenous administration (Hammarqvist et al. 1991
).
However, direct beneficial effects of ornithine or OKG on gut
structure, function or outcome have not been demonstrated
(Gardiner et al. 1995
). Therefore, any clinical impact
of the findings outlined above requires confirmation by additional
controlled studies (Jolliet et al. 1999
).
There are numerous underlying mechanisms proposed that might account
for the observed beneficial effects of OKG, including glutamine
formation, arginine, proline, polyamine generation, increase in growth
hormone and insulin secretion, etc. A principal question is whether OKG
is a true precursor for glutamine. According to textbooks, KG is the
precursor of glutamic acid, although its precursor function for
glutamine is limited. Accordingly, several reports demonstrate that the
in vivo transformation from external glutamic acid to glutamine is
restricted, corresponding to not > 5–6% of the given dose
(Darmaun et al. 1986
). Certainly labeled KG might be
recovered in tissue glutamine (Vaubourdolle et al. 1988
), yet this finding does not reflect the extent of
transformation in a quantitative manner. Human stable-isotope
studies confirm that continuous enteral delivery of labeled KG or
OKG cannot alter glutamine kinetics in burned patients
(Mittendorfer et al. 1999
). Because glutamic acid is
known to be poorly transported across the cell membrane, it can be
concluded that KG or related compounds cannot replace glutamine in
clinical nutrition unless KG is directly taken up by cells and
converted first to glutamic acid and subsequently to glutamine. This
theoretical pathway, however, has not yet been established
(Fürst et al. 1999
).
Adequate delivery of glutamine in the frame of artificial nutrition is an important measure to support healing and reduce morbidity and mortality of stressed patients. Certain clinical conditions are accompanied with characteristic alterations in organ-specific glutamine metabolism. Because the requirement exceeds the availability of glutamine, it should be ranked as conditionally indispensable and, thus, should be a mandatory part of nutritional measures. Apart from its nutritive role, glutamine possesses certain pharmacologic and/or immunologic effects. Clinical studies reveal evidence that the currently applied concept of glutamine nutrition is beneficial in providing patients with a conditionally indispensable amino acid that is otherwise difficult to deliver.
Among novel ways to deliver glutamine (glutamine dipeptides, acetylglutamine, short-chain protein hydrolysates and OKG), the glutamine dipeptide approach is the most promising. This compilation may well illustrate how far we have advanced our knowledge of the importance of a new substrate in modern artificial nutrition. There is little question that efforts made to modify the response to disease by glutamine nutrition will be rewarded with improved patient outcome.
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FOOTNOTES |
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3 Abbreviations used: ICU, intensive care unit;
OKG, ornithine -ketoglutarate.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONDipeptide conceptGlutamine dipeptides: a new...Implications for glutamine...Alternative nitrogen-containing...LITERATURE CITED |
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