A comparison effects of l-citrulline and l-arginine against cyclosporine-induced blood pressure and biochemical changes in the rats / Comparación de los efectos de L-citrulina y L-arginina frente a la presión arterial inducida por ciclosporina y los cambios bioquímicos en ratas

Objective: The use of cyclosporine A (CsA) is associated with different adverse effects including hypertension and nephrotoxicity. The present study aimed to compare the inhibitory effects of l-arginine & l-citrulline on CsA-induced blood pressure and biochemical changes in the serum of rats. Methods: Thirty-six rats were divided into 6 groups received daily: (1) 1ml distilled water, (2) 200mg/kg l-citrulline IP, (3) 25mg/kg CsA SC, (4) CsA+l-citrulline with the same dose of the former groups, (5) 200mg/kg l-arginine IP and (6) l-arginie+CsA with the same doses of group 4 for 7 days. Results: The changes in the blood pressure, heart rate, creatinine, BUN, glucose and C-reactive protein (CRP) of the serum were determined in the treated animals. Significant (p<0.001) increase was shown in the blood pressure and heart rate of CsA treated rats compared to the control group. There were also a significant (p<0.05) increase in the creatinine, BUN and glucose, but a decrease in the CRP value in the CsA-treated group. However, l-citrulline significantly (p<0.001) inhibited the changes in the blood pressure and heart rate in CsA-treated as well as it was able to reduce blood pressure in non-treated group significantly (p<0.01). l-citrulline also inhibited the increased levels of BUN and creatinine induced by CsA, while, l-arginine was able to prevent the increased blood pressure and creatinine occurs after administration of CsA. Conclusions: These findings suggest that the l-citrulline is more efficient than l-arginine against the adverse effects induced by cyclosporine. (AU)

Objetivo: El uso de ciclosporina A (CsA) está asociado a diferentes efectos adversos que incluyen hipertensión y nefrotoxicidad. El objetivo del presente estudio es comparar los efectos inhibitorios de L-arginina y L-citrulina en la presión arterial inducida por CsA, y los cambios bioquímicos a nivel sérico en ratas. Métodos: Se dividieron 36 ratas en 6 grupos, que recibieron diariamente: 1) 1ml de agua destilada, 2) 200mg/kg de L-citrulina IP, 3) 25mg/kg de CsA SC, 4) la misma dosificación que los grupos anteriores de CsA+L-citrulina, 5) 200mg/kg de L-arginina IP y 6) la misma dosificación que el grupo 4 durante 7 días de L-arginina+CsA. Resultados: Se determinaron los cambios de presión arterial, frecuencia cardiaca, creatinina, BUN, glucosa y proteína C reactiva (PCR) a nivel sérico, en los animales tratados. Se observó un incremento significativo (p<0,001) de presión arterial y frecuencia cardiaca en las ratas tratadas con CsA en comparación con el grupo control. También se produjo un incremento significativo (p<0,05) de los niveles de creatinina, BUN y glucosa, y una reducción del valor de PCR en el grupo tratado con CsA. Sin embargo, L-citrulina inhibió significativamente (p<0,001) los cambios de presión arterial y frecuencia cardiaca en las ratas tratadas con CsA, y también pudo reducir la presión arterial de manera considerable en el grupo no tratado (p<0,01). L-citrulina inhibió también los niveles incrementados de BUN y creatinina inducidos por CsA, y L-arginina fue capaz de impedir la incidencia del incremento de presión arterial y creatinina tras la administración de CsA. Conclusiones: Estos hallazgos sugieren que L-citrulina es más efectiva que L-arginina frente a los efectos adversos inducidos por ciclosporina. (AU)

Effect of citrulline on post-exercise rating of perceived exertion, muscle soreness, and blood lactate levels: A systematic review and meta-analysis.

BACKGROUND: Citrulline is one of the non-essential amino acids that is thought to improve exercise performance and reduce post-exercise muscle soreness. We conducted a systematic review and meta-analysis to determine the effect of citrulline supplements on the post-exercise rating of perceived exertion (RPE), muscle soreness, and blood lactate levels. METHODS: A random effects model was used to calculate the effect sizes due to the high variability in the study design and study populations of the articles included. A systematic search of PubMed, Web of Science, and ClinicalTrials.gov was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving healthy individuals and that investigated the acute effect of citrulline supplements on RPE, muscle soreness, and blood lactate levels. The supplementation time frame was limited to 2 h before exercise. The types and number of participants, types of exercise tests performed, supplementation protocols for L-citrulline or citrulline malate, and primary (RPE and muscle soreness) and secondary (blood lactate level) study outcomes were extracted from the identified studies. RESULTS: The analysis included 13 eligible articles including a total of 206 participants. The most frequent dosage used in the studies was 8 g of citrulline malate. Citrulline supplementation significantly reduced RPE (n = 7, p = 0.03) and muscle soreness 24-h and 48-h after post-exercise (n = 7, p = 0.04; n = 6, p = 0.25, respectively). However, citrulline supplementation did not significantly reduce muscle soreness 72-h post-exercise (n = 4, p = 0.62) or lower blood lactate levels (n = 8, p = 0.17). CONCLUSION: Citrulline supplements significantly reduced post-exercise RPE and muscle soreness without affecting blood lactate levels.

Prevention of vaginal dryness in perimenopausal women. Supplementation with Lady Prelox®.

BACKGROUND: The aim of this pilot registry study was to use a standardized supplement (Lady Prelox®, Horphag Research) - including Pycnogenol®, l-arginine, L-citrulline and rose hip extract - to improve signs and symptoms associated with vaginal dryness in pre and post-menopausal healthy women. A group of women used only a standard management (SM) and a second group added Lady Prelox®. METHODS: Four groups of women were included in the study. 34 pre-menopausal and 38 post-menopausal women took Lady Prelox®, four tablets daily for 8 weeks and 33 pre-menopausal women and 35 post-menopausal women served as controls. RESULTS: No safety problems were observed with the supplement that was well tolerated. The subgroups of controls and supplemented subjects were comparable in both the pre- and post-menopausal groups. Among pre-menopausal women, results of the female sexual function index (FSFI) were significantly improved with the supplement in comparison with the control subjects' group (P<0.05). The results of the FSFI questionnaire for post-menopausal women indicated a significant improvement at 8 weeks with Lady Prelox® (P<0.05) in comparison with controls. Preclinical items (vaginal dryness, pain/discomfort during intercourse, mucus, minimal infections, presence of candida and oxidative stress) were significantly improved (P<0.05) with Lady Prelox®) in comparison to minimal changes with the SM group. These measurements included all women. CONCLUSIONS: The effects of the supplementation with Lady Prelox® on vaginal dryness were significant. The supplement was well accepted and revealed no side effects or tolerability problems. Further studies are evaluating the effects of Lady Prelox® on other aspects of the menopausal transition that may alter the quality of life of most women in advanced age. A gentle approach with suitable dietary supplementation, represents a promising option for addressing common challenges that women experience in such conditions.

l-Citrulline Supplementation: Impact on Cardiometabolic Health.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Citrulline Malate Does Not Improve Muscle Recovery after Resistance Exercise in Untrained Young Adult Men.

The effects of citrulline malate (CM) on muscle recovery from resistance exercise remains unknown. We aimed to determine if citrulline malate supplementation improves muscle recovery after a single session of high-intensity resistance exercise (RE) in untrained young adult men. Nine young adult men (24.0 ± 3.3 years) participated in a double-blind crossover study in which they received 6 g of CM and placebo (PL) on two occasions, separated by a seven-day washout period. Each occasion consisted of a single session of high-intensity RE (0 h) and three subsequent fatigue tests sessions (at 24, 48, and 72 h) to assess the time course of muscle recovery. During the tests sessions, we assessed the following variables: number of maximum repetitions, electromyographic signal (i.e., root mean square (RMS) and median frequency (MF)), muscle soreness and perceived exertion, as well as blood levels of creatine kinase (CK), lactate, insulin, and testosterone:cortisol ratio. CK levels increased at 24 h post-exercise and remained elevate at 48 and 72 h, with no difference between CM and PL conditions. Muscle soreness increased at 24 h post-exercise, which progressively returned to baseline at 72 h in both conditions. Lactate levels increased immediately post-exercise and remained elevated at 24, 48, and 72 h in both conditions. No significant treatment × time interaction was found for all dependents variables (maximum repetitions, perceived exertion, CK, lactate, RMS, MF, and testosterone:cortisol ratio) during the recovery period. In conclusion, our data indicate that CM supplementation (single 6 g dose pre-workout) does not improve the muscle recovery process following a high-intensity RE session in untrained young adult men.

Neonatal Citrulline Supplementation and Later Exposure to a High Fructose Diet in Rats Born with a Low Birth Weight: A Preliminary Report.

A low birth weight (LBW) leads to a higher risk of metabolic syndrome in adulthood. Literature suggests that citrulline supplementation in adulthood prevents the effect of a high fructose diet on energy metabolism. Whether neonatal citrulline supplementation would alter early growth or energy metabolism in the long-term in rats with LBW is unknown. LBW pups born from dams fed a low (4%) protein diet, were nursed by normally-fed dams and received isonitrogenous supplements of either l-citrulline or l-alanine by gavage from the sixth day of life until weaning, and were subsequently exposed to 10%-fructose in drinking water from weaning to 90 days of age. The oral glucose tolerance was tested (OGTT) at 70 days of age, and rats were sacrificed at 90 days of age. Pre-weaning citrulline supplementation failed to alter the growth trajectory, OGTT, plasma triglycerides, or fat mass accretion in adulthood; yet, it was associated with increased liver triglycerides, decreased liver total cholesterol, and a distinct liver lipidomic profile that may result in a predisposition to liver disease. We conclude that pre-weaning supplementation with citrulline does not impact early growth, but might impact liver fat metabolism in adulthood upon exposure to a high fructose diet.

Treatment with L-citrulline in patients with post-polio syndrome: study protocol for a single-center, randomised, placebo-controlled, double-blind trial.

BACKGROUND: Post-polio syndrome (PPS) is a condition that affects polio survivors years after recovery from an initial acute infection by the Poliomyelitis virus. Most often, patients who suffered from polio start to experience gradual new weakening in muscles, a gradual decrease in the size of muscles (muscle atrophy) and fatigue years after the acute illness. L-citrulline is known to change muscular metabolism synthesis by raising nitric oxide (NO) levels and increasing protein synthesis. This investigator-initiated, randomised, placebo-controlled, double-blind, trial aims to demonstrate that L-citrulline positively influences muscle function and increases muscular energy production in patients with PPS. METHODS/DESIGN: Thirty ambulant PPS patients will be recruited in Switzerland. Patients will be randomly allocated to one of the two arms of the study (placebo:verum 1:1). After a 24-week run-in phase to observe natural disease history and progression, participants will be treated either with L-citrulline or placebo for 24 weeks. The primary endpoint is change in the 6-min Walking Distance Test. Secondary endpoints will include motor function measure, quantitative muscle force, quantitative muscle magnetic resonance imaging and magnetic resonance spectroscopy and serum biomarker laboratory analysis DISCUSSION: The aim of this phase IIa trial is to determine if treatment with L-citrulline shows a positive effect on clinical function and paraclinical biomarkers in PPS. If treatment with L-citrulline shows positive effects, this might represent a cost-efficient symptomatic therapy for PPS patients. TRIAL REGISTRATION: ClinicalTrial.gov, ID: NCT02801071 . Registered on 6 June 2016.

Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained females.

PURPOSE: Citrulline malate (CM) is a nonessential amino acid that increases exercise performance in males. However, based on physiological differences between genders, these results cannot be extrapolated to females. Therefore, the purpose of this investigation was to evaluate effects of acute CM supplementation on upper- and lower-body weightlifting performance in resistance-trained females. METHODS: Fifteen females (23 ± 3 years) completed two randomized, double-blind trials consuming either CM (8 g dextrose + 8 g CM) or a placebo (8 g dextrose). One hour after supplement consumption, participants performed six sets each of upper- (i.e., bench press) and lower-body (i.e., leg press) exercises to failure at 80 % of previously established one-repetition maximum. Immediately after each set, repetitions completed, heart rate and rating of perceived exertion (RPE) were recorded. RESULTS: Repeated-measures analysis of variance indicated that subjects completed significantly (p = .045) more repetitions throughout upper-body exercise when consuming CM versus placebo (34.1 ± 5.7 vs. 32.9 ± 6.0, respectively). When consuming CM, similar significant (p = .03) improvements in total repetitions completed were observed for lower-body exercise (66.7 ± 30.5 vs. 55.13 ± 20.64, respectively). Overall RPE score was significantly lower (p = .02) in upper-body exercise when subjects consumed CM versus placebo (7.9 ± 0.3 and 8.6 ± 0.2, respectively). The supplement consumed exhibited no significant effects on heart rate at any time point. CONCLUSIONS: Acute CM supplementation in females increased upper- and lower-body resistance exercise performance and decreased RPE during upper-body exercise. These data indicate that athletes competing in sports with muscular endurance-based requirements may potentially improve performance by acutely supplementing CM.

The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline.

The increasing consumption of amino acids from a wide variety of sources, including dietary supplements, natural health products, medical foods, infant formulas, athletic and work-out products, herbal medicines, and other national and international categories of nutritional and functional food products, increases the exposure to amino acids to amounts far beyond those normally obtained from the diet, thereby necessitating appropriate and robust safety assessments of these ingredients. Safety assessments of amino acids, similar to all food constituents, largely rely on the establishment of an upper limit [Tolerable Upper Intake Level (UL)] considered to be a guide for avoiding high intake, above which adverse or toxic effects might occur. However, reliable ULs have been difficult or impossible to define for amino acids because of inadequate toxicity studies in animals and scarce or missing clinical data, as well as a paucity or absence of adverse event reporting data. This review examines 2 amino acids that have been associated with in-market adverse events to show how quality specifications might have helped prevent the adverse clinical outcomes. We further highlight the importance of various factors that should be incorporated into an overall safety assessment of these and other amino acids. In addition to the traditional reliance on the established UL, well-defined quality specifications, review of synthesis and production strategies, potential interactions with drugs, contraindications with certain disease states, and cautionary use within certain age groups should all be taken into consideration.

Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests. METHODS/DESIGN: A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L-citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age-matched male children. DISCUSSION: The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and metformin is more effective than placebo in preventing loss of motor function and muscle degeneration in DMD. The MFM D1 subscore is used as a clinical outcome measure and a quantitative muscle MRI assessment as the surrogate outcome measure of fatty muscle degeneration. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01995032 . Registered on 20 November 2013.

Acute ingestion of citrulline stimulates nitric oxide synthesis but does not increase blood flow in healthy young and older adults with heart failure.

To determine if age-associated vascular dysfunction in older adults with heart failure (HF) is due to insufficient synthesis of nitric oxide (NO), we performed two separate studies: 1) a kinetic study with a stable isotope tracer method to determine in vivo kinetics of NO metabolism, and 2) a vascular function study using a plethysmography method to determine reactive hyperemic forearm blood flow (RH-FBF) in older and young adults in the fasted state and in response to citrulline ingestion. In the fasted state, NO synthesis (per kg body wt) was ∼ 50% lower in older vs. young adults and was related to a decreased rate of appearance of the NO precursor arginine. Citrulline ingestion (3 g) stimulated de novo arginine synthesis in both older [6.88 ± 0.83 to 35.40 ± 4.90 µmol · kg body wt(-1) · h(-1)] and to a greater extent in young adults (12.02 ± 1.01 to 66.26 ± 4.79 µmol · kg body wt(-1) · h(-1)). NO synthesis rate increased correspondingly in older (0.17 ± 0.01 to 2.12 ± 0.36 µmol · kg body wt(-1) · h(-1)) and to a greater extent in young adults (0.36 ± 0.04 to 3.57 ± 0.47 µmol · kg body wt(-1) · h(-1)). Consistent with the kinetic data, RH-FBF in the fasted state was ∼ 40% reduced in older vs. young adults. However, citrulline ingestion (10 g) failed to increase RH-FBF in either older or young adults. In conclusion, citrulline ingestion improved impaired NO synthesis in older HF adults but not RH-FBF, suggesting that factors other than NO synthesis play a role in the impaired RH-FBF in older HF adults, and/or it may require a longer duration of supplementation to be effective in improving RH-FBF.

Lady Prelox® improves sexual function in generally healthy women of reproductive age.

AIM: This supplement study evaluates the Female Sexual Function Index (FSFI) of 100 healthy women (37 to 45 years) with moderate sexual dysfunction who underwent a management program of lifestyle, diet, exercise, and stress control. In association with the management program a group of these women also used the supplement Lady Prelox® in tablets (20 mg Pycnogenol® pine bark extract, 200 mg L-arginine, 200 mg L-citrulline and 50 mg Rosvita® rose hip extract) for eight weeks. METHODS: One group of women was supplemented with Lady Prelox® for 8 weeks. The nine-item FSFI questionnaire was used for evaluation of women's sexual function at inclusion (baseline), after four weeks, and after eight weeks of management and supplementation. Variation in oxidative stress was also evaluated by measuring plasma free radicals. RESULTS: Following supplementation with Lady Prelox® the mean total FSFI scores increased from 14.96±2.68 to 28.25±2.35 after four weeks and 33.91±2.7 after eight weeks. Treatment values were significantly higher than in controls (who used only the management plan) with baseline values of 17.92±2.32 and scores of 23.45±1.82 after four weeks and to 23.52±2.20 after eight weeks. Women in the Lady Prelox® group had an initial value of plasma free radicals (PFR) of 398±29 Carr units: this value decreased to 344:28 at 4 weeks (P<0.05) and 332:31 at 8 weeks (P<0.05). Lower changes were observed in controls with an initial value of 389±33, decreasing to 377±32 (P<0.05) at 4 weeks and to 365; 33 (P<0.05) at 8 weeks (value significantly higher in controls not using Lady Prelox®). The supplementation was well tolerated; no unwanted effects occurred and no women had to stop the supplementation. CONCLUSION: The study suggests that supplementation with Lady Prelox significantly improves sexual function across all domains evaluated by the FSFI in healthy women of late reproductive age. The improvement in FSFI is also associated with a significant decrease in oxidative stress.

Citrulline: pharmacological perspectives and its role as an emerging biomarker in future.

L-Citrulline is a naturally occurring non-essential amino acid, an intermediate in urea cycle and conditionally essential in intestinal pathology. It is a potent hydroxyl radical scavenger and much more effective precursor of arginine and nitric oxide (NO) than arginine itself so exploited in therapeutics. Plasma citrulline concentration is used by clinicians to assess functional enterocyte mass in various chronic and acute small bowel pathologies like short bowel syndrome that has become an indication in clinical practice. Its supplementation is likely to be used in conditions like erectile dysfunction, sickle cell anemia, short bowel syndrome (to restore nitrogen balance), hyperlipidemia, cancer chemotherapy, hypercholestremia, in hyperoxic lung damage, urea cycle disorders, Alzheimers disease, multi-infarct dementia and as an immunomodulator. Its emerging role as a biomarker in intestinal pathology and early diagnosis of Rheumatoid arthritis has spread considerable interest. Antibody detection to Anti-cyclic citrullinated peptide (ACCP) antibodies can be recommended for early detection of RA decreasing joint damage and deformity, because these are detected well before the onset of disease manifestations of RA. The test is highly specific than RF (Rheumatoid factor), with moderate sensitivity, but much useful in differentiating RA from other disorders. Further studies and exploration is required in these areas.

Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension may complicate surgical correction of congenital heart defects, resulting in increased morbidity and mortality. We have previously shown that plasma levels of the nitric oxide precursors citrulline and arginine drop precipitously after congenital cardiac surgery and that oral citrulline supplementation may be protective against the development of pulmonary hypertension. In this study, we assessed the safety and pharmacokinetic profile of intravenous citrulline as a potential therapy for postoperative pulmonary hypertension. METHODS: The initial phase of this investigation was a dose-escalation study of intravenously administered citrulline in infants and children undergoing one of five congenital cardiac surgical procedures (phase 1). The primary safety outcome was a 20% drop in mean arterial blood pressure from the baseline pressure recorded after admission to the intensive care unit. Based on our previous work, the target circulating plasma citrulline trough was 80 to 100 micromol/L. Each patient was given two separate doses of citrulline: the first in the operating room immediately after initiation of cardiopulmonary bypass and the second 4 hours later in the pediatric intensive care unit. Stepwise dose escalations included 50 mg/kg, 100 mg/kg, and 150 mg/kg. After model-dependent pharmacokinetic analysis, we enrolled an additional 9 patients (phase 2) in an optimized dosing protocol that replaced the postoperative dose with a continuous infusion of citrulline at 9 mg/(kg.h) for 48 hours postoperatively. RESULTS: The initial stepwise escalation protocol (phase 1) revealed that an intravenous citrulline dose of 150 mg/kg given after initiation of cardiopulmonary bypass yielded a trough level of in the target range of approximately 80 to 100 micromol/L 4 hours later. The postoperative dose revealed that the clearance of intravenously administered citrulline was 0.6 L/(h.kg), with a volume of distribution of 0.9 L/kg and estimated half-life of 60 minutes. Because of the short half-life, we altered the protocol to replace the postoperative dose with a continuous infusion of 9 mg/(kg.h). An additional 9 patients were studied with this continuous infusion protocol (phase 2). Mean plasma citrulline levels were maintained at approximately 125 mumol/L, with a calculated clearance of 0.52 L/(h.kg). None of the 17 patients studied had a 20% drop in mean arterial blood pressure from baseline. CONCLUSIONS: In this first report of the use of intravenous citrulline in humans, we found citrulline to be both safe and well tolerated in infants and young children undergoing congenital cardiac surgery. Because of the rapid clearance, the optimal dosing regimen was identified as an initial bolus of 150 mg/kg given at the initiation of cardiopulmonary bypass, followed 4 hours later by a postoperative infusion of 9 mg/(kg.h) continued up to 48 hours. Using this regimen, plasma arginine, citrulline, and nitric oxide metabolite levels were well maintained. Intravenous citrulline needs to be studied further as a potential therapy for postoperative pulmonary hypertension.

Adverse gastrointestinal effects of arginine and related amino acids.

Oral supplements of arginine and citrulline increase local nitric oxide (NO) production in the small intestine and this may be harmful under certain circumstances. Gastrointestinal toxicity was therefore reviewed with respect to the intestinal physiology of arginine, citrulline, ornithine, and cystine (which shares the same transporter) and the many clinical trials of supplements of the dibasic amino acids or N-acetylcysteine (NAC). The human intestinal dibasic amino acid transport system has high affinity and low capacity. L-arginine (but not lysine, ornithine, or D-arginine) induces water and electrolyte secretion that is mediated by NO, which acts as an absorbagogue at low levels and as a secretagogue at high levels. The action of many laxatives is NO mediated and there are reports of diarrhea following oral administration of arginine or ornithine. The clinical data cover a wide span of arginine intakes from 3 g/d to>100 g/d, but the standard of reporting adverse effects (e.g. nausea, vomiting, and diarrhea) was variable. Single doses of 3-6 g rarely provoked side effects and healthy athletes appeared to be more susceptible than diabetic patients to gastrointestinal symptoms at individual doses>9 g. This may relate to an effect of disease on gastrointestinal motility and pharmacokinetics. Most side effects of arginine and NAC occurred at single doses of >9 g in adults (>140 mg/kg) often when part of a daily regime of approximately>30 g/d (>174 mmol/d). In the case of arginine, this compares with the laxative threshold of the nonabsorbed disaccharide alcohol, lactitol (74 g or 194 mmol). Adverse effects seemed dependent on the dosage regime and disappeared if divided doses were ingested (unlike lactitol). Large single doses of poorly absorbed amino acids seem to provoke diarrhea. More research is needed to refine dosage strategies that reduce this phenomenon. It is suggested that dipeptide forms of arginine may meet this criterion.

Anticuerpos anticitrulina en la artritis reumatoide / Antibodies to citrullinated peptides in rheumathoid arthritis

La artitris reumatoide es una enfermedad autoinmune caracterizada por la inflamación de las articulaciones sinoviales produciendo destrucción articular. En el suero de estos pacientes pueden aparecer muchos autoanticuerpos, sobre todo el factor reumatoide, que está incluido dentro de los criterios de clasificación de la enfermedad del American College of Rheumatology (ACR), a pesar de que tiene sólo un especificidad moderada para la enfermedad. Los anticuerpos antipéptidos citrulinados han proporcionado al clínico una prueba de gran ayuda para el diagnóstico precoz. Se ha demostrado que pueden preceder en años al comienzo de la enfermedad y son útiles para el diagnóstico y el pronóstico, debido a su buena sensibilidad y especificidad y su relación con el daño estructural. La respuesta inmunológica frente a antígenos citrulinados define un subtipo de artritis reumatoide inmunogenéticamente característico, en el que se ha podido establecer una relación entre factores ambientales y genéticos, y en el que la reacción inmunológica es una parte fundamental de la patogenia de la enfermedad. Se propone una teoría que relaciona su producción con el desarrollo de la inflamación sinovial crónica

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of the synovial joints leading to progressive joint destruction. The serum of these patients contains a large repertoire of autoantibodies, mainly rheumatoid factor, which is part of the ACR classification criteria in spite of having only moderate specificity. Antibodies directed to citrullinated proteins provide clinicians with a valuable tool for early diagnosis. It has been shown that these antibodies can be detected years before presentation of the first symptom and are very useful for diagnosis and prognosis, due to good sensitivity and specificity and prediction of development of erosive disease. The immune response against citrullinated antigens is characteristic of an immuno-genetic subtype of disease, in which the combined role of genes, environmental factors and autoimmunity has become the prime suspected for disease pathogenesis. A model is proposed of how these antibodies are produced and lead to chronic synovial inflammation

Elevated plasma citrulline and arginine due to consumption of Citrullus vulgaris (watermelon).

A 19-month-old girl with developmental delay was found to have moderately elevated plasma citrulline and mildly elevated plasma arginine concentrations. Dietary history revealed that she consumed large quantities of watermelon (Citrullus vulgaris), a fruit containing high free citrulline and arginine concentrations. In order to determine whether the patient's high watermelon intake could account for her elevated plasma citrulline and arginine concentrations, we studied the response of plasma citrulline and arginine to ingestion of watermelon in six healthy adult volunteers. All developed markedly elevated plasma citrulline (mean maximum 593 micromol/L, range 386-1069) and moderately elevated plasma arginine (mean maximum 199 micromol/L, range 128-251). Physicians and laboratory personnel performing metabolic investigations should be aware of watermelon-induced citrullinaemia. Its hallmarks are elevated plasma citrulline, and to a lesser extent arginine, in the absence of orotic or arginosuccinic aciduria or hyperammonaemia. This phenomenon has implications for the management of patients with urea cycle and related disorders.

[Nitrullin -- a new original Russian drug of the nitrosomethylurea group]. / Nitrullin -- novyi original'nyi otechestvennyi preparat iz gruppy nitrozomocheviny.

Hematologic thrombopenia and leukopenia formation limits use of nitrullin as a toxic hazard. The drug showed moderate effect in treating inoperable non-small cell cancer of the lung and satisfactory end results. The treatment had marked symptomatic effect in patients with this cancer and, as a consequence, improved the quality of life. Nutrullin had immuno-modulating effect. Its application alone or in combination with VPN showed good results in the management of small-cell cancer of the lung.

A highly sensitive high-performance liquid chromatography-- fluorometric method for the assay of peptidylarginine deiminase activity.

The activity of peptidylarginine deiminase (PAD) has generally been assayed by a colorimetric method using N-benzoyl-L-arginine ethyl ester (BAEE) and N-benzoyl-L-arginine (Bz-L-Arg) as the substrates. The widespread occurrence of citrulline and urea in tissues makes use of this method difficult, especially for small samples. We developed a highly sensitive high-performance liquid chromatography method with N-dansyl-glycyl-L-arginine as the substrate. This method was sensitive enough to determine previously undetectable activity of PAD in HL-60 cells. Two types of PAD (HL-60 cell and brain PAD) could be distinguished by differential competition, using either BAEE or Bz-L-Arg as a preferential substrate in the assay. These data indicate that the present method is applicable to many tissues.