An imaging approach for determining the mechanism of enhancement of intestinal absorption of an L-theanine supplement.

BACKGROUND & OBJECTIVE: Theanine (L-glutamylethylamide) contained in green tea is a functional food component that has been attracting attention due to its relaxation effect. It was shown that the ingredients added to the theanine formulations increased the absorption of theanine. If this mechanism can be elucidated, it would be possible to contribute to development of evidence-based formulations. In this study, we investigated the effect of ingredients in the formulations on the absorption of theanine in detail. MAIN METHODS: After oral administration of a mixture of theanine and additional components to Wistar rats the plasma concentration was determined by an HPLC and the pharmacokinetic parameters were calculated. In addition, a new system for evaluating intestinal blood flow was developed since the involvement of intestinal blood flow was considered as a factor that increased absorption of theanine. KEY FINDINGS: Plasma concentration of theanine increased significantly in the combined use group with eight ingredients containing piperine as compared with theanine only group. Piperine would increase theanine absorption by increased blood flow, not an inhibition of metabolism. We succeeded to develop a visual and quantitative system to evaluate the effect of these ingredients directly including piperine on the intestinal blood flow using indocyanine green while maintaining physiological conditions. SIGNIFICANCE: Increased intestinal blood flow by these ingredients including piperine enhanced the absorption of theanine. Other mechanisms may also be considered as the mechanism by which theanine absorption is increased in addition to increased blood flow.

Folate catabolites in spot urine as non-invasive biomarkers of folate status during habitual intake and folic acid supplementation.

BACKGROUND: Folate status, as reflected by red blood cell (RCF) and plasma folates (PF), is related to health and disease risk. Folate degradation products para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (apABG) in 24 hour urine have recently been shown to correlate with blood folate. AIM: Since blood sampling and collection of 24 hour urine are cumbersome, we investigated whether the determination of urinary folate catabolites in fasted spot urine is a suitable non-invasive biomarker for folate status in subjects before and during folic acid supplementation. STUDY DESIGN AND METHODS: Immediate effects of oral folic acid bolus intake on urinary folate catabolites were assessed in a short-term pre-study. In the main study we included 53 healthy men. Of these, 29 were selected for a 12 week folic acid supplementation (400 µg). Blood, 24 hour and spot urine were collected at baseline and after 6 and 12 weeks and PF, RCF, urinary apABG and pABG were determined. RESULTS: Intake of a 400 µg folic acid bolus resulted in immediate increase of urinary catabolites. In the main study pABG and apABG concentrations in spot urine correlated well with their excretion in 24 hour urine. In healthy men consuming habitual diet, pABG showed closer correlation with PF (rs = 0.676) and RCF (rs = 0.649) than apABG (rs = 0.264, ns and 0.543). Supplementation led to significantly increased folate in plasma and red cells as well as elevated urinary folate catabolites, while only pABG correlated significantly with PF (rs = 0.574) after 12 weeks. CONCLUSION: Quantification of folate catabolites in fasted spot urine seems suitable as a non-invasive alternative to blood or 24 hour urine analysis for evaluation of folate status in populations consuming habitual diet. In non-steady-state conditions (folic acid supplementation) correlations between folate marker (RCF, PF, urinary catabolites) decrease due to differing kinetics.

Antidiabetic effects of rice hull smoke extract on glucose-regulating mechanism in type 2 diabetic mice.

The aim of this study is to determine the protective effect of a liquid rice hull smoke extract (RHSE) against type 2 diabetes (T2D) in mice induced by a high-fat diet. As compared to the control group of mice on a high-fat diet (HFD), feeding the HFD supplemented with 0.5% or 1% RHSE for 7 weeks resulted in significantly reduced blood glucose and triglyceride and cholesterol concentrations, higher serum insulin levels, and improved glucose tolerance, as assessed by an oral glucose tolerance assay. The hypoglycemic effect of RHSE was accompanied by changes in enzyme activities and cognate gene expression assessed using RT-PCR. Among the glucose metabolism regulating genes evaluated, hepatic glucokinase (GCK), the glucose transporters GLUT2 and GLUT4, and peroxisome proliferator-activated receptor-γ (PPAR-γ) were up-regulated, whereas glucose-6-phosphatase (G6 Pase) and phosphoenolpyruvate carboxykinase (PEPCK) were down-regulated in the liver of mice with RHSE-supplementation. These changes resulted in restoration of glucose-regulating activities to normal control levels. Histopathology showed that a high-fat diet intake also induced liver necrosis and damage of the islet of Langerhans in the pancreas, whereas RHSE supplementation restored necrotic damage to normal levels. Immunohistochemistry showed that RHSE supplementation can restore the reduced insulin-producing ß-cell population in islet of Langerhans associated with a high-fat diet intake to nondiabetic normal control levels in a dose-dependent manner. RHSE-supplemented food could protect insulin-producing islet cells against damage triggered by oxidative stress and local inflammation associated with diabetes.

Black tea improves attention and self-reported alertness.

Tea has previously been demonstrated to better help sustain alertness throughout the day in open-label studies. We investigated whether tea improves attention and self-reported alertness in two double-blind, randomised, placebo-controlled, crossover studies. Participants received black tea (made from commercially available tea bags) in one condition and placebo tea (hot water with food colours and flavours) similar in taste and appearance to real tea in the other condition. Attention was measured objectively with attention tests (the switch task and the intersensory-attention test) and subjectively with a self-report questionnaire (Bond-Lader visual analogue scales). In both studies, black tea significantly enhanced accuracy on the switch task (study 1 p<.002, study 2 p=.007) and self-reported alertness on the Bond-Lader questionnaire (study 1 p<.001, study 2 p=.021). The first study also demonstrated better auditory (p<.001) and visual (p=.030) intersensory attention after black tea compared to placebo. Simulation of theanine and caffeine plasma time-concentration curves indicated higher levels in the first study compared to the second, which supports the finding that tea effects on attention were strongest in the first study. Being the second most widely consumed beverage in the world after water, tea is a relevant contributor to our daily cognitive functioning.

Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function.

PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function. PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12. RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2. CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.

Kinetics of folate turnover in pregnant women (second trimester) and nonpregnant controls during folic acid supplementation: stable-isotopic labeling of plasma folate, urinary folate and folate catabolites shows subtle effects of pregnancy on turnover of folate pools.

To investigate the effects of pregnancy on folate metabolism, we conducted an 84-d study in second-trimester (gestational wk 14-25) pregnant women (n = 6) and nonpregnant controls (n = 6) with stable-isotopic tracer methods. All subjects were fed a diet containing approximately 272 nmol/d (120 microg/d) folate from food, along with supplemental folic acid that contained 15% [3',5'-(2)H(2)] folic acid ([(2)H(2)]folic acid) during d 1--41 and that was unlabeled during d 42--84 to yield a constant total folate intake of 1.02 or 1.93 micromol/d (450 or 850 microg/d). Isotopic enrichment of plasma folate, urinary folate and the urinary folate catabolites para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (ApABG) was determined at intervals throughout the study. The labeling of pABG and ApABG reflected that of tissue folate pools from which the catabolites originate. After the intake of labeled folic acid was terminated on d 41, labeling of urinary folate exhibited a biphasic exponential decline with distinct fast and slow components. In contrast, during d 42--84, the enrichment of urinary pABG and ApABG exhibited primarily monophasic exponential decline, and plasma folate underwent little decline of labeling during this period. Pregnant women and controls did not differ in estimates of body folate pool size and most aspects of the excretion of labeled urinary folate and catabolites, rates of decline of excretion, and areas under the curves for folate and catabolite excretion. Pregnant women, however, tended to have a slower rate of decline of pABG than ApABG and higher enrichment at d 42 of ApABG and pABG. These data support and extend our previous findings indicating that pregnancy (gestational wk 14--26) causes subtle changes in folate metabolism but does not elicit substantial increases in the rate or extent of folate turnover at these moderately high folate intakes.

Metabolism of theanine, gamma-glutamylethylamide, in rats.

The metabolism of theanine, one of the major amino acid components in tea (Camellia sinensis), was studied in rats. High-performance liquid chromatography (HPLC) with fluorometric detection was used to evaluate the nature of theanine's metabolites in plasma, urine, and tissues. In the urine samples collected after administration of 100, 200, and 400 mg each of theanine, intact theanine, L-glutamic acid, and ethylamine, these compounds were detected in a dose-dependent manner. When 200 mg of theanine was orally administered to rats, the plasma concentrations of theanine and ethylamine reached their highest levels about 0.5 and 2 h after administration, respectively. It seems most likely that the enzymatic hydrolysis of theanine to glutamic acid and ethylamine was accomplished in the kidney. These results indicate that orally administered theanine is absorbed through the intestinal tract and hydrolyzed to glutamic acid and ethylamine in the rat kidney.

Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hemorrhage.

OBJECT: The authors previously demonstrated, in a large-animal intracerebral hemorrhage (ICH) model, that markedly edematous ("translucent") white matter regions (> 10% increases in water contents) containing high levels of clot-derived plasma proteins rapidly develop adjacent to hematomas. The goal of the present study was to determine the concentrations of high-energy phosphate, carbohydrate substrate, and lactate in these and other perihematomal white and gray matter regions during the early hours following experimental ICH. METHODS: The authors infused autologous blood (1.7 ml) into frontal lobe white matter in a physiologically controlled model in pigs (weighing approximately 7 kg each) and froze their brains in situ at 1, 3, 5, or 8 hours postinfusion. Adenosine triphosphate (ATP), phosphocreatine (PCr), glycogen, glucose, lactate, and water contents were then measured in white and gray matter located ipsi- and contralateral to the hematomas, and metabolite concentrations in edematous brain regions were corrected for dilution. In markedly edematous white matter, glycogen and glucose concentrations increased two- to fivefold compared with control during 8 hours postinfusion. Similarly, PCr levels increased several-fold by 5 hours, whereas, except for a moderate decrease at 1 hour, ATP remained unchanged. Lactate was markedly increased (approximately 20 micromol/g) at all times. In gyral gray matter overlying the hematoma, water contents and glycogen levels were significantly increased at 5 and 8 hours, whereas lactate levels were increased two- to fourfold at all times. CONCLUSIONS: These results, which demonstrate normal to increased high-energy phosphate and carbohydrate substrate concentrations in edematous perihematomal regions during the early hours following ICH, are qualitatively similar to findings in other brain injury models in which a reduction in metabolic rate develops. Because an energy deficit is not present, lactate accumulation in edematous white matter is not caused by stimulated anaerobic glycolysis. Instead, because glutamate concentrations in the blood entering the brain's extracellular space during ICH are several-fold higher than normal levels, the authors speculate, on the basis of work reported by Pellerin and Magistretti, that glutamate uptake by astrocytes leads to enhanced aerobic glycolysis and lactate is generated at a rate that exceeds utilization.

Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress.

We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.

Plasma amino acid concentrations in the overtraining syndrome: possible effects on the immune system.

Overtraining and long-term exercise are associated with an impairment of immune function. We provide evidence in support of the hypothesis that the supply of glutamine, a key fuel for cells of the immune system, is impaired in these conditions and that this may contribute to immunosuppression. Plasma glutamine concentration was decreased in overtrained athletes and after long-term exercise (marathon race) and was increased after short-term, high intensity exercise (sprinting). Branched chain amino acid supplementation during long-term exercise was shown to prevent this decrease in the plasma glutamine level. Overtraining was without effect on the rate of T-lymphocyte proliferation in vitro or on the plasma levels of interleukin-1 and -6, suggesting that immune function is not impaired in this condition. Given the proposed importance of glutamine for cells of the immune system, it is concluded that the decrease in plasma glutamine concentration in overtraining and following long-term exercise, and not an intrinsic defect in T lymphocyte function, may contribute to the immune deficiency reported in these conditions.

Hypokalaemic episodic polymyopathy in cats fed a vegetarian diet.

A previously undocumented hypokalaemic condition with a cyclical nature, comprising acute bouts of polymyopathy followed by spontaneous recoveries, is described in the cat. Cats being fed a high protein vegetarian diet developed recurrent episodes of polymyopathy, characterised by ventroflexion of the head and neck, stiff forelimb gait, lateral head-resting and generalised muscle weakness. Plasma potassium concentrations (mean +/- standard deviation) were reduced from 3.28 +/- 0.33 mmol/l at the beginning of the experiment to 2.45 +/- 0.24 mmol/l during bouts of myopathy. This hypokalaemia was associated with increased creatine kinase activities indicative of muscle damage, and decreased urinary potassium concentrations, and was caused by insufficient dietary potassium. Cats that received the same diet supplemented with potassium did not develop hypokalaemic polymyopathy. Spontaneous recoveries of affected cats were not associated consistently with increases in plasma potassium concentrations. Plasma taurine concentrations decreased and glutamic acid increased markedly in all cats fed the experimental diet. There was no evidence of thiamin deficiency associated with the high glutamic acid intake. Veterinarians should be aware that hypokalaemic cats, and in particular those on potassium-deficient diets, may show cyclical disease with episodes of polymyopathy recurring after periods of spontaneous clinical recovery. This condition in cats may be a useful animal model for familial hypokalaemic periodic paralysis in humans.

Biochemistry of migraine.

The biochemistry of migraine is complex. Many contradictory or never replicated findings in often small patient groups have been published. The following observations in the platelet-free plasma and urine appear to have some solid basis and will be discussed: 1) systemic derangement of 5-HT metabolism, relevant to the peripheral vascular component of migraine pathophysiology, 2) changes in neuroexcitatory amino acids and magnesium, which may reflect a predisposition of the migraine patient, notably those having attacks with aura, to develop spreading depression, 3) alterations in methionine-enkephalin levels, which may be a useful marker to discriminate between tension headache and migraine, 4) hormonal fluctuations which seem important to set the threshold for an attack, 5) changes of vasoactive peptides in the cranio-vascular circulation, providing the first human evidence that the trigemino-vascular system indeed is relevant in migraine, and 6) catecholaminergic changes suggesting sympathetic overactivity. Finally distinct biochemical differences between patients with migraine without aura and patients with tension headache on one hand, and between patients with migraine with aura and patients with migraine without aura on the other hand will be emphasized. Findings in platelets will be discussed only if they are complementary and supportive to the plasma and urine data.

The systemic availability of oral glutathione.

When the plasma glutathione concentration is low, such as in patients with HIV infection, alcoholics, and patients with cirrhosis, increasing the availability of circulating glutathione by oral administration might be of therapeutic benefit. To assess the feasibility of supplementing oral glutathione we have determined the systemic availability of glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, and glutamate in plasma were 6.2, 8.3, and 54 mumol.l-1 respectively. During the 270 min after the administration of glutathione in a dose of 0.15 mmol.kg-1 the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. Because of hydrolysis of glutathione by intestinal and hepatic gamma-glutamyltransferase, dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.

Changes in free amino acid concentrations in serum, brain, and CSF throughout embryogenesis.

Using the developing chick embryo as a model and a very sensitive micromethod for amino acid analysis, a complete analysis is presented of the developmental changes in free amino acid concentration in the blood, in the CSF, and in two different brain regions (optic lobe and frontal lobe) of the chick embryo (from day 4 of incubation, until day 5 post hatching). The developmental profile of Lys is the only one that is almost identical in all three compartments. The developmental profiles of the serum and of the brain are very similar for Arg and Phe, less so for Leu and Gly, and towards the end of the embryonic period, similar also for Val, Ile, Trp, and Met. The amino acid concentrations in the CSF are either much lower than in serum and brain already at the earliest stages, or they progressively decline to levels lower than those in brain and serum, most rapidly between day 6 and 8 of embryonic life. The concentrations of neuroactive amino acids (Gln, Glu, Asp, GABA, Tau, and Gly) in both brain regions begin to increase very early, and continue to rise, except Tau, which goes through a maximum at day 8. Comparative analysis of the developmental profiles of each amino acid in serum, brain, and CSF reveals that the blood supply and the cellular uptake, retention, and metabolism by neural cells are the major determinants of the free amino acid pool of the developing brain.

Glutamine prevents pancreatic atrophy and fatty liver during elemental feeding.

Rats fed an elemental, enteral diet (STD) developed pancreatic atrophy and hepatic steatosis following 60% jejunoileal intestinal resection. An isonitrogenous, isocaloric 2 g/100 ml glutamine-supplemented diet (GLN) significantly attenuated the development of pancreatic atrophy and hepatic steatosis associated with elemental feeding. Pancreatic weight, DNA, and protein were 27, 22, and 40% increased, respectively, in GLN animals. The pancreata of all animals appeared normal by light and electron microscopic examination. GLN animals had 12% less total liver wet weight, 3% less hepatic water content, and 47% less hepatic fat relative to STD rats. Histologic examination of the liver revealed extensive centrilobular fatty vacuolization in STD animals whereas GLN rats had normal looking hepatic parenchyma. Glutamine should be viewed as an important nutrient in elemental diets with trophic effects on the pancreas and protective effects against the development of hepatic steatosis.

Aspartate-induced neuronal necrosis in infant mice: protective effect of carbohydrate and insulin.

Infant mice given large doses of glutamate or aspartate develop hypothalamic neuronal necrosis. Studies by others demonstrated that simultaneous administration of carbohydrate or prior injection with insulin markedly decreased glutamate-induced neuronal damage. We investigated whether carbohydrate and insulin exert a similar protective effect against aspartate-induced neuronal necrosis. Eight-day-old mice administered aspartate at 750 and 1000 mg/kg body weight developed neuronal necrosis (45.9 +/- 7.2 and 80.8 +/- 17.3 necrotic neurons/section, respectively). When carbohydrate (1 g/kg body weight) was administered simultaneously no lesions were detected in mice administered 750 mg/kg body weight aspartate, while 30.1 +/- 14.2 necrotic neurons/section were noted at 1000 mg aspartate/kg body weight. Mice administered 1000 mg/kg body weight aspartate with prior injection of insulin had 28.4 +/- 12.6 necrotic neurons/section, while 4.2 +/- 1.4 necrotic neurons/section were noted in insulin treated mice given 750 mg aspartate/kg body weight. Carbohydrate and insulin treatments has only minimal effects on plasma aspartate concentrations.

Effect of meal components on peripheral and portal plasma glutamate levels in young pigs administered large doses of monosodium-L-glutamate.

Mean peak plasma glutamate concentrations and area under the plasma glutamate concentration-time curve are much lower in adult humans ingesting monosodium L-glutamate (MSG) in formula than in water. The present study investigated the effects of individual meal components on portal and vena caval plasma glutamate concentration in young pigs administered MSG. Portal vein catheters and gastrojejunal tubes were placed in four young male pigs, and the animals were allowed to recover. Each animal was then administered four water solutions providing 500 mg/kg body weight MSG in a Latin square design. One solution provided only MSG; the second provided MSG and 1 g/kg body weight metabolizable carbohydrate (partially hydrolyzed corn starch); the third provided MSG and 1 g/kg body weight nonmetabolizable carbohydrate (beta-cellobiose); and the fourth provided MSG and 0.4 g/kg body weight of an amino acid mixture (Aminosyn, Abbott Laboratories, North Chicago, Ill). Mean peak plasma glutamate concentration and area under the plasma glutamate concentration-time curve were significantly lower (P less than 0.05) in both portal and vena caval blood when MSG was administered with metabolizable carbohydrate than when administered in water. Simultaneous ingestion of MSG with nonmetabolizable carbohydrate (beta-cellobiose) or amino acids had no significant effect on either mean peak portal or vena caval plasma glutamate concentration or area under the plasma glutamate concentration-time curves when compared to values observed when MSG was administered alone. The data suggest that metabolizable carbohydrate is the meal component affecting plasma glutamate concentration.

Effect of carbohydrate on plasma and erythrocyte glutamate levels in humans ingesting large doses of monosodium L-glutamate in water.

In previous studies, plasma glutamate concentration was lower when equivalent doses of monosodium L-glutamate (MSG) were given with a ready-to-feed liquid formula meal (Sustagen; 0.4 g protein, 1.1 g carbohydrate, 0.06 g fat, 6.6 kcal energy/kg body weight) rather than in water. This difference was suggested to reflect a carbohydrate effect on mucosal cell glutamate metabolism. To test this hypothesis, a large dose of monosodium L-glutamate (150 mg/kg body weight) dissolved in water, with or without added carbohydrate, was administered to eight healthy adult subjects. Carbohydrate was administered at 1.1 g/kg body weight in the form of partially hydrolyzed corn starch (Polycose). In the absence of carbohydrate, the mean (+/- SD) peak plasma glutamate concentration was 59.4 +/- 46.5 mumol/dl, and the incremental area under the plasma glutamate concentration time curve was 3391 +/- 2360 mumol/(dl x min). The addition of carbohydrate to the glutamate solution significantly decreased (p = 0.001) both the mean peak plasma glutamate concentration (7.18 +/- 3.48 mumol/dl) and the incremental area under the plasma glutamate concentration-time-curve (451 +/- 20.8 mumol/(dl x min). Erythrocyte glutamate and aspartate concentrations were not affected by glutamate loading in either test. Delayed gastric emptying did not account for the carbohydrate effect. Carbohydrate is postulated to serve as a pyruvate source for mucosal cells, facilitating the transamination of glutamate and its subsequent metabolism. This process would reduce the release of glutamate to the peripheral circulation.

Effect of oral monosodium glutamate on glutamic acid levels in the nucleus arcuatus of the hypothalamus and on serum osmolality of adult and infant mice.

Monosodium glutamate (MSG) given by gavage to 7-day-old mice at 2 g/kg body weight (b.wt.) as a 20% solution w/v resulted in a 27% increase in the glutamic acid (GA) content in the nucleus arcuatus of the hypothalamus (NAH). When MSG was administered by gavage to adult mice at 4 g/kg b.wt. as a 20% solution w/v, GA levels in NAH remained unchanged. Serum osmolality, measured after oral MSG, was elevated in infant mice but was unaffected in adults.

Aspartame administration to the infant monkey: hypothalamic morphology and plasma amino acid levels.

Infant monkeys received 2 gm/kg body weight of aspartame (APM) or 2 gm/kg body weight APM plus 1 gm/kg body weight monosodium glutamate (MSG) by gastric tube. Blood samples were obtained at intervals over the ensuing 4 hours and analyzed for amino acid levels. At this time, each infant was perfused with glutaraldehyde. The hypothalamus was embedded in plastic and then serially sectioned at 1 mu. Hypothalamic morphology was normal in all eight infants given 2 gm/kg body weight APM and in the six infants given 2 gm/kg body weight APM plus 1 gm/kg body weight MSG. By light microscopy, no pycnotic nuclei, neuronal degeneration, or dendritic swelling was noted. In both experimental and control brains, localized areas of poor perfusion exhibited abnormal morphology. Elevated plasma levels of aspartate, glutamate, and phenylalanine indicated that the test compounds were administered and absorbed. Variable rates of absorption were evident, probably due to the necessity of administering APM as a slurry, due to its low solubility. On the basis of blood absorption curves, it appears that infant monkeys metabolize aspartate and glutamate and phenylalanine somewhat more rapidly than man. It is concluded that APM given alone or with MSG, in large acute doses, does not result in hypothalamic damage in the newborn monkey.