Arginine (L-Arginine)


Background


L-arginine was first isolated in 1886. In 1932, L-arginine was found to be required for the generation of urea, which is necessary for the removal of toxic ammonia from the body. In 1939, L-arginine was also shown to be required for the synthesis of creatine. Creatine degrades to creatinine at a constant rate, and is cleared from the body by the kidney.

Arginine is considered a semi-essential amino acid, because although it is normally synthesized in sufficient amounts by the body, supplementation is sometimes required (for example, due to inborn errors of urea synthesis, protein malnutrition, excess ammonia production, excessive lysine intake, burns, infection, peritoneal dialysis, rapid growth, or sepsis). Symptoms of arginine deficiency include poor wound healing, hair loss, skin rash, constipation, and fatty liver.

Arginine is a precursor of nitric oxide, which causes blood vessel relaxation (vasodilation). Preliminary evidence suggests that arginine may be useful in the treatment of medical conditions that are improved by vasodilation, such as angina, atherosclerosis, coronary artery disease, erectile dysfunction, heart failure, intermittent claudication/peripheral vascular disease, and vascular headache. Arginine also stimulates protein synthesis and has been studied for wound healing, bodybuilding, enhancement of sperm production (spermatogenesis), and prevention of wasting in people with critical illness.

Arginine hydrochloride contains high chloride content and has been used for the treatment of metabolic alkalosis. This use should be under the supervision of a qualified healthcare professional.

Most people likely do not need to take arginine supplements because the body usually makes sufficient amounts.

Synonyms


Arg, arginine, arginine hydrochloride (intravenous formulation), ibuprofen-arginate (Spedifen®), L-arginine, 2-amino-5-guanidinopentanoic acid.

Note : Arginine vasopressin is different from arginine/L-arginine, with an entirely different mechanism. NG-monomethyl-L-arginine is different from arginine/L-arginine, and functions as an inhibitor of nitric oxide synthesis.

Dietary sources of arginine : Walnuts, filberts, pecans, Brazil nuts, sesame and sunflower seeds, brown rice, raisins, coconut, gelatin, buckwheat, almonds, barley, cashews, cereals, chicken, chocolate, corn, dairy products, meats, oats, peanuts.

Evidence

These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Uses based on scientific evidenceGrade*Growth hormone reserve test / pituitary disorder diagnosis
Intravenously administered arginine can be used to evaluate growth hormone reserve in individuals with suspected growth hormone deficiency. For example, in patients with suspected panhypopituitarism, growth/stature abnormalities, gigantism/acromegaly, or pituitary adenoma. This is an FDA labeled indication for arginine.

A
Inborn errors of urea synthesis
In patients with inborn errors of urea synthesis, high blood ammonia levels and metabolic alkalosis may occur, particularly in patients with ornithine carbamoyl transferase (OCT) deficiency or carbomoyl phosphate synthetase (CPS) deficiency. Arginine can be a helpful treatment by shifting the way the body processes nitrogen, but should be avoided in patients with hyperargininemia (high arginine levels). Other drugs may have similar benefits, such as citrulline, sodium benzoate, or sodium phenylbutyrate, although dialysis may be necessary initially. This use of arginine should be supervised by a qualified healthcare professional.
A
Adrenoleukodystrophy (ALD)
Adrenoleukodystrophy (ALD) is a rare inherited metabolic disorder characterized by the loss of fatty coverings (myelin sheaths) on nerve fibers in the brain, and progressive destruction of the adrenal gland. ALD is inherited as an x-linked genetic trait that results in dementia and adrenal failure. Injections of arginine have been proposed to help manage this disorder, although most study results are inconclusive. Further research is needed to evaluate the use of arginine in ALD.
C
Burns
A randomized, controlled clinical trial designed to evaluate immune function of patients given 15mg of arginine orally suggests that arginine may help with the recovery of immune function and protein function in partial-thickness burn patients. Further research is necessary in this area before a conclusion can be drawn.
C
Coronary artery disease / angina
There is initial evidence from several studies that arginine taken by mouth or by injection improves exercise tolerance and blood flow in arteries of the heart. Benefits have been shown in some patients with coronary artery disease and angina. A small randomized, controlled clinical trial studied the effects of a medical food bar enriched with L-arginine and a combination of other nutrients in the management of chronic stable angina. The authors found that this arginine-rich medical food, when used with traditional therapy, improves vascular function, exercise capacity and aspects of quality of life in these patients. However, further research is needed to confirm these findings and to establish doses that may be safe and effective.
C
Critical illness
Some studies suggest that arginine may provide benefits when added to nutritional supplements during critical illnesses (for example, in patients being treated in intensive care units). However, it is unclear what the specific role of arginine may be in improving recovery. A randomized, controlled clinical trial was designed to study the effects of a high-protein formula enriched with arginine, fiber, and antioxidants in early nutrition therapy of critically ill patients. The study measured infections in the hospital intensive care unit (ICU), length of hospital stay, and death rates. Patients fed the high-protein diet enriched with arginine, fiber and antioxidants developed fewer hospital infections than patients fed a standard high-protein diet. There was no difference in length of ICU hospital stay or death rate.
C
Dental pain (ibuprofen arginate)
A well-designed multicenter, randomized controlled clinical trial found that ibuprofen-arginate (Spedifen®) reduced pain faster after dental surgery compared to conventional ibuprofen alone. The study included 498 patients who were given either ibuprofen-arginate, ibuprofen, or placebo after dental surgery. The degree of the relief of pain, onset of action, and tolerability of both ibuprofen-arginate and ibuprofen were compared. It was found that ibuprofen arginate relieved pain faster and adverse events with ibuprofen arginate were similar to those seen with ibuprofen alone. Another similar trial concluded that patients treated with ibuprofen arginate rated its overall effectiveness higher than those treated with ibuprofen alone. Adverse event profiles were similar across all treatment groups. Further research is merited in this area.
C
Erectile dysfunction
Early studies propose that men with low nitrate levels in their blood or urine may find arginine supplements to be useful for managing erectile dysfunction (ED). A randomized, controlled clinical trial reported improvements in patients with mild-to-moderate ED following use of a combination of L-arginine, glutamate and yohimbine hydrochloride. Notably, yohimbine hydrochloride is an FDA-approved therapy for this condition, and the effects caused by arginine alone in this combination therapy are difficult to determine. It is not clear what doses of arginine may be safe or effective in treating this condition, and comparisons have not been made with other agents used for ED.
C
Gastrointestinal cancer surgery
Supplementation with an oral combination of arginine and omega-3 fatty acids may reduce length of hospital stay and infections after surgery in gastrointestinal cancer patients. There is conflicting evidence as to when to give the combination (either before or after surgery). Both strategies have been reported as superior to conventional treatment (no artificial nutrition) at reducing infections after surgery and reducing hospital stay. In a large, randomized, controlled clinical trial, malnourished cancer patients were given oral enteral nutrition supplemented by arginine, omega-3 fatty acids and RNA before surgery. It was found that supplementation with the combination before surgery reduced complications after surgery and hospital stay. A different randomized, controlled clinical trial in patients with gastrointestinal cancer studied the effects of an enteral diet supplemented with arginine, omega-3 fatty acids and glutamine (administered after surgery) on immune function and inflammatory response. This study reported the supplement to be well-tolerated with positive effects on immune and inflammatory response. Further research is needed to determine the possible effects of arginine alone.
C
Heart failure (CHF)
Studies of arginine in patients with chronic heart failure have shown mixed results. Some studies report improved exercise tolerance. Additional studies are needed to confirm these findings before a firm conclusion can be drawn.
C
Heart protection during coronary artery bypass grafting (CABG)
Arginine-supplemented "blood cardioplegic solution" is proposed to have protective properties for the heart. A randomized, controlled clinical trial using this solution in patients undergoing heart surgery (coronary artery bypass grafting) reports improved heart protection. Further research is needed before a firm conclusion can be drawn.
C
High blood pressure
A small study suggests that arginine taken by mouth may help to dilate the arteries and temporarily reduce blood pressure in hypertensive patients with type 2 diabetes. Larger, high-quality studies are needed before a recommendation can be made.
C
Migraine headache
Preliminary studies suggest that adding arginine to ibuprofen therapy may decrease migraine headache pain.
C
Peripheral vascular disease / claudication
Intermittent claudication is a condition characterized by leg pain and fatigue due to buildup of cholesterol plaques or clots in leg arteries. A small number of studies report that arginine therapy may improve walking distance in patients with claudication. Further research is needed before a firm conclusion can be drawn.
C
Recovery after surgery
One study suggests that arginine may provide benefits when used as a supplement after surgery. It is not clear what the specific role of arginine may be in improving immune function, or what dose is safe or effective.
C
Wound healing
Arginine has been suggested to improve the rate of wound healing in elderly individuals. A randomized, controlled clinical trial reported improved wound healing after surgery in head and neck cancer patients, following the use of an enteral diet supplemented with arginine and fiber. Arginine has also been used topically (on the skin) to attempt to improve wound healing. Further research is necessary in this area before a firm conclusion can be drawn.
C
Kidney disease
It has been suggested that arginine may be a useful supplement in people diagnosed with kidney failure. However, results from available studies do not support this claim. A small randomized, controlled clinical trial studied the ability of L-arginine to improve dilation of blood vessels in children with chronic renal failure. Results showed that blood vessel dilation (endothelial function) was not improved with oral L-arginine suggesting that dietary supplementation is not a beneficial or useful clinical approach in children with chronic renal failure.
D
Kidney protection during angiography
The contrast media or dye used during angiography to map a patient's arteries (or during some CT scans) can be toxic to the kidneys, especially to people with pre-existing kidney disease. A randomized, parallel, double-blind clinical trial studied the use of L-arginine to protect kidneys in patients with chronic renal failure undergoing angiography. The authors found no evidence that injections of L-arginine protect the kidney from damage due to contrast. Other therapies, such as N-acetylcysteine (NAC), have been found beneficial at protecting the kidneys from contrast-induced damage, particularly in patients at high-risk such as those with diabetes.
D
Cyclosporine toxicity
Animal studies report that arginine blocks the toxic effects of cyclosporine, a drug used to prevent organ transplant rejection. However, results from studies in humans have not found that arginine offers any protection from cyclosporine-induced toxicity.
D
Infertility
Although there are several studies in this area, it is not clear what effects arginine has on improving the likelihood of getting pregnant. Early evidence does not support the finding that arginine has any benefits in women who are undergoing in vitro fertilization, or in men with abnormal sperm.
D
Interstitial cystitis
Arginine has been proposed as a treatment for interstitial cystitis (inflammation of the bladder). However, most well-designed studies in humans have not found that arginine offers any improvements in treating symptoms such as urinary frequency or urgency.
D
Asthma
Although it has been suggested that arginine may be a treatment for asthma, studies in humans have actually found that arginine worsens inflammation in the lungs and contributes to asthma symptoms. Therefore, taking arginine by mouth or by inhalation is not recommended in people with asthma.
F
* Key to grades
A: Strong scientific evidence for this use;
B: Good scientific evidence for this use;
C: Unclear scientific evidence for this use;
D: Fair scientific evidence against this use (it may not work);
F: Strong scientific evidence against this use (it likely does not work).


Uses based on tradition or theory
The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

AIDS/HIV, ammonia toxicity, anti-aging, beta-hemoglobinopathies, cancer, cardiac syndrome X, cold prevention, cystic fibrosis, dementia, diabetes, enhanced athletic performance, enhanced immune function, glaucoma, growth hormone stimulation, heart attack, hemolytic uremic syndrome (HUS), hepatic encephalopathy, immunomodulation, infection, pulmonary hypertension (high blood pressure in the lungs), high cholesterol, increased muscle mass, infantile necrotizing enterocolitis, inflammatory bowel disease, ischemic stroke, liver disease, lower esophageal sphincter relaxation, low sperm count, metabolic acidosis, obesity, osteoporosis, pain, peritonitis, preeclampsia, pre-term labor contractions, Raynaud's phenomenon, sepsis, sickle cell anemia, stomach motility disorders, stomach ulcer, stroke, supplementation to a low protein diet, thrombotic thrombocytopenic purpura (TTP).

Dosing

The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Standardization:

Intravenous arginine hydrochloride is available as a 10% solution (950 mOsm/L), winth 47.5mEq chloride ion per 100mL. There is no established standardization for oral arginine products.

Note : Most people likely do not need to take arginine supplements because the body usually makes sufficient amounts.

Adults (18 years and older):

Tablets/capsules: There are no standard or well-established doses of arginine, and many different doses have been used and studied. A dose that has been studied for treating coronary artery disease is two to three grams taken by mouth three times daily for three to six months. A studied dose for heart failure is 5.6 to 12.6 grams taken by mouth every day, divided into two or three equal doses, taken for six weeks. For erectile dysfunction, 1.6 grams taken by mouth three times daily for six weeks has been studied. For low sperm count, four grams daily for three months has been used. For women undergoing in vitro (test tube) fertilization, a dose of 16 grams daily by mouth has been studied, although this therapy should be discussed with the healthcare provider coordinating the in vitro program. For interstitial cystitis, 500 milligrams taken by mouth three times daily for six weeks has been used. For the long-term management of inborn disorders of the urea cycle, doses between 0.5 to 2 grams daily have been used.

Intravenous: Doses of arginine used intravenously depend on specific institutional dosing guidelines and should be given under the supervision of a healthcare provider.

Children (younger than 18 years):

Arginine supplements are not recommended in children because there is not enough scientific information available and because of potential side effects.

Safety

The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies

Anaphylaxis (severe allergic reaction) has occurred after arginine injections. People with a known allergy should avoid arginine. Signs of allergy may include rash, itching or shortness of breath.

Side Effects and Warnings

Arginine has been well tolerated by most people in studies lasting for up to six months, although there is a possibility of serious adverse effects in some individuals.

Stomach discomfort, including nausea, stomach cramps or an increased number of stools, may occur. People with asthma may experience a worsening of symptoms if arginine is inhaled, which may be related to allergy.

Other potential side effects include low blood pressure and changes in numerous chemicals and electrolytes in the blood. Examples include high potassium, high chloride, low sodium, low phosphate, high blood urea nitrogen and high creatinine levels. People with liver or kidney disease may be especially sensitive to these complications and should avoid using arginine except under medical supervision. After injections of arginine, low back pain, flushing, headache, numbness, restless legs, venous irritation and death of surrounding tissues have been reported.

In theory, arginine may increase the risk of bleeding. Patients using anticoagulants (blood thinners) or antiplatelet drugs, or with underlying bleeding disorders, should speak with a qualified healthcare provider before using arginine and should be monitored.

Arginine may increase blood sugar levels. Caution is advised in patients taking prescription drugs to control sugar levels.

Pregnancy and Breastfeeding

Arginine cannot be recommended as a supplement during pregnancy and breast-feeding because there is not enough scientific information available.

References

Bath PM, Willmot M Leonardi-Bee J, et al. Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev 2002;(4): CD000398.
Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999;27 (12) :2799-2805.
Bennett-Richards KJ, Kattenhorn M, Donald AE, et al. Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure. Kidney Int 2002;62(4): 1372-1378.
Black P, Max MB' Desjardins P, Norwood T, et al. A randomized, double-blind, placebo-controlled comparison of the analgesic efficacy, onset of action, and tolerability of ibuprofen arginate and ibuprofen in postoperative dental pain. Clin Ther 2002;24(7): 1072-1089.
Boger RH, Bode-Boger SM, Thiele W, et al. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998;32(5):1336-1344.
Braga M, Gianotti L, Nespoli L, Radaelli G, et al. Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg 2002;137(2): 174-80.
Caparros T, Lopez J, Grau T. Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. The effect on nosocomial infections and outcome. JPEN J Parenter Enteral Nutr 2001;25(6):299-308; discussion 308-309.
Carrier M, Pellerin M, Perrault LP, et al. Cardioplegic arrest with L-arginine improves myocardial protection: results of a prospective randomized clinical trial. Ann Thorac Surg 2002; 73(3): 837-41; discussion 842.
Cartledge JJ, Davies AM, Eardley I. A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. BJU Int 2000;85(4):421-426.
Cen Y, Luo XS, Liu XX. Effect of L-arginine supplementation on partial-thickness burned patients. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 1999;13(4):227-231.
Chen J, Wollman Y, Chernichovsky T, et al. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double- blind, randomized, placebo-controlled study. BJU Int 1999;83(3):269-273.
Chuntrasakul C, Siltharm S, Sarasombath S, et al. Metabolic and immune effects of dietary arginine, glutamine and omega-3 fatty acids supplementation in immunocompromised patients. J Med Assoc Thai 1998;81(5):334-343.
de Luis DA, Aller R, Izaola O, et al. Postsurgery enteral nutrition in head and neck cancer patients. Eur J Clin Nutr 2002;56(11):1126-1129.
de Luis DA, Izaola O, Cuellar L, et al. Effects of c-reactive protein and interleukins blood levels in postsurgery arginine-enhanced enteral nutrition in head and neck cancer patients. Eur J Clin Nutr 2003;57(1):96-99.
Desjardins P, Black P, Papageorge M, et al. Ibuprofen arginate provides effective relief from postoperative dental pain with a more rapid onset of action than ibuprofen. Eur J Clin Pharmacol 2002;58(6):387-94.
Gianotti L, Braga M, Nespoli L, et al. A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gasterointestinal cancer. Evid Based Nurs 2003;6(2):47.
Huynh NT, Tayek JA. Oral arginine reduces systemic blood pressure in type 2 diabetes: its potential role in nitric oxide generation. J Am Coll Nutr 2002;21(5):422-427.
Klotz T, Mathers MJ, Braun M, et al. Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int 1999;63(4):220-223.
Korting G, Smith S, Wheeler M, et al. A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis. J Urol 1999;161(2):558-565.
Lebret T, Herve JM, Gorny P, et al. Efficacy and safety of a novel combination of L-arginine, glutamate, and yohimbine hydrochloride: a new oral therapy for erectile dysfunction. Eur Urol 2002;41(6):608-613.
Lekakis JP, Papathanassiou S, Papioannou TG, et al. Oral L-arginine improves endothelial dysfunction in patients with essential hypertension. Int J Cardiol 2002;86(2-3):317-323.
Maxwell AJ, Zapien MP, Pearce GL, et al. Randomized trial of a medical food for the dietary management of chronic, stable angina. J Am Coll Cardiol 2002;39(1):37-45.
McGovern MM, Wasserstein MP, Aron A, et al. Biochemical effect of intravenous arginine butyrate in X-linked adrenoleukodystrophy. J Pediatr. 2003;142(6):709-713.
Mehlisch DR, Ardia A, Pallotta T. A controlled comparative study of ibuprofen arginate versus conventional ibuprofen in the treatment of postoperative dental pain. J Clin Pharmacol 2002;42(8):904-911.
Miller HI, Dascalu A, Rassin TA, et al. Effects of an acute dose of L-arginine during coronary angiography in patients with chronice renal failure: a randomized, parallel, double-blind clinical trial. Am J Nephrol 2003;23(2):91-95.
Sandrini G, Franchini S, Lanfranchi S, et al. Effectiveness of ibuprofen-arginine in the treatment of acute migraine attacks. Int J Clin Pharmacol Res 1998;18(3):145-150.
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January 01, 2004