Arginine In Patients Research Articles

Elevated plasma arginase-1 does not affect plasma arginine in patients undergoing liver resection

Arginine is an important substrate in health and disease. It is a commonly held view that arginase-1 release from injured erythrocytes and hepatocytes leads to arginine breakdown; however, the true relationship between plasma arginase-1 concentration and activity has remained unaddressed. In the present study, blood was sampled from patients undergoing liver resection, a known cause of hepatocyte injury and arginase-1 release, to determine arginase-1, arginine and ornithine plasma levels. Arginase activity was assessed in vitro by measuring changes in arginine and ornithine plasma levels during incubation of plasma and whole-blood samples at 37 degrees C. Arginase-1 plasma levels increased 8-10-fold during liver resection, whereas arginine and ornithine levels remained unchanged. In accordance with these in vivo findings, arginine and ornithine levels remained unchanged in plasma incubated at 37 degrees C irrespective of the arginase-1 concentration. In contrast, arginine plasma levels in whole blood decreased significantly during incubation, with ornithine increasing stoichiometrically. These changes were irrespective of arginase-1 plasma levels and were explained by arginase activity present in intact erythrocytes. Next, plasma samples with 1000-fold normal arginase-1 concentrations were obtained from patients undergoing cadaveric liver transplantation. A significant decrease in arginine plasma levels occurred in vivo and in vitro. In contrast with commonly held views, moderately increased arginase-1 plasma levels do not affect plasma arginine. Very high plasma arginase-1 levels are required to induce potential clinically relevant effects.

Pulmonary Hypertension in Thalassemia: Association with Hemolysis, Arginine Metabolism Dysregulation, and a Hypercoagulable State

Pulmonary Hypertension in Thalassemia: Association with Hemolysis, Arginine Metabolism Dysregulation, and a Hypercoagulable State

Ibuprofen arginine for pain control during scaling and root planing: a randomized, triple‐blind trial

The aim of this controlled clinical trial was to investigate the analgesic efficacy and tolerability of ibuprofen arginine in patients with mild-to-moderate periodontitis during and after non-surgical periodontal treatment. This randomized, triple-blind, placebo-controlled, parallel-group trial assessed the analgesic efficacy of ibuprofen arginine (Spedifen) in patients undergoing routine periodontal scaling and root planing. 64 patients with chronic periodontitis received either 800 mg ibuprofen arginine or placebo 30 min. before treatment. Numeric pain and electronic visual analogue scales ranging from 0 to 100 were used. The average pain levels during treatment were lower following ibuprofen arginine (quartiles: 0.5, 4.5, 11) compared with placebo (4, 16, 26), corresponding to a percentage reduction in median pain of 72% (p=0.023). The median maximum pain was 28 (inter-quartile range 10-50) following placebo and 10 (4-31) following ibuprofen arginine (p=0.065). In patients with mild-to-moderate chronic periodontitis, ibuprofen arginine was safe and superior to placebo for alleviating pain during non-surgical periodontal treatment. Its painless administration and rapid onset of action make it well suitable for pain management in a general dental office.

Pegylated Arginine Deiminase Treatment of Patients With Metastatic Melanoma: Results From Phase I and II Studies

Individuals with metastatic melanoma have a poor prognosis. Many human melanomas are auxotrophic for arginine, and arginine is not an essential amino acid in humans. We hypothesized that this auxotrophy may be therapeutically exploited. A novel amino acid-degrading enzyme (arginine deiminase) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) was used to lower plasma arginine in individuals with metastatic melanoma. Two cohort dose-escalation studies were performed. A phase I study in the United States enrolled 15 patients, and a phase I to II study in Italy enrolled 24 patients. The Italian patients also received two subsequent cycles of treatment, each consisting of four once-weekly injections of 160 U/m2. The goals of these studies were to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and the antitumor activity of ADI-SS PEG 20,000 mw. PK and PD studies indicated that a dose of 160 U/m2 lowered plasma arginine from a resting level of approximately 130 micromol/L to less than 2 micromol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival. CONCLUSION Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.

Reduced growth hormone response to growthhormone-releasing hormone combined with arginine in patients with the metabolic syndrome

Reduced growth hormone response to growthhormone-releasing hormone combined with arginine in patients with the metabolic syndrome

Oral l -Arginine in Patients With Coronary Artery Disease on Medical Management

Vascular nitric oxide (NO) bioavailability is reduced in patients with coronary artery disease (CAD). We investigated whether oral L-arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients maintained on appropriate medical therapy and thus might be useful as adjunctive therapy. Thirty CAD patients (29 men; age, 67+/-8 years) on appropriate medical management were randomly assigned to L-arginine (9 g) or placebo daily for 1 month, with crossover to the alternate therapy after 1 month off therapy, in a double-blind study. Nitrogen oxides in serum (as an index of endothelial NO release), flow-mediated brachial artery dilation (as an index of vascular NO bioactivity), and serum cell adhesion molecules (as an index of NO-regulated markers of inflammation) were measured at the end of each treatment period. L-Arginine significantly increased arginine levels in plasma (130+/-53 versus 70+/-17 micromol/L, P<0.001) compared with placebo. However, there was no effect of L-arginine on nitrogen oxides (19.3+/-7.9 versus 18. 6+/-6.7 micromol/L, P=0.546), on flow-mediated dilation of the brachial artery (11.9+/-6.3% versus 11.4+/-7.9%, P=0.742), or on the cell adhesion molecules E-selectin (47.8+/-15.2 versus 47.2+/-14.4 ng/mL, P=0.601), intercellular adhesion molecule-1 (250+/-57 versus 249+/-57 ng/mL, P=0.862), and vascular cell adhesion molecule-1 (567+/-124 versus 574+/-135 ng/mL, P=0.473). Oral L-arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

Growth Hormone (GH) Responses to GH-Releasing Hormone Alone or Combined with Arginine in Patients with Adrenal Incidentaloma: Evidence for Enhanced Somatostatinergic Tone

Growth Hormone (GH) Responses to GH-Releasing Hormone Alone or Combined with Arginine in Patients with Adrenal Incidentaloma: Evidence for Enhanced Somatostatinergic Tone

6] Measuring nitric oxide production in human clinical studies

This chapter describes various methods that can be used to measure the activity of nitric oxide synthase (NOS) during inflammation in vivo . These methods demonstrate nitrate synthesis in humans and synthesis from L-[ 15 N] arginine in patients receiving interleukin-2 (IL-2) infusions as cancer immunotherapy. Currently, the role of inducible NOS (iNOS) in human inflammatory states is a controversial issue. This stems primarily from the lack of a reproducible assay for inducing NOS in human mononuclear phagocytes in vitro under conditions where high-output nitric oxide synthesis is observed as in murine macrophages activated with proinflammatory cytokines. iNOS protein—demonstrable by western blot and low-level nitric oxide synthesis—does occur in vitro under defined conditions in mononuclear phagocytes from some individuals. The functional representation of this activity is unknown. The methods described in this chapter are useful for clinical studies toward the understanding the role of NOS in inflammatory diseases, including the biochemical mechanisms operating in cell-mediated immunity to intracellular pathogens in humans.

Improvement of cardiac performance by intravenous infusion of l-arginine in patients with moderate congestive heart failure

The aim of this study was to evaluate the hemodynamic effect of L-arginine infusion in patients with congestive heart failure. Endothelium-dependent vasodilation is impaired in patients with congestive heart failure. Nitric oxide, which was identified as endothelium-derived relaxing factor, is generated by nitric oxide synthase from L-arginine. Our hypothesis was that administration of L-arginine in patients with congestive heart failure may increase nitric oxide production and have a beneficial hemodynamic effect. Twelve patients with congestive heart failure (New York Heart Association class II or III) due to coronary artery disease (left ventricular ejection fraction < 35%) were given 20 g of L-arginine by intravenous infusion over 1 h at a constant rate. Stroke volume, cardiac output and left ventricular ejection fraction were determined with Doppler echocardiography at baseline and at 30 and 60 min and 1 h after the end of infusion. Blood and urinary levels of nitrite/nitrate (NO2/NO3), stable metabolites of nitric oxide, were measured and clearance was calculated. One hour of infusion of L-arginine resulted in a significant increase in stroke volume (from 68 +/- 18 ml to 76 +/- 23 ml [mean +/- SD], p = 0.014) and cardiac output (from 4.07 +/- 1.22 liters/min to 4.7 +/- 1.42 liters/min, p = 0.006) without a change in heart rate. Mean arterial blood pressure decreased (from 102 +/- 11 mm Hg to 89 +/- 9.5 mm Hg, p < 0.002), and systemic vascular resistance decreased significantly. Within 1 h after cessation of L-arginine infusion, blood pressure, stroke volume, cardiac output and systemic vascular resistance were statistically not different from baseline values. Clearance of NO2/NO3 increased significantly during L-arginine administration (from 13.28 +/- 0.42 ml/min to 29.97 +/- 1.09 ml/min, p < 0.001). Infusion of L-arginine in patients with congestive heart failure results in increased production of nitric oxide, peripheral vasodilation and increased cardiac output, suggesting a beneficial hemodynamic and possibly therapeutic profile.

Impaired prolactin response to arginine in patients with hyperthyroidism

Reduced PRL responses to TRH or dopamine antagonists have been described in hyperthyroid patients. Arginine stimulates PRL secretion through pathways other than the activation of TRH receptors or dopamine-dependent mechanisms. We therefore investigated PRL responses to arginine in patients with hyperthyroidism. L-Arginine (30 g infused over 30 minutes) was administered at time zero. Sixteen patients with untreated hyperthyroidism due to Graves' disease (8 female and 8 male), with a mean age (+/- SE) of 31.3 +/- 1.4 years (range 23-42), and 12 normal subjects (6 female and 6 male, ages 30.1 +/- 2.1 years, range 22-47) were studied. Prolactin was measured by RIA between -30 and 120 minutes, at 15-minute intervals. Basal PRL levels were similar in the hyperthyroid patients and normal control subjects. The hyperthyroid women showed blunted PRL responses compared to normal women (peak PRL levels, 364 +/- 44 mU/l, vs 760 +/- 156, P < 0.02). PRL responses to arginine, small but clearly detectable in normal men, were completely abolished in hyperthyroid men (peak PRL levels, 248 +/- 48 mU/l, vs 112 +/- 14, P < 0.01). PRL responses to arginine are impaired in hyperthyroid patients. Therefore, arginine should be added to the list of PRL stimuli whose responses are blunted in hyperthyroidism. Inhibition of PRL gene expression, and thus reduced pituitary PRL synthesis and storage, may explain why PRL responses to all secretagogues are reduced in these patients.

Assessment of dietary intake of lysine and arginine in patients with herpes simplex

In this study, dietary intake of the amino acids lysine and arginine did not differ significantly between normal controls and patients with herpes virus. Both groups of subjects consumed significantly more lysine than arginine on a daily basis. Those results are not surprising given the American population's preference for high lysine foods, such as meat and dairy products, as opposed to foods high in arginine, such as legumes, whole grains, and nuts. The mean daily intakes of lysine and arginine for the 16 subjects studied were 8.11 gm +/- 2.28 and 6.32 gm +/- 1.74, respectively. The standard deviations of the mean intakes indicate that there is a large variability in the intake of both amino acids and the ratios of the two amino acids in individual diets. This information is important, considering the conflicting results obtained previously by researchers investigating the efficacy of lysine therapy for herpes infections. The extent of the variability in total amino acid intake or ratio of lysine to arginine in the diet cannot be determined from previous studies. More important, the possible effects of these ranges on the interpretation of study results remain unknown. In order for future studies to accurately determine the effects of supplemental lysine in the treatment of herpes infections, close monitoring of dietary intake is essential.

Plasma arginine in cancer of the gastrointestinal tract: effect of surgical treatment.

The concentration of 21 amino acids was measured in the venous plasma of 41 patients with cancer of the gastrointestinal tract who had lost weight, 12 patients who had lost a similar amount of weight from non-malignant, non-septic conditions (benign weight loss), 12 patients with cancer of the gastrointestinal tract who had not lost weight and 21 control patients. Sixteen patients with localised tumours were restudied eight and 12 weeks after successful removal of the primary growth. Six patients with pyloric stenosis (benign weight loss) were similarly studied for comparison after corrective surgery. The concentration of the amino acid arginine was significantly greater in patients with cancer both with weight loss (71.2 +/- 4.1 mumol/l mean +/- SEM) and without weight loss (66.8 +/- 4.1 mumol/l) when compared both with patients with benign weight loss (34.6 +/- 3.2 mumol/l) and with control patients (48.2 +/- 3.5 mumol/l) (p less than 0.05). In patients with cancer subjected to surgery the concentration of arginine (76.4 +/- 7.5 mumol/l) fell to normal levels eight weeks after operation and remained normal 12 weeks after surgery (48.6 +/- 4.4 mumol/l) (p less than 0.05). This was in contrast with the rise in plasma arginine in patients with pyloric stenosis after surgery, suggesting that the raised level of arginine was due to the presence of the primary tumour.

Increased peripheral venous somatostatin concentration and decreased glucagon response to arginine in patients with insulin dependent diabetes mellitus without residual B-cell function. Increased plasma SRIF in IDDM.

The glucagon response to insulin hypoglycaemia is frequently reduced in patients with IDDM. In the present study arginine infusion, thought to act directly on the islet cells, was used to stimulate somatostatin (SRIF) and glucagon in IDDM without residual B-cell function. Thirteen IDDM patients' were compared with 13 sex- and age matched normal controls following an arginine infusion. The plasma SRIF concentrations in the 'IDDM group' and normal controls increased from 24.2 +/- 2.5 to 31.1 +/- 3.9 pmol/l (P less than 0.01) and 19.7 +/- 1.7 to 23.9 +/- 3.4 pmol/l respectively after 10 min (P less than 0.01). The plasma glucagon concentrations increased from 27 +/- 4.7 to 176 +/- 23.1 pmol/l (P less than 0.01) and 36 +/- 5.0 to 302 +/- 31.9 pmol/l (P less than 0.01) respectively after 20 min. Thus, in long standing IDDM without residual B-cell function, increased plasma SRIF concentrations are found and the glucagon response to arginine is reduced. The last observation further explains why these patients are especially vulnerable to hypoglycaemia.

Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.

In order to assess whether patients with noninsulin-dependent diabetes mellitus (NIDDM) possess normal insulin secretory capacity, maximal B cell responsiveness to the potentiating effects of glucose was estimated in eight untreated patients with NIDDM and in eight nondiabetic controls. The acute insulin response to 5 g intravenous arginine was measured at five matched plasma glucose levels that ranged from approximately 100-615 mg/dl. The upper asymptote approached by acute insulin responses (AIRmax) and the plasma glucose concentration at half-maximal responsiveness (PG50) were estimated using nonlinear regression to fit a modification of the Michaelis-Menten equation. In addition, glucagon responses to arginine were measured at these same glucose levels to compare maximal A cell suppression by hyperglycemia in diabetics and controls. Insulin responses to arginine were lower in diabetics than in controls at all matched glucose levels (P less than 0.001 at all levels). In addition, estimated AIRmax was much lower in diabetics than in controls (83 +/- 21 vs. 450 +/- 93 microU/ml, P less than 0.01). In contrast, PG50 was similar in diabetics and controls (234 +/- 28 vs. 197 +/- 20 mg/dl, P equals NS) and insulin responses in both groups approached or attained maxima at a glucose level of approximately 460 mg/dl. Acute glucagon responses to arginine in patients with NIDDM were significantly higher than responses in controls at all glucose levels. In addition, although glucagon responses in control subjects reached a minimum at a glucose level of approximately 460 mg/dl, responses in diabetics declined continuously throughout the glucose range and did not reach a minimum. Thus, A cell sensitivity to changes in glucose level may be diminished in patients with NIDDM. In summary, patients with NIDDM possess markedly decreased maximal insulin responsiveness to the potentiating effects of glucose. Such a defect indicates the presence of a reduced B cell secretory capacity and suggests a marked generalized impairment of B cell function in patients with NIDDM.

Hormonal responses to intravenous glucose and arginine in patients with pancreatitis.

19 subjects with an acute episode of pancreatitis, and 5 patients with chronic pancreatitis received intravenous glucose tolerance tests with measurement of glucose, insulin and glucagon. Patients recovering from acute pancreatitis demonstrated defects in their ability to dispose of a glucose load. 10 patients had overt glucose intolerance; of these, 4 were insulin-deficient, 3 had a loss of an acute insulin response to glucose, and 3 had marked hyperglucagonemia with normal to increased insulin levels. These abnormalities were seen in response both to intravenous glucose and intravenous arginine. Therefore, according to this study, at least three factors are clearly implicated in the production of glucose intolerance after an acute episode of pancreatitis: hypoinsulinemia, delayed insulin secretory response and hyperglucagonemia.

Insulin response to glucose and arginine in patients with isolated ACTH deficiency (author's transl)

It is generally accepted that plasma insulin levels (IRI) are low in patients with isolated ACTH deficiency. But, a comparison of IRI levels before and after replacement therapy has not yet been reported. We studied the insulin response to glucose and arginine administration (O-GTT, ATT) in 4 cases whom we encountered during the last 4 years. In O-GTT, 50g of glucose was given. In ATT, after 0.5g/kg arginine was infused intravenously, blood specimens were drawn at 0, 5, 15, 30, 60, 90,120 and 180 minutes. Plasma insulin was determined by a double antibody radioimmunoassay, and glucose (BS) was determined by an autoanalyser.The results were as follows : O-GTT : Before replacement therapy using glucocorticoid, in all 3 cases in whom the test was done, BS curves showed a normal pattern. Fasting plasma IRI levels and ∑IRI were low in 2 cases (cases 1 and 3). In the other one (case 4), plasma IRI levels at fasting, 120 and 180 minutes were undetectable. However, the peak IRI level at 60 minutes was very high (269uU/ml). One month after the initiation of replacement therapy ∑Bs increased in all cases. Fasting IRI, peak IRI levels and ∑IRI also increased in 2 cases (cases 1 and 3). In case 4, although fasting IRI increased, peak IRI level and ∑IRI markedly decreased.ATT : Before replacement therapy, BS curves showed low responses in all 4 cases. Plasma IRI peaks were observed at 5 minutes in all cases, and they showed low or low normal. During therapy, BS peak levels and plasma IRI peak levels increased in all cases, especially in case 4.From the above results, the insulin response to O-GTT and ATT in patients with isolated ACTH deficiency were divided into 2 groups. One showed concordance with the results in O-GTT and ATT before and after replacement therapy. The other showed dissociation from the results in O-GTT and NIT before and after replacement therapy. It was supposed that the differences in insulin response might be caused by a localization of the lesions in the brain.

Impaired Plasma Insulin Response to Arginine in Hyperthyroidism: Important Role of the Rise of Blood Glucose in the Second Phase of Insulin Release Induced by Arginine

Intravenous infusion of 30 gm. of L-arginine over a period of 45 minutes elicited a biphasic insulin response and a moderate blood glucose rise in normal subjects. In patients with hyperthyroidism, both insulin peaks, especially the second one, were low, with virtual absence of the blood glucose response. A single intravenous injection of 4 gm. of arginine provoked similar uniphasic plasma insulin responses in both normal subjects and hyperthyroid patients. Pretreatment with either glucose or xylitol almost completely restored the biphasic insulin response to arginine in patients with hyperthyroidism, whereas pretreatment with aminophylline only partially improved the insulin response. Combined administration of a small amount of glucose (2.25 mg./kg./min.) with arginine also restored the normal second-phase insulin release, with blood glucose rises similar to those in normal subjects given arginine alone. It is concluded that the plasma insulin response to arginine is impaired, especially in its second phase, in patients with hyperthyroidism due to the absence of a blood glucose rise. The second phase of arginine-induced insulin release seems more dependent on glucose than the first phase.

Growth hormone response to insulin and to arginine in patients with familial hypercholesterolaemia

Human growth hormone (HGH) response to i.v. insulin (0.1 U/kg body weight) and arginine infusion (25 g of l-arginine for 30 min) was studied in 9 patients (5 males and 4 females) with primary familial hypercholesterolaemia and belonging to 4 families. Mean age was 28 ± 2 years (range 18–36) and body weight was < 105% of ideal body weight. Glucose tolerance and insulin response to oral glucose were normal in all patients. HGH release after insulin and after arginine was slightly increased as compared to 21 normal controls, but the differences were not significant. Insulin and glucagon response to arginine in these patients was within the normal range. Plasma glucose and free fatty acids were normal after both insulin and arginine. Moreover, no significant correlation was found between fasting cholesterol and HGH peaks after insulin and after arginine, nor between cholesterol and insulin and glucagon responses. Despite marked hyperlipidaemia, HGH-deficient patients examined by other authors never present signs of atherosclerotic disease. Our data suggest that HGH, in the presence of elevated cholesterol levels, might play an important role in the development of atherosclerotic lesions.

STIMULATION OF IMMUNOREACTIVE INSULIN AND HUMAN GROWTH HORMONE RELEASE BY ADMINISTRATION OF ARGININE IN PATIENTS WITH DIABETIC RETINOPATHY

ABSTRACT The effect of arginine hydrochloride (30 g), given twice at 90 min intervals, on the release of immunoreactive insulin and of human growth hormone was studied in healthy subjects (HS), in diabetics without and with various degrees of retinopathy and in acromegalics. The insulinogenic index estimated by the ratio of μU IRI per ml/mg per 100 ml of blood glucose was maximal in HS after the first administration of arginine. It was highest in acromegalics and diminished in all the diabetic subjects. The release of human growth hormone as estimated by the mean sum of increments above the basal levels (x̄ + sem) during period I and II was 80.2±15 ng/ml and 59.0±18 ng/ml in HS (n = 7), 38±8.6 ng/ml and 36±16.3 ng/ml in diabetics without retinopathy (n = 9), 4.2±0.4 ng/ml and 19±7 ng/ml in insulin treated diabetics with retinopathy (n = 9), and 22.7±10.7 ng/ml and 46±10.5 ng/ml in orally treated diabetics with retinopathy (n = 7). Patients suffering from proliferative retinopathy (n = 9) exhibited values of 32.8±10.6 ng/ml during period I and 43.5±10.6 ng/ml during period II. The secretory response of HGH to arginine in acromegalics (n = 6) was not significant. The data reported suggest an impaired secretory capacity for the release of human growth hormone to the administration of arginine in patients with diabetic retinopathy. The observations do not support the hypothesis that an exaggerated release of HGH plays a role in the development of diabetic retinopathy.