Intravenous essential amino acid therapy.
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Biomedical subjects
Publications and source records attributed to N N Yoshimura.
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OBJECTIVE: To determine the compatibility and stability of paclitaxel in polyolefin containers. DESIGN: The following paclitaxel concentrations were determined by a stability-indicating HPLC method: 0.3 and 1.2 mg/mL diluted in dextrose 5% for injection, USP (D5W) or sodium chloride 0.9% for injection, USP (NS). The solutions were prepared in polyolefin containers and the stability and compatibility were monitored for 48 hours when stored at ambient temperature (20-23 degrees C) and normal fluorescent lighting. A mixture of the drug carrier consisting of approximately 10% polyoxyethylated castor oil (Cremophor EL) and 10% ethanol in D5W and NS, without paclitaxel, was studied to differentiate the effect of paclitaxel from the effect of the drug carrier on the container. Paclitaxel concentrations, pH changes, and visual clarity were used as stability and compatibility indicators. RESULTS: Paclitaxel concentrations remained at 96-99 percent of the initial concentration for up to 48 hours when placed in the polyolefin containers. No changes in color or visual clarity were noted. Only minor changes in the pH of the admixtures were observed. CONCLUSIONS: Paclitaxel diluted in D5W or NS at concentrations of 0.3 and 1.2 mg/mL is stable and compatible in flexible, polyolefin containers for up to 48 hours.
The purpose of this study was to evaluate the effect of increased arginine levels in intravenous hyperalimentation (IVH) therapy on wound healing and thymic immune function. Groups of SD rats, 275-325 g, underwent placement of internal jugular catheter, 7-cm dorsal skin wounding, insertion of polyvinyl alcohol sponges subcutaneously, and closure of wounds with stainless-steel sutures. Twenty-four hours later, rats were started on IVH at a rate of 0.8-1 ml/100 g body wt/hr. All IVH solutions contained 20% dextrose, adequate amounts of minerals and vitamins, and two different amino acid mixtures: (A) Fre III (4.05 g ARG/liter) (n = 13); (B) experimental (7.50 g ARG/liter) (n = 11). Solutions were isonitrogenous, and contained similar amounts of essential amino acids. After 7 days of IVH, weight gain did not differ between the two groups; however, cumulative N balance was superior in group A. Wound healing was improved in group B as assessed by fresh wound strip breaking strength, fixed breaking strength, and the amount of reparative collagen deposition as assessed by the hydroxyproline content of the implanted sponges. Group B animals also had improved thymic function as assessed by thymic weight, the total number of thymic lymphocytes/gland and mitogenic reactivity of thymic lymphocytes to PHA and Con A. The experiments indicate that high arginine levels in IVH solutions improve wound healing and thymic immune function following injury.
The ability to conserve body protein during very low calorie diets in ten obese men was observed to correlate with plasma free amino acid concentrations, urinary N tau-methylhistidine: creatinine ratios, resting oxygen consumption, and serum triiodothyronine levels. A diet consisting of only protein, 1.3 g/kg ideal body weight/24 h, was given for 40 days. Cumulative nitrogen deficit ranged from -64 g to -227 g. Nitrogen balance on days 36 to 40 ranged from + 1.37 g/24 h to -3.30 g/24h. Nitrogen balance during this period had a significant direct correlation with pre-diet concentrations of branched-chain amino acids (r = 0.69 to 0.89), methionine (r = 0.85), histidine (r = 0.66), alanine (r = 0.73), arginine (r = 0.70), ornithine (r = 0.66), total essential (r = 0.87, and nonessential (r = 0.68) amino acids, with initial serum levels of triiodothyronine (r = 0.66) and with the fall in triiodothyronine over the 40 days (r = 0.79). Initial resting oxygen consumption was directly correlated (r = 0.78) with final nitrogen balance and inversely with total nitrogen loss (r = -0.81). On day 0, triiodothyronine levels also correlated positively (r ranging from 0.71 to 0.93) with plasma concentrations of several essential and nonessential amino acids. These correlations suggest that individuals who ultimately will or will not achieve nitrogen equilibrium during very low calorie diets can be identified prior to dieting. These data are consistent with the hypothesis that individuals with higher initial protein flux and triiodothyronine levels are better able to adjust the balance between synthesis and degradation to attain nitrogen equilibrium during hypocaloric dieting.
The effects of soy or collagen protein, 1.3 g/kg desirable body weight per day, on fasting and postprandial plasma free amino acid concentrations were evaluated in eight obese men during a 40-day very-low-calorie reducing regimen. The interrelationships among individual plasma amino acids were also examined. In both protein-fed groups, fasting plasma histidine, phenylalanine, tyrosine, threonine and alanine levels decreased by day 40 whereas glycine increased. The decrease in plasma threonine and increase in plasma glycine were more pronounced in the collagen-fed group (n = 4) than in the soy-fed group (n = 4). Serine increased only in the collagen-fed group. The postprandial increases of all essential amino acids, with the exception of valine and phenylalanine, were less on day 26 than on day zero. Except for threonine levels, plasma amino acid profiles were similar during very-low-calorie dieting and during prolonged fasting. However, essential amino acid levels were better maintained by soy than by collagen protein diets.
Decreases in brain serotonin levels have been implicated in the pathogenesis of human depression. While circulating levels of tryptophan (TRP) might possibly reflect concentration of brain serotonin, a more relevant peripheral measure may be the ratio of plasma TRP to five other neutral amino acids (TRP/5aa ratio). In depressed subjects and normal controls, plasma TRP (free and total), phenylalanine (PHE), tyrosine (TYR), leucine, isoleucine, and valine were measured on three days. When depression was most severe, depressed patients had lower TRP/5aa ratios and total TRP levels and higher PHE and TYR levels. After the patients' conditions improved, these differences disappeared. As Hamilton depression scores improved, the plasma TRP/5aa ratios increased significantly. This finding tends to support the idea that changes in brain serotonin level reflect changes in depression severity.
Carnitine is an essential metabolite whose function is to transport activated long-chain fatty acids across the mitochondrial membrane. It is consumed in the diet and is synthesized from lysine and methionine to meet body needs. Hepatic fat deposition has been reported in experimental animals and patients receiving total parenteral nutrition (TPN) fluids devoid of preformed carnitine. In the present experiment, nitrogen balance, hepatic fat deposition and serum and tissue carnitine were determined in rats receiving a hypercaloric TPN regimen containing 0, 10, 50, and 100 mg DL-carnitine per 100 g body weight for 14 days. Rats fed a stock diet served as controls. Increased nitrogen balance was observed in TPN rats receiving the highest dose of carnitine supplementation. Hepatic fat deposition induced by the hypercaloric infusion was ameliorated but not eliminated by infusing carnitine. Serum, liver and skeletal muscle carnitine concentrations were maintained, whereas that of heart decreased in TPN rats without carnitine supplementation. Between 90 and 100% of the administered L-carnitine was excreted. It is suggested that the observed effects of carnitine on nitrogen balance and hepatic fat deposition are due to as yet undefined pharmacological properties. The significant decrease of carnitine in cardiac muscle resulting from TPN in a patient population already stressed and traumatized and the metabolic and physiological effects of this decrease deserve further exploration.
Nitrogen balance and thymic immune function studies were carried out in rats subjected to anesthesia, jugular vein catheterization, and bilateral femoral fractures, who were then given for 5 days: A) D5W; B) D20 FreAmine II (total arginine 1.55 gm/L); or C) D20 FreAmine III (4.05 gm of arginine/L). Administration of hypercaloric amino acid mixtures had strong positive effects on nitrogen retention and thymic function when compared to isotonic dextrose infusion. The administration of solution C had the most positive effect on nitrogen balance and on thymic immune function. The data suggest that increased arginine administration may prove beneficial to injured patients.
Two experiments were conducted to estimate total non-protein energy and nitrogen requirements in growing healthy male Wistar rats nourished by parenteral nutrition. In experiment 1, non-protein energy varying from 30 to 70 kcal/day/rat were administered to animals receiving a constant dose of 80 mg nitrogen, plus vitamins and minerals. In experiment 2, nitrogen dosages varying from 0 to 280 mg N/day/rat with a constant dose of 60 kcal non-protein energy were studied. The formulation of the amino acid solution used in both experiments was based upon recommended oral amino acid requirements for growing rats. Dextrose served as the source of non-protein energy. Weight gain and nitrogen balance during a 6-day experimental period were used to determine requirements. Plasma free amino acids were also analyzed to evaluate the amino acid solution. Results indicate that under total parenteral nutrition conditions 578 to 621 mg/kg body weight3/4 nitrogen and 171 to 182 kcal/kg body weight3/4 non-protein energy are required to achieve growth of approximately 3 g/day. Inconsistent responses of plasma amino acid concentrations to the amounts infused were observed. It is suggested that the determined requirements can be applied as guidelines to research using the rat as an animal model in total parenteral nutrition.
Branched chain amino acids (BCAA) serve as intermediate energy substrates for peripheral tissues. Experiments were conducted to evaluate protein-sparing properties of BCAA at different doses without dextrose. Forty healthy male adult Wistar rats, weighing 437 +/- 34 gm, were randomly assigned to one of five groups. Four groups of eight rats were cannulated at the jugular vein and infused with 3% amino acid solutions containing 13, 23, 50 or 100% BCAA; an additional eight fasted rats served as controls. Results show that weight loss was not significantly different between groups, but was lower than in the fasted rats. Nitrogen balance (NB) was least negative in the 23% BCAA group, followed by 13, 50 and 100% BCAA. Protein-sparing index (PSI), defined as that portion of the infused nitrogen that is used for sparing body proteins, agreed with the calculated fat/protein ratios. Higher PSI and fat/protein ratios resulted from solutions containing balanced amino acid patterns (13 and 23%). No obvious imbalances in plasma amino acid patterns were observed. It is concluded that more protein conservation can be achieved with amino acid solutions containing a balanced amino acid pattern and that the effect of additional BCAA on protein conservation is limited in adult rats.
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The optimal levels of arginine (Arg) for growth and immunity were studied in mildly depleted, noninjured rats maintained on intravenous hyperalimentation. Three groups of S-D rats (eight/group, weighing 275-300 g) underwent catheter insertion, 1 day of fasting, and then 7 days of intravenous hyperalimentation consisting of 20% dextrose, adequate minerals and vitamins, and three amino acid regimens: (1) FreAmine II (1.55 g Arg/liter); (2) FreAmine III (4.05 g Arg/liter); (3) experimental (7.5 g Arg/liter). The increase in arginine levels was achieved by lowering the glycine levels. There were no differences among the groups in terms of body weight gain (6.9 vs 8.3 vs 10.0 g) or in cumulative N balance (574 vs 660 vs 642 mg). Liver, spleen, and adrenal weights did not differ. Thymus weight was greater in groups B and C: (A) 345 +/- 27 mg vs (B) 445 +/- 34 mg, p less than 0.05, vs (C) 438 +/- 26 mg, p less than 0.05) as were the total number of lymphocytes/thymus (X 10(-9) (A) 0.93 +/- 0.12 vs (B) 1.37 +/- 0.18, p less than 0.05, vs (C) 1.46 +/- 0.15, p less than 0.05). Mitogen-induced thymocyte blastogenesis (cpm) was greatest in group C in response to phytohemagglutinin: (A) 9.558 +/- 3,799 vs (B) 20,088 +/- 5,890, NS, vs (C) 37,234 +/- 6,209, p less than 0.01 vs A and p less than 0.05 vs B) and Concanavalin A: (A) 71,035 +/- 15,228 vs (B) 111,734 +/- 15,021, NS, vs (C) 172,967 +/- 19,861, p less than 0.01 vs A and p less than 0.05 vs B). In the intravenous hyperalimentation-maintained noninjured rat ARG concentrations more than 1.55 g/liter do not enhance N retention or growth. Larger doses of ARG have strong thymic immunostimulatory effects without any toxicity or growth reduction.
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