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Publication numberUS3920838 A
Publication typeGrant
Publication dateNov 18, 1975
Filing dateSep 4, 1973
Priority dateSep 4, 1973
Publication numberUS 3920838 A, US 3920838A, US-A-3920838, US3920838 A, US3920838A
InventorsGeorge L Blackburn, Jean-Pierre Flatt
Original AssigneeGeorge L Blackburn, Flatt Jean Pierre
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Amino acid therapy
US 3920838 A
Abstract  available in
Images(10)
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Claims  available in
Description  (OCR text may contain errors)

United States Patent [191 Flatt et al.

[ Nov. 18, 1975 AMINO ACID THERAPY [76] Inventors: Jean-Pierre Flatt, Box 53,

Princeton, Mass. 01541; George L. Blackburn, 100 Memorial Drive, Cambridge, Mass. 02142 [22] Filed: Sept. 4, 1973 [21] Appl. No.: 393,710

[52] US. Cl. 424/319; 424/177 [51] Int. Cl. A61K 31/195; A61K 37/18 [58] Field of Search 424/319, 177

[56] References Cited OTHER PUBLICATIONS .luergens et a1. Chem. Abst. Vol. 68 (1968) p. 76201r. Mayer et a1. Chem. Abst. Vol. 72 (1970) p. 40349p. Knauff Chem. Abst. Vol. 75 (1971) p. 144,015e.

Primary Examiner-Sam Rosen Attorney, Agent, or FirmRobert L. Goldberg 571 ABSTRACT The invention described herein is a method of treatment of patients during periods of severe negative caloric balance due to dysfunction or disuse of the gastro-intestinal tract for reasons such as trauma, burn, sepsis, other illness or physicians prescription. The method is based on the parenteral application of amino acids while substantially withholding the patients intake of carbohydrates. This method of treat- I 9 Claims, 13 Drawing Figures U.S. Patent Nov. 18,1975 Sheet 1 of 10 3,920,838

Prot AQ e|c |ns -\FFA KB 1900 Col/Day ATP co FIG! 2 CONCENTRATIONS ADP 4=ENERGY ATP EXPENDITIJFIE CO H 2 0 Urea FIGZ US. Patent Nov. 18, 1975 Sheet6of 10 KETONE BODIES AND N-BALANCE DURING TOTAL AND PARTIAL STARVATIONY 4 O D w 5 +5 A.A.

- 1? STARVATION I? 5 erv 2 H- 9* H? 4 a |o DAYS STARVATION OF; PROTEIN SPARING THERAPY KETONE BODIES (m M) FIG.8

N- BALANCE (g /doy) U.S. Patent Nov. 18, 1975 INSULIN (mU/L) Sheet 7 of 10 3,920,838

CORRELATION BETWEEN GLUCOSE'AND INSULIN LEVELS 00 w A A.A.

"'STARVATION GLUCOSE m M US. Patent Nov. 18, 1975 Sheet90f 10 3,920,838

. ll'llll' l 'lll EFFECT OF PERIPHERAL INTRAVENOUS FEEDING o w m 63 zorrmmoxm zwwomtz m ZED nub/$43230 l A mino ACIDS DAYSO lglkgldoy FIG.||

US. Patent Nov. 18,1975 Sheet 10 of 10 I 3,920,838

CUMULATIVE A Nu 1 gN 1128.0.

g [lnsJ-W F -[em] 8 PROTEIN 513] V [FFALIFB] AA 0 w Fl G. l2

GAIN loo GI IOO en lo V 9 U0 '7Og cm o w \9 Q ?S -l0- x 1 l -L l v Q LOSS NUMBER OF 8 7 8 4 DAY PERIODS FIG.I3

AMINO ACID THERAPY BACKGROUND OF THE INVENTION gastro-intestinal tract and/or because of physicians prescription. Suchpatients are thus temporarily incapable of ingesting protein, carbohydrates, fats, vita-.

mins, and other nutrients, and must turn to endogenous sources and to nutrients provided parenterally, for the energy required for survival and convalescence.

Normal daily requirements for men and women leading a sedentary life, as recommended by the Food and Nutrition Board of the National Research Council, are about 1 gm of protein and 35 to 38 kcal/kg of body weight. Such an allocation will provide about I 1 gm of nitrogen and 2500 cal for a 70-kg man, or 1440 cal/m of body surface area/day.

Basal metabolic requirements vary with age and sex, but most daily requirements are met by a range of 850 to 1 I00 cal/m for men and 720 to 960 cal/m for women. With relatively minimal activity, provision of l 100 callm /day and ID to 12 gm of nitrogen as amino acids or as protein should thus be sufficient to prevent starvation and use of endogenous sources of protein and fat 'in patients who do not have an excessively increased metabolic rate. Such, however, is not the case.

In Cuthbertson, D. P., The Disturbances of Metabolism Produced by Bony and Nonbony Injury, with Notes on Certain Abnormal Conditions of bone, Biochem. J., 24: 1244, 1930, it was first reported that there was a marked loss of nitrogen, phosphorus and sulfur in young men suffering from long bone fractures who were on a diet presumed adequate to maintain balance. Losses continued up to 2 months and were at their peak 6 days after injury. Since that time, loss of nitrogen following trauma, elective operation, sepsis and burns in excess of that expected under normal conditions with an equivalent caloric balance has been confirmed by many others and Cuthbertson has greatly expanded on the subject in Cuthbertson, D. P. further Observations on the Disturbance of Metabolism Caused by Injury, with Particular Reference to the Dietary Requirements of Fracture Cases, Brit. J. Surg., 23:505, I936. It is widely believed that the incremental increase in nitrogen excretion after injury reflects the mobilization of F. D., acids to meet increased demands for metabolic fuels. Moore, F.D., Bodily Changes During Surgical Convalescence,Ann. Surg., 137:289, 1953 using serial measurements of body composition concluded that the tissue loss during surgical convalescence is approximately half fat and half lean body mass by weight.

Patients, not taking nourishment orally for any reason such as trauma, sepsis, disease, injury or because of 2 than in those with previously reduced protein intake or pre-existing wasting diseases. Initial weight loss is rapid,

up to l kg/day in an average adult male. Within 4 to 5 days th ereis a decline in both nitrogen excretion and rate of weight loss, as an increasing proportion of the total caloric needs are supplied from body fat. Water and sodium retention occur and further reduce apparent weight loss.

The amount of carbohydrate reserves in the body is small, perhaps 200 to 250 gm. This is soon utilized,

and, unless replenished by intake of exogeneous carbo I hydrate, glucose must be manufactured by the liver in order to maintain an adequate fasting blood glucose level of some 60 mg/lOO ml, to supply sufficient glucose for the brain and the nervous system as well as certain other tissues such as bone marrow, renal medulla and redcells. The liver'performs gluconeogenesis during starvation using as substrates glycerol, deaminated amino acids residues, lactate, and pyruvate. The body partial oxidation of fatty acids to ketone bodies which are released into the circulation together with freefatty I acids. These ketones bodies are the major metabolic dysfunction of the gastro-intestinal tract, in the absence fuels formost other tissues during starvation. Low levels of blood glucose and insulin promote the release of amino acids from muscle into the circulation. Several of these amino acids are converted by the liver into glucose with the nitrogen converted into urea. This accounts for relatively high urea nitrogen losses early in starvation and explains why intake of glucose orally or intravenously in reducing the need for gluconeogenesis will reduce nitrogen losses.

It is known that severe loss of nitrogen accompanying severe weight loss during trauma, sepsis, disease, injury or other illness is a major contributor to morbidity and mortality in patients. It has been reported by Studley, H. D., Percent of Weight Loss: A Basic Indicator of Surgical Risk, .Iour. Am. Med. Assoc., 1061458, that a mortality figure of 30% was reached with patients suf-' fering from ulcer, colitis, severe burns,acute renal failure, and peritonitis when the patients weight loss reached 20% of the original body weight. In thos patients who had an acute 30% loss of original 'body weight, there was a near mortality rate. Taylor and Keys, Criteria of Physical Fitness in Negative Nitrogen Balance, Ann. N. Y. Acid. Sci., 73:465, 1958 noted material changes in physical fitness when protein loss exceeded grams (or some 15% from a total of about 1000 grams contained in the total cellular proteins of an average male.)

In view of the above, it is customary to attempt to avoid starvation in patients unable to take nutrients orally for extended periods of time. Such patients, following trauma or surgical procedures are usually treated by infusion of parenteral fluids, typically receiving from 200 to 600 cal/day in the form of glucose (carbohydrate), thereby avoiding complete starvation. It is recognized that glucose, in addition to providing some substrate for oxidation, reduces the urinary excretion of nitrogen and therefore, the overall catabolism of labile protein by nearly 50 percent, and further reduces or prevents starvation ketosis. Schwartz, Editor-in- Chief, Principles of Surgery," The Blakiston Division, McGraw Hill Book Company, New York, 1969, pp 77-81, in particular, page 79. Thus, the art has sought to prevent starvation, or at least the symptoms of starvation such as starvation ketosis, by the administration of parenteral fluids containing carbohydrate, typically 3 glucose.

To further diminish nitrogen losses, which reflect de creases of the lean body mass, it is customary to parenterally administer amino acids, but always in combination with other substrates to meet the energy requirements (carbohydrates). Thus Moore, F. D., Metabolic Care of the Surgical Patient, W. B. Saunders Company, Philadelphia, 1959, recommended that parenteral protein (amino acids) not be administered in ex cess of a ratio of 1 gm of nitrogen to 150 cal. More recently, Lawson, L. G., Parenteral Nutrition in Surgery," Brit. J. Surg., 52:795, 1965, has again confirmed the importance of administering amino acids or protein hydrolysates simultaneously with carbohydrate and/or fat solutions. According to Lawson, this therapy results in a reduction of negative nitrogen balance, compared to the infusion of carbohydrate alone, but does not prevent net nitrogen losses.

Based upon the realization that excessive nitrogen loss is detrimental, and possibly even fatal, as observed by Studley, supra, and that nitrogen loss is greatly increased in patients that are diseased, or affected by trauma, sepsis or other illness, as described by Cuthbertson, Stephen and Randall, and Moore, supra, there has been a constant search for a method of treatment that would minimize nitrogen loss further, or even eliminate the same, especially in treating patients undergoing a prolonged period of severely negative caloric balance due to their inability to take nourishment orally.

STATEMENT OF THE INVENTION The invention described herein is a method of treatment of patients during periods of severely negative caloric balance due to dysfunction or disuse of the gastrointestinal tract because of trauma, sepsis, injury or other illness. This method of treatment is characterized by a considerable reduction or prevention of nitrogen losses in the patient during treatment, and in some cases, the method even achieves a limited positive nitrogen balance.

The method of treatment of the invention comprises the parenteral administration of a source of amino acids to the patient in the substantial absence of carbohydrates. This therapeutic approach is in sharp contrast with methods conventionally used in the prior art, which require that amino acids be administered only in combination with substantial amounts of carbohydrates, frequently requiring the use of hyperosmolar infusates through a central venous catheter.

The elimination of net nitrogen losses by the method of the invention is indeed surprising since it is taught in the prior art that carbohydrate infusion alone decreases nitrogen losses, which is one of its major purposes. It is also surprising that the treatment method of the invention can be carried out over a prolonged period of time in the absence of carbohydrate intake since carbohydrate is considered to be a necessary metabolic fuel, necessary to prevent the symptoms of starvation such as starvation ketosis, whereas the method described herein does not provide the patient with exogenous carbohydrate, and yet this therapy can be carried out over a prolonged period of time without endangering the patient.

The invention described herein, in part, is based upon the recognition that starvation ketosis occuring during severe negative caloric balance allows more adequate fat mobilization, whereby endogenous fat stores meet almost all energy requirements, with little or no catabolism of protein, whereas administration of carbo- DESCRIPTION OF THE DRAWINGS In the drawings,

FIG. 1 is a schematic representation of energy metabolism in man during prolonged starvation;

FIG. 2 is a schematic representation of a proposed metabolic fuel regulatory system;

FIG. 3 presents nitrogen balance data of 9 patients receiving intravenous peripheral protein sparing therapies;

FIG. 4 is a metabolic study protocol of a 70 year old woman FIG. 5 is a metabolic study protocol of a 52 year old male;

FIG. 6 represents substrate profiles resulting from the administration of different types of infusates to pa tients;

FIG. 7 diagramatically represents fatty acid and nitrogen balance during total or partial starvation;

FIG. 8 diagramatically represents a correlation between ketosis and nitrogen balance during total and partial starvation;

FIG. 9 shows the relationship of glucose to insulin during total and partial starvation;

FIG. 10 shows the relationship between insulin levels and nitrogen balance during glucose infusion compared to acid infusion;

FIG. 11 graphically summarizes the urinary nitrogen loss of a 32 year old female suffering from a perforated duodenal ulcer;

FIG. 12 shows the fuel-regulatory scheme as a basis for comparing metabolic consequences of glucose and amino acid infusions; and

FIG. 13 represents the accumulated nitrogen loss over four days in patients receiving various infusates.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the description which follows, for a clearer understanding of the invention, certain definitions will be given and certain theoretical explanations will be offered, some of which might appear to be redundunt in view of that described above. It is repeated here, as necessary, to provide a complete description. It should be clearly understood, however, that with respect to any theoretical explanation offered, it is as currently understood, but is not to be construed as binding or in any way limiting of the invention.

The term patient, as used hereafter, is intended to mean any patient treated in accordance with the practice of the invention. The reason for treatment by parenteral administration of amino acids is not critical, it being understood that such treatment is due to doctors prescription necessitated by the condition of the patient whether it be due to injury, sepsis, trauma or other illness.

The term amino acid as used herein is intended to mean those amino acids used in patient therapy such as those L-amino acids, both essential and non-essential, conventionally infused into patients along with glucose. The term is intended to include protein hydrolysates and dipeptides.

The term nitrogen balance refers to the difference between intake and excretion of nitrogen. A negative nitrogen balance therefore refers to a loss situation where the excretion of nitrogen exceeds intake.

The term starvation" means the condition known in the art to exist in a patent as a result of deprivation and lack of nourishment. As used in relation to patients treated in accordance with this invention, it is used in a slightly different sense as the patient will exhibit the symptoms of starvation such as ketosis, but not nitrogen loss.

The term parenteral administration is used in its conventional sense to include intravenous infusion into peripheral veins as well as other methods known to the art.

Since the process of the subject invention is a therapy involving starvation in patients suffering stress, it is necessary to understand the regulatory system which controls the availability and utilization of metabolic fuels during starvation and the effect of disease on adaptation to starvation.

Glucose and free fatty acids (FFA) are the major metabolic fuels supplied by the blood to peripheral tissue for energy production. Important metabolites of FFA oxidation in the liver are ketone bodies cacetoacetate and 3-hydroxy-butyrate, which when released into circulation by the lever can substitute for glucose as a source of energy for parts of the body including the brain during starvation.

Protein, when oxidized, yields 4 kcal/g. Approximately half of the amount of protein lost during starvation is by direct oxidation of amino acids, while the other half is used for the production of glucose in the liver, via gluconeogenesis, a process which assumes great significance when the supply of exogeneous carbohydrate is restricted. This is important to supply glucose for the brain early in starvation by providing ketone bodies (KB) as a substitute source of energy for the brain. The bodys metabolic adaptation to starvation minimizes glucose utilization and the consumption of protein.

FIG. 1 of the drawings describes energy metabolism in man during prolonged starvation. The numbers shown near the double-lined arrows express the daily calorie fluxes occurring .to meet the overall energy expenditure. It is of interest to note that protein catabolism provides only 5% (90 in 1,900 kcal) of the total calorie requirement, while ketone bodies supply the peripheral tissue with some 500 cal, or 25% of the bodys total calorie expenditure. The remainder is covered by oxidation of FFA.

The efficiency of proteinand glucose-sparing in the body during prolonged starvation is made possible by adaptive mechanisms for using ketones as a major source of energy fuel. The rate of ketone production was recently determined to be 130 g per day by the third day of total starvation. Even the brain, which normally derives 100% of its energy from glucose. can substitute ketones to the extent of 70% of its energy requirement.

Ketogenesis thus represents a vital mechanism in the physiologic adaptation to starvation, facilitating the use of endogenous fat stores by tissues which ordinarily cannot utilize FFA as such. When the bodys triglyceride reserves are used to supply most of its energy requirements, nitrogen loss can be reduced to only 4 to 5 g per day, late in starvation.

In a patient with a strongly negative caloric balance, therefore, the presence of ketone bodies should be re garded as beneficial. It is important to note that starvation does not lead to the pathologic ketosis that occurs in decompensated diabetes. Ketone bodies stimulate insulin secretion, and since insulin strongly inhibits ketogenesis, a feedback control is established which prevents ketosis from reaching pathological levels.

Failure to recognize this physiological role of ketogenesis in the starved patient accounts for the common medical practice of supplying at least 100 g of glucose per day to minimize ketosis as discussed above. Unfortunately, making glucose available tends to interfere with the metabolic pathways which enable the body to conserve its protein under conditions of partial starvation.

It is helpful at this point to consider some of the major control phenomena involved in the regulation of energy metabolism in men. The structure of the metabolic fuel regulatory system proposed in FIG. 2 is very simple yet it includes enough interactions to explain how the integration of carbohydrate, fat and amino acid metabolism takes place. FIG. 2 shows the concentrates of circulating insulin (Ins), glucose (Gluc), free fatty acids (FFA), ketone bodies (KB) and the various amino acids (AA). The plasma concentration of each of these substances is determined by its ratesof release into and removal from the circulation.

The pathways for oxidative degradation of the various fuels lead to terminal reactions which these pathways have in common. The metabolic pathways thus serve as a metabolism funnnel. In this integration of metabolic oxidations, the total energy generated equals the energy expended. The interactions between insulin and the metabolic fuels include three major feedback loops corresponding to the major nutrient substrates.

Insulin facilitates peripheral uptake of glucose, in particular by muscle, and adipose tissue, where it also stimulates the conversion of glucose to glycogen, or triglyceride, respectively. Thus, insulin lowers blood glucose levels, as illustrated in FIG. 2 by the arrow which suggests that insulin pushes glucose levels down. The release of insulin by the pancreas is stimulated by increasing concentrations of blood glucose. Thus, glucose concentration push blood insulin levels up, as suggested by another arrow in the figure. Since glucose has a positive effect on insulin concentration, and insulin, a negative effect on glucose concentration, the interactions between glucose and insulin create a negative feedback loop of the simplest possible design. The existence of a negative feedback loop in a regulatory system has a stabilizing effect, but it requires in addition a set point if the system is to avoid drifting away from a particular operating range.

A steady state condition is established when the inflows of glucose and of insulin are equal to their outflows, and when their concentrations thus remain constant. The most common steady state condition is that encountered in the post-absorptive state. Under these conditions glucose levels in man are adjusted so as to remain within a relatively narrow range of to mg%. Insulin secretion seems to occur to the extent required to achieve a fasting blood glucose concentration which is near the physiological norm. This norm apparently constitutes the primary set point in the glucose insulin feedback loop.

Insulin decreases the release of free fatty acid from adipose tissue by reducing cyclic AMP mediated activation of a hormone sensitive lipase, as well as by increasing glycerol-phosphate availability for FFA rees terification. Ketone body levels tend to fluctuate in parallel with free fatty acid levels. Insulin has in addition an antiketogenic action on the liver so that ketogenesis can be suppresed even in a situation where FFA levels are high. The effects of insulin on FFA and ketone body production thus tends to lower the levels of these substrates in the blood as shown by an arrow in FIG. 2.

Although FFA at very high levels, and perhaps more significantly the ketone bodies, appear to be able to directly stimulate insulin secretion, the major feedback effect on insulin secretion is considered here to occur indirectly under normal physiological conditions. Free fatty acids and ketone bodies can be used as substrates for energy production by most tissues, where their utilization is to a large extent proportional to their concentration in the circulation. Since the total oxidation of substrate is limited by the energy expenditure, elevation of FFA and KB levels will reduce the consumption of glucose for energy production in the body. The extent to which glucose can be spared is demonstrated during prolonged starvation, when glucose oxidation is reduced to some 50 grams per day. In reducing glucose outflow, FFA and KB tend to elevate the levels of glucose, and they are thus able to indirectly promote insulin secretion. This effect is attenuated, however, because it operates through an intermediate, glucose, subject to diverse influences. Furthermore this feedback effect can function only to the extent required to reduce blood glucose, but not necessarily FFA levels to near normal values. Since, on the other hand, insulin levels directly affect FFA release from adipose tissue, the feedback regulation between insulin and FFA plus KB is asymmetrical in nature.

The organisms ability to regulate carbohydrate metabolism is commonly determined by performing glucose tolerance tests. When the removal of a glucose load proceeds more slowly than under standardized post-absorptive conditions, this is taken to indicate an impairment in carbohydrate tolerance. However, to the extent that this is due to elevation of FFA levels, a

reduced rate of glucose removal is due to a physiologically normal phenomenon, of crucial importance in sparing glucose when carbohydrate intake is restricted. Under these conditions a decrease in the rate of glucose removal from the circulation should perhaps not be regarded so much as an impairment, but rather as an indication of the organisms ability to adapt to carbohydrate or caloric deprivation. The qualification implied by the term impairment could then be reserved for situations where a reduced ability to utilize exogenous glucose is due to causes different, or manifest beyond, an elevation of FFA levels.

Insulin enhances the uptake of amino acids by peripheral tissues, where it promotes the conversion of amino acids into proteins, while its effects on different amino adids is variable, the predominant action of insulin is to lower plasma amino acid concentration (arrow pointing downwards in FIG. 2). As in the case of glucose, the action of insulin includes stimulation of transport, stimulation of synthesis, resulting in the deposition of glycogen, fat or protein, and inhibition of the rate of breakdown of these substances.

Glucogenic amino acids are converted to glucose in the liver and to a limited extent in the kidney. Amino acids thus increase glucose formation. This tends to elevate blood glucose levels (arrow in FIG. 2), which in turn stimulates insulin release. This indirect effect of amino acids on insulin levels is similar to that of the FFA in the feedback loop involving fat metabolism: in

one case this is due to increasing glucose formation while in the other case it is achieved by reducing glucose utilization. Furthermore, just as ketone bodies can stimulate insulin secretion directly, certain amino acids can directly increase the release of insulin. This stimulation operates most effectively when prevailing glucose concentrations are relatively elevated. The arrow the proportion of these nutrients in the food ingested.

The efficiency with which this goal is achieved is illustrated by the fact that a relatively stable body composition is maintained during long periods in the life of an organism, even though the proportions of different nutrients ingested varies widely. Certain minimum requirements for amino acids, vitamins, and minerals must of course be satisfied without which various forms of malnutrition would develop, but this is not pertinent to the discussion of fuel metabolism presented here. Maintenance of a constant lean body mass is sought by the organism even when the intake of calories does not match the caloric expenditure. Thus excesses or deficits in the caloric balance are translated largely into changes in the amounts of fat stored in adipose tissue. The nitrogen balance remains close to zero even during periods during which intakes of protein and calories are high. This shows that the degradation of amino acids can vary over a considerable range in order to match protein intake.

It warrants an important conclusion, namely that amino acid oxidation can be rapid in spite of the prevalence of anabolic conditions associated with high insulin levels. Indeed administration of large doses of insulin can adversely affect the nitrogen balance, by increasing the need for gluconeogenesis from protein. On the other hand, during periods of deprivation, where low insulin levels prevail, the consumption of metabolic fuels shifts so as to minimize amino acid degradation and to preserve body protein masses with remarkable efficiency.

In order to function under such variable conditions, a considerable degree of integration between amino acid, carbohydrate and fat metabolism must be possible. To the extent that the metabolic fuel regulatory system described in FIG. 2 gives a correct description of the major physiological regulatory interactions in the system, it appears that this integration is achieved primarily by the use of a component common to the three feedback loops involved in the control of carbohydrate, lipid and amino acid metabolism. This common component is insulin, and its importance in the control of all aspects of energy metabolism has been increasingly recognized.

The structure of the regulatory system is such that glucose, more than the other metabolic fuels is able to influence insulin levels. This is enhanced by the ability of the B-cells in the pancreas to perceive, and to react to changes in glucose concentration. Furthermore the maintenance of normal fasting blood glucose levels appears to provide the fundamental set point in the metabolic fuel regulatory system. Carbohydrates constitute more than half or sometimes most of the nutrients ingested, and glucose is qualitatively and quantitatively one of the most important substances for energy production in peripheral tissues; Fluxes through the glucose pool must therefore be able to, vary widely, but with glucose levels remaining within a relatively narrow concentration range, to avoid hypoglycemia or glucosuria, and thisin spite of a rather limited capacity for storage of carbohydrate. Thus it is not surprising thatv glucose should play a predominant role in the regulation of insulin levels.

In the regulatory system discussed here no explicit provision is made for hormones or other agents which directly enhance catabolism of glycogen, fat, or protein. Some of these are short lived emergency sigwill increase when insulin levels become low. Whether I the release is due to a relative lack of. insulin or to relatively high levels of lipolytic signals does'not need tobe specified in the simplified model developed here.

Thus, as a result of its basic structure, the'regulatory system allows forone of the metabolic fuels to influence the metabolism of the others. The important point of the above is .that from this scheme, it can be submit ted that infusion of amino acids'without carbohydrates may allow more efficient utilization of endogenous fat men was obtained. The volumes were measured and a1 iquots were frozen at C until analysis of total nitrogen, urea nitrogen, and creatinine were completed.

acetoacetate were determined enzymatically after deproteinization with perchloric acid. Free fatty acids stores than accompanied by carbohydrate, allowing a metabolic state to develop simulating total starvation,

where amino acid oxidation is reduced, and where the administered amino acids can be effectively used for protein synthesis. The validity of thisiapproachto protein sparing therapy is established by the following test procedures. I v

Nineteen surgical patients requiring intravenous fluid replacement were treated with the following parenteral were titrated acidmetrically. Insulin was measured by radioimmunoassay and urinary nitrogen by a microK- jeldahl method. 1 v

Daily urinary nitrogen excretion was determined on and the urinary nitrogen excretion. The overall nitrogen balance was calculated by adding l A grams of nitrogen to the urinary nitrogen loss to account for fecal I and cutaneous losses. v

Thefollowing table representsa clinical description of 10 patients receiving 2 to 3 liters of-parenteral infusion per day for 10 to 14 days.

Weight (kg) Age Sex.

JS 58.6 56 i M Obstructing cancer of colon 7 LM 56.3 52 F Pelvic abscess FC 61.2 69] F Small bowel obstruction CW 54.5 52 M Reactive hepatitis, I subhepatic abscess 1C 76.2 28 M Stab wound of liver JY t 89.5 64 M Gunshot to abdomen with peritonitis BH 64.3 37 F subheptatic abscess with perforated duodenal ulcer RW 54.5 47 M Emphysema, Chronic lung A disease, ileus 60.0 v 42 'M Pancreatitis and pseudocyst SW 7 32.0 --S6 F Subtotal gastrectomy and solutions: (1) 5% dextrose solution (DSW) to deliver 100 grams of dextrose per 24 hours, (2) 3% crystalline L-amino acid solutions containing essential and nonessential amino acids delivered 90 grams of amino acids per 24 hours and (3) solutions containing 3% L-amino acids and 5% dextrose to deliver 70 grams of amino acids plus 100 grams of dextrose per 24 hours. The compositions of the L-amino acid solution is as follows:

Urine was collected over a successive 24 hour period beginning immediately after the 7:00 A.M. blood specidumping syndrome The following table represents a clinical description of the remaining 9 patients receiving a similar therapy but who were generally more severely ill and strated a higher proteincata'bolism.

Weight (ltg) ,A e-

74 Entero cutaneous fistula No adverse effects could be attributed to the intrave-' nous therapy in any patient; no infections, cellulitis, thrombosis or pyrogenic responses occurred. Except in one patient, (C.W.) with reactive hepatitis, serum enzymes (SGOT and LDH), bilirubin and ammonia levels remained within normal limits.

The first 10 patients represented moderate protein catabolism, averaging a daily nitrogen loss of 7.1 g i 3.5 g on administration of dextrose in water. This is equivalent to loss of 44 g of protein per day (6.25 g of protein/gN), which, if this protein was mobilized from muscle tissue, represents a loss of about 0.5 pounds per day of muscle tissue.

Infusion of an amino acid solution, instead of the routinely used 5% glucose infusate, resulted in a reduction in the nitrogen loss from 8.5 to l .0 gN/day. The infusion of a mixture of glucose and amino acids resulted in some improvement in the nitrogen balance but not to the degree observed with amino acid infusion alone.

In the subsequent study of the 9 additional patients, the infusion of amino acids instead of glucose resulted in a reduction in nitrogen loss from 1 1.8 to l .0 g/day, as shown in FIG. 3.

The metabolic study of a 70 year old female with bowel obstruction secondary to adhesions is shown in FIG. 4. Intravenous infusion of isotonic dextrose (D5W) or L-amino acids (3%) solutions were given in amounts shown in terms of calories delivered per day. A significant amount of protein was spared with the amino acid infusion as evidenced by a sharp improvement in nitrogen balance (ANu). The addition of carbohydrate to the amino acid infusate did not improve the nitrogen balance. When the administration of amino acid infusates was discontinued, the nitrogen balance became negative. The protein sparing which occurred with the infusion of amino acids is associated with a decreased level of insulin and blood glucose and increased levels of serum free fatty acids and ketone bodies.

A metabolic study in a 52 year old man with a duodenal fistula, subhepatic abscess and reactive hepatitis is shown in FIG. 5. Serum glutamic oxalacetic transaminase levels averaged 1,800 mU/ml and bilirubin was I 1 mg per cent. Although the clinical studies had to be interrupted early because of the patients condition (day 9), the data clearly show that the nitrogen balance was better with the infusion of amino acids (days 14 to 17) than with glucose. When the infusate was changed from glucose 100 g per day) to amino acids (70 to 90 g per day) the nitrogen balance rapidly returned to normal. (See days 7 to 8 and 13 to 14). Furthermore, the addition of glucose to the amino acid infusion (day 18) had an unfavorable effect.

FIG. 6 gives the substrate profiles with the administration of different types of infusates as well as the daily nitrogen balances. When 100 g of glucose was delivered per day, the daily nitrogen deficits were 8.5g. This figure is about half the nitrogen deficit seen in the initiation of a period of total starvation. Thus, the infusion of isotonic glucose solution had a definite protein-sparing effect, which is a well known fact. Nevertheless, the cumulative N loss (ANu) over a 4 day period amounted to 28.9 g i 4 g which is equivalent to the loss of about 2 pounds of muscle tissue. The substrate profile does not show the characteristic pattern of starvation, that is, elevated levels of free fatty acids and mild ketosis, even though the caloric balance is severely negative.

The addition of amino acids to the glucose infusion improved the nitrogen balance, and the nitrogen loss over a 4 day period amounted to [5 g i 6 g. The substrate profile was not significantly altered from that observed with glucose alone.

In sharp contrast, the substrate profile during the administration of amino acids alone show the elevation of free fatty acids and ketone bodies which are typical of starvation. The nitrogen balance (ANu) during peripheral infusion of amino acids alone is practically zero. demonstrating that amino acid infusion achieves protein-sparing to the extent that nitrogen loss was reduced to fecal and skin losses which are insignificant when compared with urinary nitrogen excretion.

The substrate profile data indicates that the success achieved with the infusion of amino acids alone is due to better adaptation of the organism to a state of severely negative caloric balance mobilizing its fat reserves readily as rapidly as it does during total starvation. The limited effectiveness of peripheral proteinsparing therapy which includes glucose seems to be related to the interference of exogenous glucose with the normal physiological adaptation to a state of severe negative caloric balance.

In FIG. 7 daily nitrogen balance (ANu) and serum free fatty acid levels are shown as determined in the three metabolic situations studied. The greatest nitrogen losses are seen to occur when free fatty acids are the lowest, which is typically the case in the surgical patients receiving D5W. The same patients when treated with amino acids infusions showed a significant increase in FFA levels, from 0.4 i 0.2 to 1.0 i 0.2 mEq/L. After two to three weeks of adaptation, the nitrogen balance in the patients undergoing total starvation shows a deficit of some 6 g per day.

Associated with elevation of FFA was the appearance of ketone bodies in the circulation. FIG. 8 shows the correlation between ketosis and nitrogen balance. The surgical patients receiving intravenous glucose essentially had no ketonemia (serum B-hydroxybutyrate and acetoacetate =0.l i: 0.05mM). The prevention of ketosis by limited carbohydrate administration has been one of the expressed purposes of therapy with intravenous D5W. The same patients, when given isotonic amino acid infusions, developed ketosis within 36 hours, which was associated with considerable improvement in the nitrogen balance. Ketosis did increase with time during intravenous feeding with amino acids, reaching values of some 2mM.

The release of insulin by the pancreas increases with the concentration of glucose in blood. FIG. 9 shows the relationship of glucose to insulin in the four physiological situations studied. The highest value for glucose and insulin were found in the patients receiving 5% dextrose in water. The substitution of glucose by amino acids in the infusate led to significant decreases in the level of glucose from 123 :15 to i l 1 mg%: and insulin from 31 i 6 to 23 i 5 U/ml. Stimulation of insulin secretion by amino acids at this level of protein intake, and when blood glucose concentrations are low, is thus relatively weak.

Since insulin is considered to be the key anabolic hormone, the relationship between insulin levels and nitrogen balances is illustrated in FIG. 10. As previously described substitution of glucose by amino acid infusion has the effect of decreasing insulin levels but this is associated with a striking improvement of the nitrogen balance. The success of amino acid infusion for protein sparing in surgical patients during periods of semi-starvation with intravenous feedings hinges on the ability of the absorbed amino acids to be utilized to replenish the amino acid pools which sustain protein synthesis rather than being expended primarily for the production of energy.

FIG. 11 summarizes the urinary nitrogen loss in a study conducted on a 32 year old female suffering from a perforated duodenal ulcer caused by a subphrenic abscess. Urinary nitrogen loss averaged 6.7 g/day while receiving 5% dextrose solution intravenously. The infusion of isotonic dextrose was replaced by the infusion of isotonic solutions of essential and nonessential amino acids, there was no significant increase in her 13 urinary nitrogen excretion. After 17 days the patient returned to convention protein sparing therapy using dextrose in water. Despite a sharp reduction in nitrogen intake, only a slight reduction in urinary nitrogen excretion took place. Thus total amino acid degradation during amino acid infusion without glucose is not much greater than during glucose infusion. However since the amino acid mixture supplies approximately 9 g of amino acid nitrogen per day, the nitrogen balance can become essentially equal to zero. This protein sparing effect was associated with lowering of blood glucose from 7.2mM (130 mg) to 3.8 mM (70 mg) and a corresponding insulin level decrease from 30 to uU/ml. Free fatty acids and ketone bodies raised to 1 mM (=lmEq/liter) and 2.0 mM respectively. Fistula drainage decreased and the fistula was closed by the 25th day of treatment.

It should be noted above that the conventional metabolic care of severely ill patients includes the administration of some 100 to 150 gm of carbohydrate per day by peripheral intravenous infusion of 5% dextrose in water. The aim is to replace the glucose catabolized by the patient, and to spare his tissue proteins by reducing the need for gluconeogenesis. The limitation with this therapy is that glucose administration provokes an insulin response which impedes the mobilization of endogenous fat, preventing endogenous fat to be used maximally for energy production. Some of the infused glucose is therefore needed to make up for reduced oxidation of FFA and KB, thus sparing endogenous fat rather than protein. The extent to which caloric contribution from fat stores will be reduced depends on the degree of insulin resistance, which in turn is related to the severity of the injury, sepsis or disease, as well as the nutritional status. Thus the protein-sparing efficiency of small amounts of carbohydrate varies a great deal. At best in the moderately injured patient, .nitrogen losses can be reduced only to some 7 to 8 g per day. The peripheral infusion of amino acids in addition to isotonic glucose seems to be of little value in improving nitrogen balance. The inflow of both glucose and amino acids elicits an especially sharp insulin response which may reduce fat mobilization to such an extent that the infused nutrients need to be used mainly for energy production.

The invention described herein approaches the problem of preserving the body s protein masses by administering amino acids infusates containing no glucose, thus allowing the development of starvation ketosis. With energy production supported largely by FFA and KB oxidation, as in total starvation, the infused amino acids can be used to replenish the pools of amino acids available for protein synthesis.

FIG. 12 shows the fuel-regulatory scheme as a basis for comparing the metabolic consequences of glucose or amino acid infusions. These two types of proteinsparing therapy differ in two main aspects: (1 their effects on glucose and insulin levels and hence on the intensity of the anabolic signal conveyed by insulin to muscle and adipose tissue, and (2) their direct relevance to the purpose of maintaining adequate amino acid pools for protein synthesis.

Under conditions of caloric deprivation, rapid mobiincluding ketogenesis than when glucose is given facilitating the organisms adaptation to conditions of negative caloric balance, while at the same time replenishing the amino acid pools supporting protein synthesis.

The metabolic studies performed on patients receiving peripheral intravenous infusions indicate that protein-sparing therapy with amino acid infusates is far more effective and that it may be subject to less variability in reducing protein losses than the conventional treatment with isotonic glucose solutions. The studies presented here show a reduction in nitrogen loss of some 8 to 10 g per day by using amino acids instead of glucose.

As soon as amino acid infusions are initiated, an appreciable inflow of amino acid nitrogen bec'omes available to offset nitrogen losses. This alone results in immediate improvement in nitrogen balance, even before the effects of starvation ketosis becomes operative. The

to g of amino acids which can be administered intravenously by peripheral isotonic or near isotonic infusions provides 11 to 14 g of amino acid nitrogen. This is sufficient to achieve a satisfactory nitrogen balance even when amino acid degradation is not as efficiently reduced as when starvation ketosis is fully established. (FIG. 13)

In terms of dosage, the amino acids are administered in amounts sufficient to restore amino acid pools in a patient and may vary within relatively broad limits dependent upon body' weight of the patient and related variables including the extent of injury or disease. Typically, using 3% amino acid solutions, though solutions containing up to 6% amino acids are possible and solutions containing from 2.5 to 4.5% are preferred, rate of infusion is adjusted so that from about 50 to 130 grams of amino acid are delivered per 24 hours and preferably from 60 to grams or approximately 0.6 to 1 gm of amino acids per kg body weight per day.

The amino acids delivered are the L-amino acids that have been used in the prior art in combination with glucose being delivered as hyperosmotic solutions through a central venous catheter. These materials are well known and need no further elucidation. However,'it should be noted that various amino acids provide specific functions and a therapy using selected amino acids in specified proportions can be formulated.

Finally, it should be noted that the amino acids may be in the form of protein hydrolysates or dipeptides and may be combined in aqueous solution with suitable electrolytes, fats, pH adjusters and the like, other than carbohydrate, typically used in parenteral administration.

'We claim:

1. A method of treatment of patients sufi'ering trauma, sepsis, infection, injury or other diseases during periods of severe negative caloric balance due to disuse of the gastro-intestinal tract, said method comprising the steps of developing and maintaining a metabolic state simulating caloric starvation by substantially withholding exogeneous carbohydrates from the patient while parenterally administering amino acid solutions to said patients while maintaining a negative caloric balance, said parenteral administration of amino acid solution continuing at leastun til said patient begins to use the gastro-intestinal tract to take oral nour ishment, said amino acid solution containing amino acids in an amount sufficient to replenish depleted amino acid pools in said patient.

2. The method of claim 1 where said source of amino acids is selected from the group of aqueous solutions comprising L-amino acids, protein hydrolysates and dipeptides.

3. A method of treatment of patients suffering trauma, sepsis, infection or injury during periods of severe negative caloric balance due to disuse of the gastro-intestinal tract, said method comprising the steps of developing and maintaining a metabolic state simulating caloric starvation by withholding exogeneous carbohydrates from the patient while parenterally administering amino acid solutions to said patient while maintaining a negative caloric balance, said parenteral administration of amino acid solutions continuing at least until said patient begins to use the gastro-intestinal tract to take oral nourishment, said amino acid solution being an aqueous solution of a member selected from the group of L-amino acids, protein hydrolysates, dipeptides and mixtures thereof, the amino acid concentration not exceeding 6% by weight of the solution and 16 being sufficient to provide a dosage of from 0.06 to l gram of amino acid per kilogram of patient body weight per 24 hour period.

4. The method of claim 3 where said amino acid solutions are aqueous solutions of L-amino acids.

5. The method of claim 4 where said parenteral administration is by infusion into a peripheral vein.

6. The method of claim 5 where said concentration is 7. The method of claim 6 where the dosage is to 1 10 grams of amino acid per 24 hour period.

8. The method of claim 4 where said L-amino acids are a mixture of essential and non-essential amino acids.

9. The method of claim 8 where said essential amino acids are isoleucine, leucine, lysine, methonine, phenylalanine, theonine, tryptophan and valine and said non-essential amino acids are alanine, argininine, histidine, proline, serine, glycine and cysteine.

Non-Patent Citations
Reference
1 *Juergens et al. -- Chem. Abst. Vol. 68 (1968) p. 76201r
2 *Knauff -- Chem. Abst. Vol. 75 (1971) p. 144,015e
3 *Mayer et al. -- Chem. Abst. Vol. 72 (1970) p. 40349p
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Classifications
U.S. Classification514/400, 514/419, 514/567, 514/423, 514/561, 514/565, 514/562, 514/5.5, 514/1.4
International ClassificationA61K38/01
Cooperative ClassificationA61K38/01
European ClassificationA61K38/01