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L-arginine

Common Name(s): Arginine, L-arginine

Clinical Overview

Use

L-arginine is classified as a nonessential amino acid, but it may be considered essential or semiessential under conditions of stress, during which L-arginine synthesis becomes compromised. L-arginine has been evaluated for use in cardiovascular disease because of its antiatherogenic, anti-ischemic, antiplatelet, and antithrombotic properties, and for use in renal disease, diabetes, cystic fibrosis, sickle cell disease, and erectile dysfunction. Its immunostimulatory effects and potential benefits in ophthalmic conditions and preeclampsia have also been evaluated.

Dosing

L-arginine has been studied for a variety of conditions using various dosages and treatment durations; current daily dosage trends range from 6 to 30 g orally in 3 divided doses. Oral and intravenous (IV) formulations have been the most commonly studied.

Contraindications

Contraindications have not been identified. However, L-arginine is not recommended following acute myocardial infarction.

Pregnancy/Lactation

L-arginine supplementation has shown beneficial effects in women with hypertension and in those at risk for preeclampsia. However, due to minimal data regarding safety and efficacy in pregnancy and lactation, L-arginine should only be used in these populations if recommended by and under the supervision of a health care provider.

Interactions

Nitrates: Caution is warranted in patients concomitantly using L-arginine supplementation and nitrates. L-arginine may potentiate the effects of isosorbide mononitrate and other nitric oxide donors, such as glyceryl trinitrate (ie, nitroglycerin) and sodium nitroprusside. Insulin: Caution is warranted in patients using insulin concomitantly with L-arginine; effects on insulin are unpredictable. Cholesterol-lowering drugs: Caution is warranted in patients using cholesterol-lowering drugs concomitantly with L-arginine; effects on cholesterol-lowering drugs are unpredictable.

Adverse Reactions

Nausea, diarrhea, dyspepsia, palpitations, headache, and numbness have been reported with L-arginine use. Bitter taste may occur with higher doses. Because of L-arginine's vasodilatory effects, hypotension may occur. IV preparations containing L-arginine hydrochloride have a high chloride content that may increase the risk for metabolic acidosis in patients with electrolyte imbalances. Hyperkalemia and elevations in serum urea nitrogen (BUN) levels may occur in patients with renal and/or hepatic impairment.

Toxicology

High concentrations of nitric oxide are considered toxic to brain tissue.

Source

Approximately 80% of arginine comes from dietary intake of proteins and body protein breakdown. The remaining arginine comes from endogenous de novo production in the kidneys.Morris 2017 Sources of amino acid arginine are meats (eg, seafood, pork), milk and milk products, chocolate, watermelon, legumes (eg, soybeans, chickpeas), oats and wheats, and nuts (eg, peanuts, walnuts).McNeal 2016 The physiologically active form, L-arginine, is the natural product obtained by enzymatic or chemical hydrolysis of proteins. In the laboratory, arginine can be precipitated from gelatin hydrolysate. L-arginine can also be synthesized from L-ornithine and cyanamide in an aqueous solution in the presence of barium hydroxide.Budavari 1989 Because L-arginine can be synthesized endogenously from L-citrulline, it is classified as a nonessential amino acid in adults. However, in children and in individuals with certain conditions (eg, infection, trauma), L-arginine synthesis may become compromised, in which case L-arginine may be considered semiessential.Morris 2017, Schwedhelm 2008

History

L-arginine is commonly sold as a health supplement, with claims of benefit in various cardiovascular diseasesCheng 2001 and erectile dysfunction.Cumpanas 2009, Gentile 2009 In the 1800s, L-arginine was first isolated from animal horn as the stereoisomer of arginine.Cheng 2001

Chemistry

L-arginine (C6H14N4O2,), or 2-amino-5-guanidino-pentanoic acid, is a conditionally essential acid in mammals that is physiologically active in the L-form.Calabro 2014, NIH 2018 It is synthesized from glutamine, glutamate, and proline in the intestinal-renal axis in humans.Morris 2017, Wu 2009 Part of the side chain closest to the backbone is long and hydrophobic, and the end of the side chain is a complex guanidinium group. It is slightly soluble in ethanol and insoluble in ethyl ether. It is strongly alkaline and has a pKa of 2.24.NIH 2018

Uses and Pharmacology

L-arginine is classified as a nonessential amino acid but may be considered essential or semiessential under conditions of stress when the capacity of endogenous arginine synthesis is exceeded, including during periods of growth (ie, childhood, pregnancy) or trauma (eg, liver disease, severe sepsis, wound healing, cancer).Morris 2017, Rodríguez 2008, Wu 2009 Normal serum levels of L-arginine range from 50 to 150 mcM.Rodríguez 2008 Because most arginine in the typical American diet is obtained from meat and fish, which provide about 5.5 g daily, vegetarians may be at risk for arginine deficiency.Cheng 2001 L-arginine's suggested metabolic and physiologic roles in the body include the following: building block of proteins; precursor of nitric oxide; induction of vasodilation; synthesis of creatine; reduction in xanthine oxidase activity; induction of bone and tendon formation and skin epithelization; simulation of energy metabolism through maintenance of adenosine triphosphate levels; simulation of the release of growth hormone and prolactin; simulation of insulin synthesis and secretion; improvement in immune defense function; neuroprotective effects; reduction in growth of tumors; improvement in kidney function; reduction in platelet aggregation; improvement in sperm motility and production; and prevention of leukocyte adhesion to the vascular endothelium and leukocyte migration into the vascular wall.Hristina 2014 L-arginine also plays an important role in the detoxification of ammonia from the body.Calabrò 2014

Nitric oxide is produced by a variety of animal and human cells and is involved in many physiological and pathophysiological processes.Luiking 2010 L-arginine is a substrate for 4 enzymes: nitric oxide synthases, arginases, arginine glycine amidinotransferase, and L-arginine decarboxylase.Rodríguez 2008 Nitric oxide, along with L-citrulline, is generated from L-arginine metabolism by the nitric oxide synthase enzymes.Rodríguez 2008, Schwedhelm 2008 Arginases metabolize L-arginine to L-ornithine and urea.Morris 2017, Rodríguez 2008 Following oral administration, L-arginine undergoes presystemic (ie, via GI flora) and systemic (ie, via gut and liver arginases) elimination.Schwedhelm 2008

Most studies affirm stereospecificity of nitric oxide synthase for L-arginine, but trial results in steroid-naive patients with asthma show concentrations of exhaled nitric oxide to be similar for patients administered either L- or D-arginine, suggesting an alternative mechanism of action.Chambers 2001

L-arginine is a vital amino acid required for the survival of certain parasites, such as Leishmania spp., the causative agent of leishmaniasis.Wanasen 2008

Cardiovascular effects

L-arginine may have beneficial effects on cardiovascular health through its antiatherogenic, anti-ischemic, antiplatelet, and antithrombotic properties.Cheng 2001

Animal and in vitro data

Increased concentrations of L-arginine may improve vascular disease by maintaining nitric oxide levels.Wascher 1996 Nitric oxide had a direct scavenging effect on superoxide radicals, inhibited platelet adhesion and aggregation, and modulated endothelial permeability.Brandes 2000, Wascher 1997 In human microvascular endothelial cells, nitric oxide regulated tissue factor, reducing endotoxin and cytokine-induced expression.Yang 2000

Clinical data

In a randomized clinical trial designed to evaluate the effect of oral L-arginine 9 g/day supplementation for 6 months following an acute ST-segment elevation myocardial infarction, no significant change in vascular stiffness or left ejection fraction was observed. However, 8.6% of patients in the L-arginine group died, while no deaths occurred in the control group (P=0.01), and the trial was terminated. Researchers concluded that L-arginine should not be given to patients following an acute myocardial infarction and suggested that diffuse atherosclerosis in older patients may worsen clinical outcome.Schulman 2006

In a small study of patients with native coronary artery disease, intramural administration of L-arginine (6 mL of 100 mg/mL) significantly reduced the neointimal volume compared with saline (25 mm3 vs 39 mm3; P=0.049) following stent deployment. At the 6-month follow-up, patients who received L-arginine had a significantly less neointimal volume percentage compared with those receiving saline (17% [±13%] vs 27% [±21%]; P=0.048), suggesting that L-arginine may be a viable option for the prevention of restenosis.Suzuki 2002

In patients with 1- or 2-vessel coronary artery disease, L-arginine 150 mcmol/min given via intracoronary infusion increased poststenotic coronary flow while having no effect on nondiseased vessels. Additionally, use of angiotensin-converting enzyme inhibitors and an optimized lipid profile were associated with a positive response to L-arginine treatment.Lauer 2008

In another clinical trial, oral L-arginine therapy was ineffective in improving nitric oxide bioavailability in patients with coronary artery disease.Blum 2000 Patients with angina have shown improved exercise tolerance after L-arginine supplementation.Ceremuzyński 1997 In one study, 18 patients with chronic limb ischemia due to advanced peripheral arterial disease who underwent implantation of autologous bone marrow cells and received antioxidants and L-arginine daily for 6 weeks experienced improvements in ankle brachial index at 3 and 12 months posttreatment. There was also an improvement in ischemic ulcers in 13 of the 18 patients; although 2 patients required amputation of the ischemic limb, mean maximum walking distance significantly increased at 3 months and was sustained up to 18 months.Napoli 2008

In a case report, a 41-year-old woman with a 35-year history of type 1 diabetes and exertional angina pectoris was diagnosed with microvascular angina and started on L-arginine supplementation with 2 dietary bars a day, each containing L-arginine 3.3 g. The patient reported that her angina episodes disappeared and her exercise capacity increased. However, after 8 weeks of therapy, L-arginine supplementation was replaced with atorvastatin 40 mg daily because of availability issues with the supplement. The patient's angina episodes reemerged within 1 week, and her exercise capacity worsened after 8 weeks. She was restarted on the L-arginine supplement, with a subsequent disappearance of angina symptoms, which suggests that L-arginine supplementation may warrant further study as a potential treatment option for diabetes mellitus patients with microvascular angina.Schwartz 2003

In a study of patients with coronary artery disease, angina pectoris functional class IV, and previous revascularization who were receiving maximum medical therapy, L-arginine 9 g/day orally for 3 months improved angina pectoris functional class (from IV to II) in 7 of 10 patients. Upon discontinuation of L-arginine, symptoms deteriorated back to functional class IV.Blum 1999

Patients who underwent coronary artery bypass grafting were randomized in a 2×2 factorial model to receive either ten 200 mcg injections of vascular endothelial growth factor (VEGF)-165 plasmid DNA or placebo in the anterior myocardium, plus oral L-arginine 6 g/day or placebo for 3 months. Combination therapy with VEGF-165 and L-arginine was associated with improved anterior wall perfusion at 3 months compared with baseline.Ruel 2008

In a study evaluating improvement in coronary endothelial function following L-arginine supplementation based on race, an intracoronary infusion of L-arginine (3,200 mcmol over 10 minutes) augmented endothelium-dependent vascular relaxation (defined as peak coronary blood flow) to a greater extent in black patients without coronary artery disease compared with matched white subjects, suggesting that L-arginine supplementation may offer cardiovascular benefits in certain populations.Houghton 2002

Supplementation of L-arginine 700 mg orally 4 times daily prevented nitrate tolerance when transdermal nitroglycerin was given continuously. Treadmill walking time increased 4 hours and 24 hours after nitroglycerin patch application and was significantly greater than time with placebo (P<0.05).Parker 2002

The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) prospective, single-center, randomized, double-blind, placebo-controlled study funded by the National Heart, Lung, and Blood Institute is the largest study to date assessing the effects of L-arginine on functional capacity in patients with peripheral artery disease. One hundred thirty-three patients with intermittent claudication were randomized to receive L-arginine 3 g/day orally or placebo for 6 months. Plasma L-arginine levels significantly increased among those receiving supplementation. Although absolute claudication distance improved in those receiving long-term L-arginine (mean improvement, 11.5%), the improvement was significantly less than in those receiving placebo (28.3%; P=0.024), suggesting an adverse effect with prolonged treatment. This may be attributable to a derangement in the nitric oxide synthase pathway caused by arginine, with a paradoxical reduction in nitric oxide production.Wilson 2007

L-arginine has demonstrated improvement in cardiac performance in patients with severe congestive heart failure (CHF)Bednarz 2004, Bocchi 2000, Wascher 1997; however, in one trial of CHF patients, all hemodynamic variables remained unchanged with L-arginine supplementation. In the same study, L-arginine caused an increase in stroke volume and cardiac index in healthy controls.Piccirillo 2004 When given in combination with losartan 50 mg on 2 consecutive days in 9 patients with stable New York Heart Association class II or III heart failure, L-arginine 20 g IV (after second dose of losartan) improved cardiac index and stroke volume compared with losartan alone.Koifman 2006

Low-dose, L-arginine–enriched blood demonstrated a protective effect in ischemia/reperfusion injury, with a lower incidence of perioperative myocardial infarction and a decreased length of stay in the intensive care unit and hospital.Kiziltepe 2004

In men with hypertension and type 2 diabetes mellitus, oral supplementation with L-arginine 1,200 mg/day in combination with N-acetylcysteine 600 mg twice daily for 6 months improved endothelial function by enhancing nitric oxide bioavailability. Specifically, the combination reduced systolic (P<0.05) and diastolic mean arterial blood pressure (P<0.05), total cholesterol (P<0.01), low-density lipoprotein cholesterol (P<0.005), and high-sensitivity C-reactive protein (P<0.05); improved intima-media thickness during endothelial postischemic vasodilation (P<0.02); and increased high-density lipoprotein levels (P<0.05).Martina 2008

Statins have been shown to upregulate the production of nitric oxide synthase. Ninety-eight elderly subjects had their levels of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, screened, and were then randomized to receive simvastatin 40 mg/day, oral L-arginine 3 g/day, or combination therapy for 3 weeks. In subjects with high ADMA levels, simvastatin alone did not affect endothelium-dependent vasodilation. Although L-arginine alone was associated with improvements in endothelium-dependent vasodilation, there was a greater effect with combination therapy. In those with low ADMA levels, simvastatin alone, L-arginine alone, and combination therapy all improved endothelial function.Böger 2007

Cigarette smoking increases leukocyte adhesion to endothelial cells and is associated with abnormalities in endothelial function. In one study, an increase in monocyte/endothelial cell adhesion was noted in smokers versus nonsmokers (46.4% [±4.5%] vs 27% [±5.2%]; P<0.001). After administration of oral L-arginine 7 g, monocyte/endothelial cell adhesion in smokers declined to 35.1% (±4%) (P=0.002). No reversibility was noted with vitamin C.Adams 1997

In various disease states, arginase levels are elevated and limit the production of nitric oxide. Investigators have suggested the use of the "global arginine bioavailability ratio" (GABR, defined as arginine/[ornithine+citrulline]) to assess levels of arginine as well as its major catabolic products (ie, ornithine, citrulline) as a better predictor for the development and progression of major adverse cardiovascular events compared to assessment of arginine levels alone. In an assessment of plasma samples from 1,010 patients, samples from those with obstructive coronary artery disease had lower plasma arginine levels but higher ornithine and citrulline levels, resulting in lower median GABR levels. GABR remained associated with obstructive coronary artery disease even after adjusting for risk factors, high-sensitivity C-reactive protein, and creatinine clearance.Tang 2009

A meta-analysis of 11 double-blind, randomized, placebo-controlled trials (N=387) investigating the effects of L-arginine on blood pressure in subjects with and without a variety of health conditions (eg, high cholesterol, type 2 diabetes, coronary artery disease, polycystic ovary syndrome), most of whom were normotensive, identified statistically significant reductions in systolic and diastolic blood pressure by 5.39 mm Hg and 2.66 mm Hg, respectively. Substantial heterogeneity was observed. Studies enrolled groups of 12 to 79 subjects and administered L-arginine in doses of 4 to 24 g/day orally (median, 9 g/day) for durations of 2 to 24 weeks (median, 4 weeks). None of the individual studies appeared to demonstrate appreciable impacts on overall combined effect sizes when sensitivity analyses were conducted.Dong 2011

The American College of Cardiology Foundation/American Heart Association Guideline for the management of peripheral artery disease (2005/2011) stated that the effectiveness of L-arginine for patients with intermittent claudication is not well established (level B evidence).Anderson 2013

Cystic fibrosis

Clinical data

In cystic fibrosis, a deficiency in nitric oxide formation in the airways may contribute to airway obstruction. In a clinical study, nebulized L-arginine (18 mL of a 7% solution containing L-arginine 1.3 g) given to patients with cystic fibrosis was compared with a saline (placebo) solution given to healthy controls. Inhaled L-arginine was associated with increased nitric oxide concentrations (P<0.0001) as measured by fractional exhaled nitric oxide (FENO; single-breath online measurements assessing lower airway nitric oxide performed at a constant expiratory flow of 50 mL/min). A significant increase in mean forced expiratory volume in the first second of expiration (FEV1) occurred 4 hours after L-arginine inhalation (P<0.0005). No change in forced vital capacity was noted. Patients treated with nebulized saline experienced a small but statistically significant improvement in FENO, but FEV1 declined after inhalation. Nebulized L-arginine may be a treatment option to improve lung function in patients with cystic fibrosis; further studies are needed.Grasemann 2006

Diabetes

Animal and in vitro data

Oral L-arginine was associated with improvements in neuropathic pain in streptozotocin-induced diabetic rats. However, glucose levels, polyphagia, and weight loss were not impacted by L-arginine administration.Rondon 2017

Clinical data

L-arginine administration stimulates insulin secretion and enhances insulin-mediated glucose disposal, with various mechanisms suggested, including beta-cells in the pancreas take up positively charged L-arginine molecules, resulting in plasma membrane depolarization; metabolism of L-arginine by arginase yields ornithine and urea; and nitric oxide is produced from L-arginine by the enzyme nitric oxide synthase.Cheng 2001, Tsai 2009 In one study, L-arginine supplementation (9 g/day orally for 1 month) in patients with type 2 diabetes resulted in improved peripheral and hepatic insulin sensitivity. No changes in body weight, glycated hemoglobin, serum potassium, diastolic blood pressure, or heart rate were demonstrated. Systolic blood pressure decreased in the L-arginine group.Piatti 2001

In a study of 144 middle-aged patients with impaired glucose tolerance and metabolic syndrome, oral L-arginine 6.4 g/day or placebo was given for 18 months. After 18 months, patients were followed for 90 months to assess long-term effects on the incidence of diabetes. At the end of this 9-year period, there were no differences in the probability of developing diabetes; however, the cumulative incidence of diabetes was 40.6% in the L-arginine group and 57.4% in the placebo group. This resulted in an adjusted hazard ratio for diabetes (L-arginine vs placebo) of 0.66 (95% CI, 0.48 to 0.91; P<0.02).Monti 2017

In a study of the vasodilator effects of L-arginine, coinfusion with insulin enhanced the potency of arginine, with increases in renal and ocular hemodynamic parameters observed.Dallinger 2003

Patients with diabetes have low levels of L-arginine and increased levels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase. In a double-blind, vehicle-controlled, 2-period, crossover pilot study, the efficacy of a cream containing L-arginine 4 mg/cm2 in improving vascular function of the feet was assessed. The topical preparation improved both flow and temperature in the feet. Originally, the study sought to assess the effects after a washout period of 1 week, but this period was determined to be inadequate (ie, the effect of L-arginine persisted throughout the washout period). The protocol was changed to assess the cumulative effect of L-arginine administration. This unique L-arginine formulation may be a potential treatment option for improving blood flow and, ultimately, for reducing microvascular complications associated with diabetes.Fossel 2004 Another clinical study demonstrated that 8 of 11 (73%) patients with diabetic ulcers who received L-arginine 10 mM subcutaneously at the wound site reached total wound healing. The remaining 3 patients also showed improvement but discontinued the study because of relocation.Arana 2004

In a study of healthy male athletes, 0.1 g/kg of arginine powder (L-arginine 45.5%) in 150 mL of water increased glucose and insulin levels at 15 and 30 minutes, respectively, after exercise. Free fatty acid levels were reduced in the 30- and 45-minute postexercise recovery periods.Tsai 2009

Endothelial dysfunction

Clinical data

A study of patients with acute leukemia assessed the effects of L-arginine supplementation on endothelial function. Patients received either chemotherapy with anthracycline antibiotics (control group); or chemotherapy with anthracycline antibiotics plus an L-arginine IV infusion administered the day before and during anthracycline antibiotic administration, followed by L-arginine aspartate 5 mL orally 3 times a day for 1 month. L-arginine improved endothelial function and increased superoxide dismutase and total nitric oxide synthase activities.Skrypnyk 2017

Erectile tissue and function

Animal and in vitro data

Relaxation of cavernous smooth muscle in the penis requires nitric oxide synthesized by L-arginine, suggesting a potential role for L-arginine in erectile dysfunction. Studies in rats produced an erectile response and altered vascular tone.Bivalacqua 2000 Daily L-arginine dosed at 0.65 g/kg was found to be effective in preventing radiation-induced damage to penile structures in rats.Medeiros 2014

Clinical data

In a controlled crossover study of men with impotence, no difference was established between oral L-arginine 500 mg 3 times daily and placebo.Klotz 1999

L-arginine has been studied in combination with the standard of care, oral type-5 phosphodiesterase (PDE-5) inhibitors, for erectile dysfunction. The efficacy of a combination of L-arginine, nicotinic acid, and propionyl-L-carnitine (PLC) with and without the PDE-5 inhibitor vardenafil was assessed in men with diabetes and erectile dysfunction. Erectile function, measured by the International Index of Erectile Function (IIEF), improved by 2 points in those receiving the combination of L-arginine, nicotinic acid, and PLC. A group receiving vardenafil alone demonstrated an improvement in IIEF score by 4 points, and the group receiving L-arginine, nicotinic acid, and PLC plus vardenafil improved by 5 points. Those receiving placebo did not show an incremental improvement.Gentile 2009 In another study, L-arginine 600 mg/day added as adjuvant therapy in men nonresponsive to tadalafil 20 mg was associated with improved responses to 2 IIEF questions related to the ability to achieve and maintain an erection sufficient for sexual activity.Cumpanas 2009

Exercise performance

Clinical data

The effect of L-arginine supplementation on exercise performance was evaluated in a small (N=9), randomized, double-blind, crossover study in men ranging in age from 19 to 38 years. A 500 mL solution containing 6 g of L-arginine or placebo was administered orally 1 hour prior to monitored cycling machine sessions, and there was a 10-day washout period between active and placebo treatments. Significantly different mean (± standard deviation) values were observed with L-arginine compared with placebo, including for plasma nitrite levels (331±198 nM vs 159±102 nM; P<0.05), systolic blood pressure (123±3 mm Hg vs 131±5 mm Hg; P<0.01), and steady-state oxygen uptake (VO2) during moderate-intensity exercise (1.48±0.12 L/min vs 1.59±0.14 L/min; P<0.05). Outcomes were significantly better for L-arginine during severe-intensity exercise for VO2 slow component amplitude reduction (0.58±0.23 L/min vs 0.76±0.29 L/min; P<0.05) and time to exhaustion (707±232 seconds vs 562±145 seconds; P<0.05).Bailey 2010

Nutritional/Metabolic/Immunostimulatory action

Animal and in vitro data

In jaundiced rats, L-arginine supplementation demonstrated anabolic and immunostimulatory properties.Kennedy 1994 Improved pressure ulcer healing,Liu 2017 as well as healing of bone (in combination with inositol and silicon), burns, GI tract, and tendons have been implicated.Curtis 2016, Drmic 2017, Hristina 2014, Yaman 2016

Clinical data

In a randomized clinical trial of patients with tuberculosis, arginine supplementation in addition to chemotherapy resulted in reduced C-reactive protein levels and constitutional symptoms after the first month of treatment. Additionally, improvements in body mass index were noted after the first and second months of treatment with arginine.Farazi 2015

Studies of malnourished patients with head and neck cancer given arginine-enhanced enteral nutrition showed lower fistula rates, decreased length of hospital stay, and a trend toward improved survival; however, other trials were unable to demonstrate a positive clinical outcome.De Luis 2005, De Luis 2015, van Bokhorst 2001 In a study of patients who had undergone surgery for esophageal cancer, L-arginine given enterally as part of an immuno-enhanced diet with omega-3 fatty acids and RNA inhibited the decrease in platelets following surgery and reduced prothrombin activity and thrombin-antithrombin III complex levels. Additionally, the proportion of T-cells was higher in patients receiving this enteral product on postoperative days 1 and 7. Thus, an immuno-enhanced diet containing L-arginine may be beneficial following surgery for esophageal cancer to reduce the risk for infectious complications.Aiko 2008

In a randomized, double-blind pilot study, the efficacy of L-arginine 36.2 g given enterally was compared with that of placebo (alanine 51.2 g) in patients undergoing skin transplantation as part of reconstructive surgery. No differences were noted between the 2 treatment groups in relation to angiogenesis, reepithelialization, and neutrophil count. Most patients found the solutions difficult to drink due to bad taste, which may have influenced the results given the small study sample.Debats 2009 In a study by the same investigators, IV arginine administration produced similar results, with no improvements in terms of healing of human skin graft donor sites noted.Debats 2011

In a systematic review of the literature, 2 randomized clinical trials evaluating the use of arginine in premature infants were identified. Arginine supplementation reduced the risk of necrotizing enterocolitis, an effect thought to be related to reduced nitric oxide levels and to hypoxic-ischemic injury, which leads to increased mesenteric vascular resistance.Mitchell 2014 In these studies, there was a 59% reduction in stage II and III necrotizing enterocolitis with arginine supplementation compared to placebo (relative risk [RR], 0.41 [95% CI, 0.2 to 0.85]; P<0.02). Additionally, a 60% reduction was observed in all stages of necrotizing enterocolitis in patients receiving arginine (RR, 0.4 [95% CI, 0.23 to 0.69]; P=0.001). At age 3, there were no significant differences between the groups in terms of any neurodevelopmental disability.Mitchell 2014 In another review that included 3 trials evaluating arginine supplementation in neonates for necrotizing enterocolitis, a significant reduction in the risk of development of necrotizing enterocolitis stage I (RR, 0.37 [95% CI, 0.15 to 0.9]) and stage III (RR, 0.13 [95% CI, 0.02 to 1.03]) was observed in those receiving arginine compared with the control group. No adverse effects such as hypotension or effects on glucose homeostasis were attributable to arginine.Shah 2017

Ophthalmic use

Animal and in vitro data

In both rabbit and human posterior ciliary arteries, L-arginine induced vascular relaxation in a concentration-dependent manner.Chuman 2017

Clinical data

In a randomized clinical trial evaluating effects of an infusion of arginine 1 g/min for 30 minutes in healthy adults, a reduction in mean arterial pressure and an increase in retinal and choroidal blood flow occurred. The effects were apparent for 30 minutes after the infusion ended, suggesting a role for arginine in ocular diseases associated with endothelial dysfunction, such as diabetes or glaucoma.Garhöfer 2005

Preeclampsia

Clinical data

In a randomized clinical trial of hypertensive pregnant women, an infusion of arginine 20 g per 500 mL produced a hypotensive effect on systolic and diastolic blood pressure. Fetal heart rate was not affected.Neri 2004 Another trial in women with preeclampsia showed no effect on mean diastolic pressure after 2 days of oral treatment with arginine 12 g/day.Staff 2004

Renal disease

Animal and in vitro data

Supplementation with L-arginine 300 mcg/kg/min IV decreased renal dysfunction in rats with renal ischemia/reperfusion injury.Tong 2017

Clinical data

Arginine supplementation did not improve endothelial dysfunction in children with chronic renal failure,Bennett-Richards 2002 nor was it protective against contrast media–induced nephrotoxicity in adults with chronic renal failure.Miller 2003

Progressive renal dysfunction in patients with decompensated cirrhosis may be due to increased levels of nitric oxide. In a prospective, collaborative study, plasma nitric oxide and L-arginine levels increased progressively with worsening renal function, with both levels being higher in patients with hepatorenal syndrome type II.Kayali 2009

Sickle cell disease

Sickle cell disease represents a state of arginine deficiency. In patients with sickle cell disease, endothelial cells become activated and are damaged by neutrophils that release harmful substances. Vasoocclusive events and tissue damage are mediated by neutrophils. Superoxide anion released from endothelial cells and neutrophils plays a role in breaking down nitric oxide. The production of superoxide anion in these cells is enhanced in a state of L-arginine deficiency.Gladwin 2003, Morris 2005, Waugh 2001 Excessive arginase activity resulting in L-arginine deficiency is characteristic for patients with sickle cell disease.Morris 2017

Clinical data

In a clinical study of 5 patients with sickle cell disease, 0.1 g/kg orally twice daily of the L-arginine precursor L-citrulline improved the sense of well-being in patients. Supplementation was also associated with increased arginine levels and with reduced total leukocyte counts and segmented neutrophil counts. Continuous L-citrulline therapy maintained lower total leukocyte counts and segmented neutrophil counts.Waugh 2001

In a randomized, placebo-controlled trial, 38 children with sickle cell disease who were hospitalized for vasoocclusive crises were given IV or oral L-arginine 100 mg/kg 3 times daily or placebo for 5 days or until discharge. In the group receiving L-arginine, total parenteral opioid use was reduced by 54%, and pain scores were lower at discharge. Hospital length of stay was not impacted significantly with supplementation, although there was a trend favoring treatment.Morris 2013

In 10 patients with sickle cell disease and pulmonary hypertension (mean age, 32.7±15 years) given oral L-arginine 0.1 g/kg 3 times daily for 5 days, supplementation was associated with a 15.2% mean reduction in pulmonary artery systolic pressure (63.9±13 mm Hg to 54.2±12 mm Hg; P=0.002). Of the 9 compliant patients, follow-up echocardiography results at 1 month showed that 4 patients reverted to baseline pulmonary artery systolic pressure values, 1 patient worsened and was admitted for acute chest syndrome, and 4 patients persistently improved; 2 of the patients who improved were started on transfusion therapy, and 1 of these patients continued treatment with L-arginine therapy at a dosage of 0.1 g/kg twice daily.Morris 2003

The effects of L-arginine 0.1 to 0.2 g/kg divided 3 times daily versus sildenafil 25 to 100 mg 3 times daily on safety, cardiopulmonary function, and fetal hemoglobin in patients with sickle cell disease were assessed. L-arginine did not improve pulmonary pressure or 6-minute walking distances, while sildenafil did. However, fetal hemoglobin levels were reduced by 2.9% (±16.1%) from baseline in patients receiving L-arginine, whereas in patients treated with sildenafil, fetal hemoglobin levels increased.Little 2009

Stroke

Animal and in vitro data

In rats, IV L-arginine dosages between 50 and 250 mg/kg improved survival rate during heatstroke (54 to 245 minutes) in rats. Specifically, L-arginine reduced intracranial hypertension and increased levels of nitric oxide metabolite in the hypothalamus.Chen 2008

Clinical data

A Cochrane review of randomized clinical trials concluded that there is insufficient evidence regarding the effects of nitric oxide donors, L-arginine, or nitric oxide synthase inhibitors to recommend their use in acute ischemic stroke; glyceryl trinitrate is the only drug that has been assessed. In patients with acute stroke, glyceryl trinitrate reduces blood pressure and increases heart rate and headache but does not change clinical outcomes (high-quality evidence).Bath 2017

High concentrations of nitric oxide are considered toxic to brain tissue.Bath 2017

Other uses

In a clinical trial evaluating intrauterine growth restriction therapy, L-arginine 3 g/day orally for 20 days resulted in an improvement in the weight of newborn infants compared with no intervention.Sieroszewski 2004

L-arginine was beneficial in some patients with valproate overdose complicated by hyperammonemia.Schrettl 2017

Dosing

L-arginine has been studied for a variety of conditions using various dosages and treatment durations (up to 18 months); current daily dosage trends range from 6 to 30 g orally in 3 divided doses.Morris 2017 Oral and IV formulations have been the most commonly studied. Oral L-arginine supplementation is limited by GI and hepatic extraction of L-arginine as well as by potential for GI distress, often dose dependent. Therefore, L-citrulline supplementation may be considered for use to increase L-arginine levels and nitric oxide bioavailability.Allerton 2018

Pregnancy / Lactation

A systematic review of the literature (N=884 women) found that L-arginine supplementation reduced the risk for preeclampsia in pregnant women who either had hypertension or were considered to be at risk for preeclampsia.Dorniak-Wall 2014 In general, due to minimal data regarding safety and efficacy in pregnancy and lactation, L-arginine should only be used in these populations if recommended by and under the supervision of a health care provider.

Interactions

Nitrates: Caution is warranted in patients concomitantly using L-arginine supplementation and nitrates. L-arginine may potentiate the effects of isosorbide mononitrate and other nitric oxide donors, such as glyceryl trinitrate (ie, nitroglycerin) and sodium nitroprusside.Stokes 2003

Insulin: Caution is warranted in patients using insulin concomitantly with L-arginine; effects on insulin are unpredictable.Fleischmann 2002, Piatti 2001

Cholesterol-lowering drugs: Caution is warranted in patients using cholesterol-lowering drugs concomitantly with L-arginine; effects on cholesterol-lowering drugs are unpredictable.Fleischmann 2002, Piatti 2001

Adverse Reactions

Nausea, diarrhea, dyspepsia, palpitations, headache, and numbness have been reported.Morris 2017 In a trial of malnourished patients with head and neck cancer, enteral arginine supplementation was associated with diarrhea.De Luis 2015 In a study evaluating effects of L-arginine 9 g/day over 6 months on exercise capacity in patients with stable angina pectoris, no adverse reactions were reported.Ceremuzyński 1997 Higher doses may be associated with a bitter taste that may affect patient compliance.Chagan 2002 Due to L-arginine's vasodilatory properties, hypotension may occur. IV preparations containing L-arginine hydrochloride have a high chloride content that may be unsafe for patients with electrolyte imbalances; L-arginine's acidity may cause metabolic acidosis due to a sudden drop in blood pH, which has been associated with arrhythmias. Hyperkalemia resulting from displacement of intracellular potassium may occur in patients with hepatic and/or renal impairment who are receiving L-arginine treatment. In patients with renal impairment, L-arginine therapy may cause an increase in BUN and urea because of a diminished ability to eliminate urea.Böger 2001

Toxicology

High concentrations of nitric oxide are considered toxic to brain tissue.Bath 2017 A 21-month-old child received an accidental overdose of L-arginine while being tested for growth hormone deficiency and subsequently developed cardiopulmonary arrest; 36 hours after successful resuscitation, she developed fatal myelinolysis.Gerard 1997

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