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1.
Acute porphyrias: a German monocentric study of the biochemical, molecular genetic, and clinical data of 62 families.
Bronisch, O, Stauch, T, Haverkamp, T, Beykirch, MK, Petrides, PE
Annals of hematology. 2019;(12):2683-2691
Abstract
In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values.
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2.
Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study.
Winzeler, B, Cesana-Nigro, N, Refardt, J, Vogt, DR, Imber, C, Morin, B, Popovic, M, Steinmetz, M, Sailer, CO, Szinnai, G, et al
Lancet (London, England). 2019;(10198):587-595
Abstract
BACKGROUND Differential diagnosis of diabetes insipidus is challenging. The most reliable approach is hypertonic saline-stimulated copeptin measurements. However, this test is based on the induction of hypernatraemia and requires close monitoring of plasma sodium concentrations. Arginine-stimulated copeptin measurements might provide an alternative, simple, and safe test. METHODS In this prospective diagnostic study, we recruited a development cohort from University Hospital Basel, Basel, Switzerland, and a validation cohort from five centres in Basel, Aarau, Luzern, Bern, and St Gallen, Switzerland, and the University Hospital Würzburg, Würzburg, Germany. For both cohorts, patients were eligible for inclusion if they were aged 18 years or older, were newly referred with polyuria (>50 mL/kg bodyweight per day) or had a known diagnosis of central diabetes insipidus or primary polydipsia. We also recruited a comparator cohort of healthy controls in parallel to each cohort, comprising adults (aged 18 years and older, with normal drinking habits, and no history of polyuria) and children who underwent arginine stimulation to diagnose growth hormone deficiency (children were only included in the comparator cohort to the development cohort as proof of concept). Patients and healthy controls underwent arginine stimulation with measurement of plasma copeptin at baseline and 30, 45, 60, 90, and 120 min. The primary objective in the development cohort was to determine the diagnostic accuracy of plasma copeptin concentrations to discriminate between diabetes insipidus and primary polydipsia, and in the validation cohort was to confirm those results. Adverse effects of the test were monitored in all participants, with tolerability of the test rated using a visual analogue scale (VAS) that ranged from no (0) to maximum (10) discomfort. This trial is registered with ClinicalTrials.gov, number NCT00757276. FINDINGS Between May 24, 2013, and Jan 11, 2017, 52 patients were enrolled in the development cohort (12 [23%] with complete diabetes insipidus, nine [17%] with partial diabetes insipidus, and 31 [60%] with primary polydipsia) alongside 20 healthy adults and 42 child controls. Between Oct 24, 2017, and June 27, 2018, 46 patients were enrolled in the validation cohort (12 [26%] with complete diabetes insipidus, seven [15%] with partial diabetes insipidus, and 27 [59%] with primary polydipsia) alongside 30 healthy adult controls (two patients in this cohort were excluded from the main analysis because of early vomiting during the test). In the pooled patient and control datasets, median arginine-stimulated copeptin concentrations increased in healthy adult controls (from 5·2 pM [IQR 3·3-10·9] to a maximum of 9·8 pM [6·4-19·6]) and in participants with primary polydipsia (from 3·6 pM [IQR 2·4-5·7] to a maximum of 7·9 pM [5·1-11·8]), but only minimally in those with diabetes insipidus (2·1 pM [IQR 1·9-2·7] to a maximum of 2·5 pM [1·9-3·1]). In the development cohort, a cutoff of 3·5 pM at 60 min provided the highest diagnostic accuracy of 94% (95% CI 84-98). The accuracy of this cutoff in the validation cohort was 86% (95% CI 73-94). By pooling the data from both cohorts, an optimal accuracy of 93% (95% CI 86-97) was reached at a cutoff of 3·8 pM copeptin at 60 min (sensitivity 93%, 95% CI 86-98; specificity 92%, 95% CI 84-100). The test was safe and well tolerated, with median VAS scores of 3·5 (IQR 2-4) in patients with diabetes insipidus, 3 (2-4) in those with primary polydipsia, 1 (1-3) in healthy adults, and 1 (0-5) in healthy children in the pooled participant dataset. INTERPRETATION Arginine-stimulated copeptin measurements are an innovative test for diabetes insipidus with high diagnostic accuracy, and could be a simplified, novel, and safe diagnostic approach to diabetes insipidus in clinical practice. FUNDING Swiss National Science Foundation and University Hospital Basel.
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Effects of single and combined metformin and L-citrulline supplementation on L-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications.
Hanff, E, Hafner, P, Bollenbach, A, Bonati, U, Kayacelebi, AA, Fischer, D, Tsikas, D
Amino acids. 2018;(10):1391-1406
Abstract
The L-arginine/nitric oxide synthase (NOS) pathway is considered to be altered in muscular dystrophy such as Becker muscular dystrophy (BMD). We investigated two pharmacological options aimed to increase nitric oxide (NO) synthesis in 20 male BMD patients (age range 21-44 years): (1) supplementation with L-citrulline (3 × 5 g/d), the precursor of L-arginine which is the substrate of neuronal NO synthase (nNOS); and (2) treatment with the antidiabetic drug metformin (3 × 500 mg/d) which activates nNOS in human skeletal muscle. We also investigated the combined use of L-citrulline (3 × 5 g/d) and metformin (3 × 500 mg/d). Before and after treatment, we measured in serum and urine samples the concentration of amino acids and metabolites of L-arginine-related pathways and the oxidative stress biomarker malondialdehyde (MDA). Compared to healthy subjects, BMD patients have altered NOS, arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) pathways. Metformin treatment resulted in concentration decrease of arginine and MDA in serum, and of homoarginine (hArg) and guanidinoacetate (GAA) in serum and urine. L-Citrulline supplementation resulted in considerable increase of the concentrations of amino acids and creatinine in the serum, and in their urinary excretion rates. Combined use of metformin and L-citrulline attenuated the effects obtained from their single administrations. Metformin, L-citrulline or their combination did not alter serum nitrite and nitrate concentrations and their urinary excretion rates. In conclusion, metformin or L-citrulline supplementation to BMD patients results in remarkable antidromic changes of the AGAT and GAMT pathways. In combination, metformin and L-citrulline at the doses used in the present study seem to abolish the biochemical effects of the single drugs in slight favor of L-citrulline.
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Islet amyloid polypeptide response to maximal hyperglycemia and arginine is altered in impaired glucose tolerance and type 2 diabetes mellitus.
Guardado-Mendoza, R, Chávez, AO, Jiménez-Ceja, LM, Hansis-Diarte, A, DeFronzo, RA, Folli, F, Tripathy, D
Acta diabetologica. 2017;(1):53-61
Abstract
AIMS: Pancreatic islet amyloid deposition is a characteristic feature of type 2 diabetes mellitus (T2DM). Islet amyloid polypeptide (IAPP) is co-secreted with insulin, but its secretion profile and relationship to insulin and C-peptide in response to glucose and non-glucose stimuli has not been clearly defined. METHODS Forty subjects (13 NGT, 12 IGT and 15 T2DM) participated in an OGTT and two-step hyperglycemic (225 and 400 mg/dl) clamp (80 min/step) followed by an IV arginine bolus. Acute insulin (AIR), C-peptide (ACPR) and IAPP (AIAR) responses during each hyperglycemic step and following arginine (AIRArg) were assessed. RESULTS AIR and ACPR during both hyperglycemic steps and after arginine progressively decreased from NGT to IGT to T2DM. Fasting IAPP concentrations were higher in T2DM compared to NGT and IGT subjects. The acute IAPP0-10 was markedly decreased only in T2DM, while the acute IAPP80-90 response during the second step (80-160 min) of hyperglycemic clamp and in response to arginine was markedly impaired in both IGT and T2DM. The ratio of IAPP/C-peptide during the first (225 mg/dl) and second step (400 mg/dl), and in response to arginine, was decreased in T2DM versus both NGT and IGT (p < 0.01). The acute IAPP0-10 correlated with ACPR0-10 (r = 0.665, p < 0.001) and AIR0-10 (r = 0.543, p < 0.001). CONCLUSIONS Basal IAPP secretion is higher in T2DM and IGT versus NGT but is reduced in response to hyperglycemia and arginine. The IAPP/C-peptide ratio is reduced with prolonged and more severe hyperglycemia in T2DM individuals. CLINICAL TRIAL REGISTRATION NCT00845182.
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The efficacy of "Abound™," a nutritional supplement containing L-glutamine, L-arginine, citric acid, and calcium HMB, for skin disorders that developed as adverse drug reactions to anti-EGFR antibody preparation administration: pilot study.
Matsuhashi, N, Takahashi, T, Tanahashi, T, Matsui, S, Sasaki, Y, Tanaka, Y, Okumura, N, Yamaguchi, K, Osada, S, Yoshida, K
International journal of colorectal disease. 2016;(5):1055-1057
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The effect of arginine on oral biofilm communities.
Nascimento, MM, Browngardt, C, Xiaohui, X, Klepac-Ceraj, V, Paster, BJ, Burne, RA
Molecular oral microbiology. 2014;(1):45-54
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Abstract
Alkali production by oral bacteria via the arginine deiminase system (ADS) increases the pH of oral biofilms and reduces the risk for development of carious lesions. This study tested the hypothesis that increased availability of arginine in the oral environment through an exogenous source enhances the ADS activity levels in saliva and dental plaque. Saliva and supra-gingival plaque samples were collected from 19 caries-free (CF) individuals (DMFT = 0) and 19 caries-active (CA) individuals (DMFT ≥ 2) before and after treatment, which comprised the use of a fluoride-free toothpaste containing 1.5% arginine, or a regular fluoride-containing toothpaste twice daily for 4 weeks. ADS activity was measured by quantification of ammonia produced from arginine by oral samples at baseline, after washout period, 4 weeks of treatment, and 2 weeks post-treatment. Higher ADS activity levels were observed in plaque samples from CF compared to those of CA individuals (P = 0.048) at baseline. The use of the arginine toothpaste significantly increased ADS activity in plaque of CA individuals (P = 0.026). The plaque microbial profiles of CA treated with the arginine toothpaste showed a shift in bacterial composition to a healthier community, more similar to that of CF individuals. Thus, an anti-caries effect may be expected from arginine-containing formulations due in large part to the enhancement of ADS activity levels and potential favorable modification to the composition of the oral microbiome.
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Insulin-mediated activation of the L-arginine nitric oxide pathway in man, and its impairment in diabetes.
Rajapakse, NW, Chong, AL, Zhang, WZ, Kaye, DM
PloS one. 2013;(5):e61840
Abstract
AIMS/HYPOTHESIS Impaired L-arginine transport has been reported in cardiovascular diseases, providing a possible mechanism for reduced nitric oxide (NO) production. Given that cardiovascular diseases are also associated with insulin resistance, and insulin is known to induce vasodilation via a NO-dependent pathway, we hypothesised that abnormal insulin modulation of L-arginine transport may contribute to vascular dysfunction in diabetes. METHODS Forearm blood flow (FBF) responses to insulin and sodium nitroprusside (SNP) were measured in control and type 2 diabetic volunteers using venous occlusion plethysmography. Effects of intra-arterial insulin on the forearm veno-arterial flux of arginine and related amino acids were determined by HPLC. The effect of locally delivered insulin on arginine transport was assessed during an intra-arterial infusion of [4,5-(3)H] L-arginine. RESULTS In controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2±12.2 vs. 33.0±13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [(3)H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123±22 vs. 150±28 ml/min; p<0.05) but not in diabetics. CONCLUSION These findings suggest that insulin resistance may contribute substantially to the onset and development of cardiovascular disease in type 2 diabetics via abnormal insulin-mediated regulation of L-arginine transport.
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[Arginine and lysine as products of basic carboxypeptidase activity associated with fibrinolysis].
Zhloba, AA, Subbotina, TF, Lupan, DS, Bogova, VA, Kusheleva, OA
Biomeditsinskaia khimiia. 2013;(5):570-7
Abstract
Blood carboxypeptidases play an important role in the regulation of fibrinolysis. We have proposed here the method for the assay of blood carboxypeptidase activity associated with coagulation/fibrinolysis using the natural substrate fibrin and the detection of basic amino acids arginine and lysine as products in the conditions close to those in vivo. Plasma samples from 15 patients with arterial hypertension were investigated. The coagulation and subsequent fibrinolysis were initiated by addition of standard doses of thrombin and tissue plasminogen activator, respectively. Arginine and lysine concentrations before, during, and after completion of fibrinolysis were determined using HPLC. The parameters of fibrinolysis were evaluated by clot turbidity assay. Fibrinolysis led to a large and significant increase in concentrations of arginine and lysine in the incubation mixture by 101 and 81%, respectively. The duration of fibrinolysis initiation significantly correlated to the degree of increase of these amino acids: r(s) = -0.733 and -0.761 for arginine and lysine, respectively (p < 0.05). The rates of amino acids liberation during fibrinolysis demonstrate different pattern: arginine generation had two maximums: at the beginning of clot lysis and at his end, whereas the liberation of lysine occurred mainly at the middle of fibrinolysis. Thus, the carboxypeptidase activity associated with fibrinolysis can be considered as a local source of the essential aminoacids.
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Biosafety and antioxidant effects of a beverage containing silymarin and arginine. A pilot, human intervention cross-over trial.
Valentová, K, Vidlář, A, Zatloukalová, M, Stuchlík, M, Vacek, J, Šimánek, V, Ulrichová, J
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2013;:178-83
Abstract
The study objective was to investigate the potential of a beverage containing silymarin and L-arginine to alter basic physiological and urodynamic parameters in 22 normal healthy men aged 38-59 years. The volunteers drank 500 ml/day beverage without silymarin and L-arginine for 10 days followed, after a 7-day washout period, by the beverage with 400mg silymarin and 295 mg L-arginine for 10 days. Blood and urine samples were collected on days 0, 10 and 27. The beverages were well-tolerated with no adverse effects. Most of the biochemical, hematological and urodynamic parameters remained unchanged. Total antioxidant capacity, total level of antioxidants, lipoperoxidation products (malondialdehyde), advanced oxidation products of proteins in plasma and glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase levels in erythrocytes were not influenced. Serum γ-glutamyl transferase, malondialdehyde level and activity of glutathione S-transferase in erythrocytes were lowered at day 27 and the concentration of total plasma SH-groups was higher on day 10. Using an ex vivo system, we found that silymarin/silybin at 10-100 μM is able to adsorb onto human erythrocytes and the complexes displayed antioxidant properties as studied using ex situ square-wave voltammetry. The trial showed that silymarin in vivo may protect erythrocytes against oxidative damage.
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Clinical assessment of a supplement of Pycnogenol® and L-arginine in Japanese patients with mild to moderate erectile dysfunction.
Aoki, H, Nagao, J, Ueda, T, Strong, JM, Schonlau, F, Yu-Jing, S, Lu, Y, Horie, S
Phytotherapy research : PTR. 2012;(2):204-7
Abstract
A double-blind parallel group comparison design clinical study was conducted in Japanese patients with mild to moderate erectile dysfunction to investigate the efficacy of a supplement containing Pycnogenol® and L-arginine. Subjects were instructed to take a supplement (Pycnogenol® 60 mg/day, L-arginine 690 mg/day and aspartic acid 552 mg/day) or an identical placebo for 8 weeks, and the results were assessed using the five-item erectile domain (IIEF-5) of the International Index of Erectile Function. Additionally, blood biochemistry, urinalysis and salivary testosterone were measured. Eight weeks of supplement intake improved the total score of the IIEF-5. In particular, a marked improvement was observed in 'hardness of erection' and 'satisfaction with sexual intercourse'. A decrease in blood pressure, aspartate transaminase and γ-glutamyl transpeptidase (γ-GTP), and a slight increase in salivary testosterone were observed in the supplement group. No adverse reactions were observed during the study period. In conclusion, Pycnogenol® in combination with L-arginine as a dietary supplement is effective and safe in Japanese patients with mild to moderate erectile dysfunction.