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Arginine

Nutrient Name: Arginine.
Synonym:L-Arginine.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Antihypertensive medications Angiotensin-converting enzyme (ACE) inhibitors Potassium-sparing diuretics / /	Possible additive effect on potassium levels, phosphorus levels, vascular dilation, and blood pressure from concomitant administration. Resultant tendency toward elevated potassium levels and lowered blood pressure could theoretically produce cardiovascular instability or therapeutic benefit, depending on patient variability, communication and compliance, and therapeutic strategy.	Well-managed coadministration possibly appropriate, with close supervision and regular monitoring.
Cyclosporine	L-Arginine, as substrate for nitric oxide (NO) synthesis, may alter vasodilator mechanism(s), particularly NO blockade, possibly responsible for cyclosporine-induced vascular dysfunction, and by enhancing NO levels, decrease cyclosporine nephrotoxicity.	Coadminister, if appropriate. Close supervision and regular monitoring warranted.
Sildenafil Phosphodiesterase-5 inhibitors	Vasodilation involved in erection requires NO and arginine is the precursor of NO synthesis. NO enables therapeutic action of sildenafil, which may be enhanced by arginine intake, especially in men with low levels or abnormal metabolism of NO.	Coadminister; consider evaluating NO status. Communication, observation, and occasional management appropriate.
Theophylline, aminophylline	Increased arginase activity and NO deficiency can contribute to airway reactivity. Arginine is substrate for NO synthesis. Preliminary evidence indicates that theophylline or aminophylline could theoretically create a beneficial additive or synergistic effect by reducing arginase activity and increasing arginine's availability to be converted to NO.	Coadminister, if appropriate. Close supervision and regular monitoring warranted.

nutrient description

Chemistry and Forms

Arginine is a complex amino acid often found at the active (or catalytic) site in proteins and enzymes because of its amine-containing side chain. With four nitrogen atoms per molecule, it is the most abundant nitrogen carrier in humans and animals.

Physiology and Function

Arginine's primary function is generally considered to be the transport, storage, detoxification, and excretion of nitrogen, in particular, and metabolism of protein, in general, through the urea cycle. Arginine is also the substrate for nitric oxide synthase and arginase, two important metabolic pathways. Nitric oxide (NO), a key vasodilator, neurotransmitter, and cell-signaling molecule, is formed by the three different nitric oxide synthases from the N-guanido terminal of the amino acidL-arginine and from molecular oxygen. Nitric oxide synthase (NOS) also converts arginine to citrulline. Arginase converts arginine to ornithine and urea. Arginase I and arginase II control the transformation of arginine into ornithine, which subsequently forms proline and polyamines, which exert multiple effects on connective tissue, smooth muscle, and mucus synthesis. The NOS and arginase pathways interfere with each other through substrate competition.

As the precursor to NO, arginine plays a key role in the circulatory and respiratory systems, particularly endothelial function, vasodilation, and airway physiology. Arginine also functions as a key immunomodulator, particularly increasing the number of T cells, enhancing T cell function, and supporting tissue regeneration. Recent studies have reported increases in arginase in conditions including reperfusion injury, asthma, psoriasis, arthritis, and human breast cancer. Helper T cell type 2 (Th2) cytokines induce arginase expression. During allergic inflammation, increased interleukin-4 (IL-4) and/or IL-13 expression results in increased expression of arginase and amplification of the arginase-dependent pathway, with concomitant suppression of NO generation. Furthermore, in relation to neuroendocrine function, arginine strongly influences adrenal and pituitary functions, especially through stimulation of catecholamines, norepinephrine, insulin and glucagon, prolactin, and growth hormone (GH). Lastly, arginine is involved in synthesis of spermine and spermidine, polyamines required for cell division and growth, and numerous aspects of reproductive function. Hepatic metabolism of arginine produces hydrogen ions (H⁺).

Arginine is generally considered a conditionally essential amino acid because adult humans can generally synthesize it de novo from ornithine, glutamine, glutamate, and proline. However, arginine must be obtained through the diet during the juvenile period in humans and in those not synthesizing adequate amounts to meet metabolic demands, especially after acute trauma, burns, or surgery and during infections, chronic illness, or wound healing. In all situations, dietary intake remains the primary determinant of plasma arginine levels, since the rate of arginine biosynthesis does not increase to compensate for depletion or inadequate supply.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Arginine's central role in promoting NO formation forms the basis of its therapeutic effect in the treatment of cardiovascular disease, asthma, interstitial cystitis, female sexual dysfunction, and male erectile dysfunction. In particular, a growing body of research has focused on arginine's ability to induce vasodilation and improve endothelial function through its role as a substrate for NO synthesis. Arginine hydrochloride has been used clinically in correcting severe metabolic alkalosis because of its high chloride content. Findings from preliminary double-blind trials indicate the efficacy of arginine in the treatment of acquired immunodeficiency syndrome (AIDS) cachexia, angina, congestive heart failure (CHF), endothelial function in type 1 diabetes, erectile dysfunction, hypertension, and other conditions. Arginine has also been used therapeutically to enhance several aspects of healthy function, including supporting wound healing and resistance to infection; elevating production of GH and related hormones; increasing exercise tolerance, lean muscle mass, and total strength; improving sperm motility and sexual vitality; and reducing low-density lipoprotein (LDL) cholesterol.

Historical/Ethnomedicine Precedent

Arginine has not been used historically as an isolated nutrient.

Possible Uses

Angina, athletic performance, burns, chronic renal failure, congestive heart failure, cystic fibrosis, enhancing formation of muscle mass, erectile dysfunction, female infertility (in vitro fertilization), gastritis, hepatic insufficiency, human immunodeficiency virus (HIV) support, hypercholesterolemia, hypertension, inflammatory bowel disease, immunity enhancement, intermittent claudication (intravenous only), interstitial cystitis, male infertility (oligospermia), metabolic alkalosis, peripheral vascular disease, surgery preparation and recovery, trauma, wound healing enhancement.

Deficiency Symptoms

Arginine deficiency is uncommon and is usually related to overall protein malnutrition (especially protein deficiency), compromised health status or elevated physiological stress (e.g., burns, injury, infection), excessive ammonia production, or enzyme deficiency. Primary symptoms include rash, hair loss, poor wound healing, constipation, fatty liver, and cirrhosis.

Dietary Sources

The best dietary sources of arginine are meat (especially lamb), peanuts, soybeans, hazelnuts, shrimp, eggs, and milk products. Other foods containing significant mounts of arginine include: almonds, cashews, Brazil nuts, filberts, pecans, sesame and sunflower seeds, walnuts, raisins, coconut, gelatin, chicken, chocolate, brown rice, barley, buckwheat, corn, and oats.

Lysine competes with arginine for absorption, so a diet low in lysine may enhance the effects of arginine intake.

Dosage Forms Available

Capsules, powder, or tablets, containing a salt ofL-arginine, such asL-arginine hydrochloride, or arginine glutamate; the free base amino acid is also sometimes used, although it is more problematic to use in a capsule or tablet because it is very hygroscopic.

Well absorbed orally, with time to peak serum concentration approximately 2 hours.
Best taken away from meals, in divided doses, throughout day.
Intravenously administered for pituitary function test.

Dosage Range

Adult

Dietary: Optimal levels of intake have not been established.
Supplemental/Maintenance: 1.5 to 6.0 grams per day, usually 2 to 3 g/day; best in divided doses because absorption of doses greater than 3 g is usually poor. Arginine can be synthesized endogenously, and supplementation is usually not necessary for most individuals.
Pharmacological/Therapeutic: Researchers and practitioners of nutritional therapeutics have used a wide range of dosages, from 2 to 30 g daily, with 6 g daily being representative for most conditions. For example, 6 to 15 g daily has been used in CHF treatment. Long-term use is usually not advisable.

Pediatric (<18 Years)

Dietary: Optimal levels of intake have not been established.
Supplemental/Maintenance: Usually not administered as a nutritional supplement to children.
Pharmacological/Therapeutic: Usually not administered therapeutically to children, except possibly in relation to burns, injuries, or surgery; in such cases, dosage levels would be proportional to typical adult doses by weight.

Laboratory Values

Research laboratory methods for measuring NOS activity are available, but they are not used clinically to any significant degree. Serum and urine amino acid profiles are available, but not likely to be clinically relevant to the status of arginine-derived NO production capability, because more factors are involved than simply the amount of arginine present in tissues and body fluids. Therefore, effects of arginine supplementation are best judged clinically. Various measures of circulatory and endothelial function are most likely to show changes if supplemental arginine enhances NOS activity, as well as blood pressure, erectile function, and exercise tolerance.

safety profile

Overview

Dosage levels of 1 to 6 g per day generally are well tolerated by healthy adults. Adverse effects are estimated to occur in 1% to 10% of patients administered arginine, with more severe reactions associated with intravenous (IV) administration.

Nutrient Adverse Effects

General Adverse Effects

Minor gastrointestinal (GI) distress is occasionally associated with supplemental intake; headache also may occur. Excessive doses of arginine (>40 g/day) may cause diarrhea, most likely as a result of poor absorption at higher dosage levels. Rapid IV infusion may produce flushing.

Despite numerous studies demonstrating the immune-enhancing activity of arginine, including research with breast cancer, some researchers have suggested that high doses of arginine can increase the growth of cancer cells in humans. ^1-4Clinicians with experience in integrative oncology have observed that amino acids, particularly arginine, can have opposite effects at different stages in the disease process, for tissues at different sites, and for different individuals. Further research into such aspects of nutritional therapeutics within cancer prevention and treatment are warranted to delineate such patterns and determine their implications in developing therapeutic strategies. However, pending such studies, the influence of arginine on growth of cancers can generally be qualified as unpredictable.

Adverse Effects Among Specific Populations

Individuals with a history of gastritis, reflux esophagitis, or peptic ulcer disease may experience exacerbations with arginine administration, possibly from stimulation of gastrin. However, the evidence for such concern is mixed.

Hyperphosphatemia can be induced by arginine in patients with severe hepatic disease and kidney problems. The maximum safe dosage levels for arginine administration in individuals with compromised hepatic function have not been established.

Pregnancy and Nursing

Data on long-term safety for arginine administration in pregnant or lactating women are lacking, and maximum safe dosage levels have not been established.

Infants and Children

Data on long-term safety for arginine administration in infants and children are lacking, and maximum safe dosage levels have not been established.

Contraindications

Administration ofL-arginine after acute myocardial infarction (MI) may lead to worsened clinical outcomes or death, particularly in older patients with diffuse atherosclerosis, and should be avoided except under the direct supervision of a physician trained and experienced in such interventions. ⁵ As a possible explanation for these results, it has been hypothesized thatL-arginine may only help to alleviate vascular stiffness in patients with preexistingL-arginine deficiency. Continued research is warranted to clarify the role ofL-arginine in cardiovascular health.

Avoidance of arginine supplementation by individuals with active or past herpes simplex virus (HSV) infections has often been asserted based on the theory that elevated arginine levels might stimulate viral replication or provoke an outbreak, especially in the context of low lysine levels. Although supported by broad anecdotal reports and older in vitro data, ⁶ evidence from clinical trials is lacking to confirm elevated susceptibility and validate this contraindication. Nevertheless, caution is warranted. If herpetic reactivations consistently occur shortly after initiating arginine administration or otherwise increasing intake, clinical anecdotes have suggested that a therapeutic trial of coadministration with equal amounts ofL-lysine may be useful. Currently, no clinical evidence indicates whether or notL-lysine coadministration may interfere withL-arginine's bioavailability, based on the known competition between the two amino acids for intestinal absorption.

Arginine administration is generally contraindicated in individuals with hepatic or renal failure, except when clinically appropriate and then only under direct medical supervision. ⁷

Individuals with a known history of hypersensitivity to arginine generally need to avoid supplemental intake.

Precautions and Warnings

Arginine administration, at usual dosage levels, is generally considered safe in individuals with stable type 2 diabetes mellitus. However, regular monitoring of blood glucose levels is appropriate in diabetic individuals supplementing with arginine because of possible effects on insulin and glucagon. ⁶

interactions review

Strategic Considerations

Despite positive findings from a range of disparate studies, scientific research on the therapeutic use of arginine has not matured; evidence of interactions involving arginine, based on well-designed clinical trials and documented case reports, is uneven and often absent. In many cases, well-known pharmacological principles enable us to predict many probable patterns of interaction, but the body of evidence articulating mechanisms, actions, and efficacy has not yet produced a consistent set of clinically applicable knowledge and related practices. Medical conditions and pharmaceutical agents that deplete or impair arginine status inherently influence relationships between NO and arginase and their interdependent levels and functions and consequently affect cardiac, muscular, and respiratory tissues and processes of growth, inflammation, and expansion/contraction. Interactions involving arginine are primarily characterized by their beneficial effect in supporting the therapeutic strategy and reducing drug adverse effects; such action inherently invokes the occasional bimodal interaction that carries potential for adverse or supportive character largely dependent on communication, observation, and responsive clinical management. Thus, for example, drugs that reduce arginase activity would theoretically increase arginine's availability to be converted to NO. Further research into this apparent bimodal activity of NO, and arginine, is warranted because some aspects of current knowledge suggest that excess NO levels might be involved in chronic inflammatory disorders. Any resulting evidence of peroxynitrate/nitrite formation from NO in situations of increased oxidative stress in the context of inadequate antioxidant reserves would suggest that clinicians give further attention to antioxidant reserves when administering arginine.

In some respects, arginine has already established a role for itself within the inpatient clinical setting, more so than in conventional outpatient care. Within critical care guidelines, arginine hydrochloride is considered a fourth-line treatment for uncompensated metabolic alkalosis after sodium chloride, potassium chloride, and ammonium chloride supplementation has been optimized. The immunomodulatory actions of arginine in nourishing hospitalized patients represent an area of continued research and significant potential benefit. Research on immunonutrition using arginine as part of parenteral formulas in combination with other nutrients has focused on mucosal barrier function, cellular defense, and local or systemic inflammation; results have been promising but mixed.

Within nutritional pharmacology and integrative therapeutic strategies, arginine is primarily used as a component of multifactorial interventions to promote detoxification (especially excretion of ammonia), stimulate immune function and modulate inflammation, aid wound healing, enhance healthy function of cardiac and vascular tissue, and promote secretion of several hormones, including glucagon, insulin, and GH. Thus, the emerging concept of immunonutrition as a proactive component of an integrative therapeutic strategy represents a convergence of conventional practice and nutritive therapies, with further research inevitable.

nutrient-drug interactions

Angiotensin-Converting Enzyme (ACE) Inhibitors

Benazepril (Lotensin), combination drug: benazepril and amlodipine (Lotrel); captopril (Capoten); captopril and hydrochlorothiazide (Acezide, Capto-Co, Captozide, Co-Zidocapt); cilazapril (Inhibace), enalapril (Vasotec); combination drugs: enalapril and felodipine (Lexxel); enalapril and hydrochlorothiazide (Vaseretic); fosinopril (Monopril), lisinopril (Prinivil, Zestril), lisinopril and hydrochlorothiazide (Prinzide, Zestoretic); moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace) trandolapril (Mavik).

Potassium-Sparing Diuretics

Amiloride (Midamor), spironolactone (Aldactone), triamterene (Dyrenium).Combination drugs: amiloride and hydrochlorothiazide (Moduretic), spironolactone and hydrochlorothiazide (Aldactazide), triamterene and hydrochlorothiazide (Dyazide, Maxzide).

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Hyperkalemia and hypotension are uncommon but potentially serious adverse effects associated with angiotensin-converting-enzyme (ACE) inhibitors, as a class (especially when combined with a potassium sparing diuretic or aldosterone antagonist), as well as with other antihypertensive agents.8-10Arginine administration can elevate potassium levels and produce arterial dilation. Intravenous arginine infusions can be used to treat metabolic alkalosis (in patients unresponsive to sodium chloride or potassium chloride supplementation) and are particularly known to induce hyperkalemia; they are also employed in laboratory testing for GH deficiency. Insulin and GH are also both responsive to arginine intake. Concomitant administration of arginine and antihypertensive medications (e.g., ACE inhibitor, potassium-sparing diuretic) could result in an additive effect on potassium levels, phosphorus levels, vascular dilation, and blood pressure lowering.

Research

Key factors that contribute to the potential interaction between arginine and ACE inhibitors have been the subject of human research, but comprehensive research is still in preliminary stages. Coadministration of arginine with ACE inhibitors alone or with other antihypertensive agents could potentially enhance the therapeutic effect on hypertension. However, unsupervised concomitant use of ACE inhibitors and arginine could result in excessive arginine levels, which would primarily manifest as excessive arterial dilation and inadvertent hypotension, through an additive effect.

In a small clinical trial involving 19 normal subjects, Massara et al.11noted that plasma phosphorus fell significantly; in 11 of 12 subjects, plasma potassium levels rose significantly after a 0.5 g/kg arginine infusion. In another small, controlled trial, Pezza et al.12found that hypertensive patients refractory to enalapril and hydrochlorothiazide responded favorably when arginine (2 g three times daily orally) was coadministered. In a double-blind trial involving 35 patients with essential hypertension, Abbott and Bakris13observed improved arterial dilation in subjects who received 6 gL-arginine in a one-time dose versus placebo (although it not did not change blood pressure immediately). No clinical trial or formal interactions research has been performed specifically investigating the effects of concomitant arginine and ACE inhibitor administration.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing antihypertensive medications such as ACE inhibitors or potassium-sparing diuretics are advised to ask patients about possible arginine supplementation and, if deemed clinically appropriate, closely supervise and regularly monitor such individuals for possible interactions between these agents. The nature of the possible interaction is variable, potentially beneficial or adverse, and still largely uncertain; effects in any given individual are likely to be influenced by such factors as dosage, timing, general health status, comorbid conditions, and pharmacogenomic variability. Physicians providing IV arginine should exercise special caution in administering such diagnostic procedures or therapeutic interventions to individuals who are also taking ACE inhibitors.

Caution and careful management are warranted in any patient supplementing with arginine while taking antihypertensive medications. Well-designed clinical trials comparing the effects of concomitant administration of antihypertensive medications and arginine are warranted to further determine arginine's ability to complement conventional antihypertensive therapy, determine parameters of appropriate usage and contraindications, and elucidate therapeutic protocols for effective integrative therapeutics.

Cyclosporine

Effect and Mechanism of Action

L-Arginine is the substrate for nitric oxide (NO) synthesis. A diminished role of the NO/cyclic guanosine monophosphate (cGMP)–mediated vasodilator mechanism, particularly NO blockade, may be responsible for cyclosporine-induced vascular dysfunction. Nitric oxide can decrease cyclosporine nephrotoxicity; it can also have both effector (cytotoxic) and regulatory roles in immune function.L-Arginine is also the substrate for both nitric oxide synthase (NOS), which produces NO, and a component in the experimental NOS inhibitor, N-nitro-L-arginine-methyl ester (L-NAME); both substances have been shown to modify acute cyclosporin A (CsA)–induced intrarenal vasoconstriction.

Research

Arginine has many beneficial effects on the kidneys and may be beneficial in many forms of renal disease, including hypertension and ureteral obstructive nephropathy. A series of studies using a rat model indicate that oral administration ofL-arginine can prevent chronic cyclosporine nephrotoxicity through effects on NO metabolites and cGMP.14-16Initially, Andoh et al.14found that “chronic CsA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement.” Later, Lee et al.16conducted in vitro experiments using tissue isolated from the thoracic aorta of normal rats and those acutely treated with CsA to investigate vascular relaxation response to acetylcholine and tissue levels of NO metabolites and cGMP. They found that acute treatment with CsA in vitro greatly attenuated the vasorelaxation response to acetylcholine and that such response was completely restored byL-arginine. The vascular accumulation of NO metabolites in response to acetylcholine was decreased significantly by CsA, but coadministration ofL-arginine prevented this effect. While CsA decreased cGMP accumulation in response to acetylcholine (and sodium nitroprusside), acetylcholine-stimulated cGMP generation was restored, although not completely, byL-arginine, but it did not affect sodium nitroprusside–stimulated cGMP generation. After chronic CsA treatment in the whole animal, the vasorelaxation response to acetylcholine was decreased significantly, along with tissue levels of NO metabolites; administration ofL-arginine preserved this effect. The authors concluded: “CsA causes anL-arginine-sensitive vascular dysfunction which is associated with impaired generation of NO and cGMP.”16Other research with animals indicates that arginine may inhibit tumor growth by activating macrophage cytotoxic effects.17

Zhang et al.18conducted a randomized, double-blind clinical trial involving 11 young renal allograft recipients, age 11 to 22 years, with chronic renal transplant dysfunction treated with CsA. The subjects were randomly assigned to a 6-week treatment period with placebo, followed by two subsequent 6-week periods withL-arginine supplementation (0.1 g/kg/day) or 6-week treatment withL-arginine, followed by two subsequent 6-week periods with placebo. At the end of each treatment period, 24-hour blood pressure readings were taken, and glomerular filtration rate (GFR), renal perfusion function (RPF; PAH clearance), and urinary excretion of protein, albumin, nitrate, cGMP, and urea were evaluated. These researchers found that subjects receiving arginine did not demonstrate significant changes in GFR, RPF, proteinuria/albuminuria, mean systolic/diastolic blood pressure, compared with placebo. These researchers concluded that arginine administration “did not improve renal function and did not decrease proteinuria in CsA-treated renal allograft recipients with chronic transplant dysfunction possibly because of inhibition of NO-cGMP forming mechanism.”18Given the negative results of this small clinical trial, with the suggestive preclinical data, clinicians might consider the question of how a trial might be designed with a stronger opportunity for a positive outcome. Higher doses, longer term, starting arginine vs. placebo concurrent with CsA, or other design variants might enable investigators to determine if CsA nephropathy can be prevented, if correction is not obtainable. Arginine may also increase oxidative stress by forming peroxynitrite radicals (NO reacting with superoxide radicals), so some measure of oxidative stress and correction with either dietary or supplemental antioxidants may be needed to demonstrate benefit.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The body of research on arginine can reasonably be interpreted as supporting the general hypothesis that arginine may provide a salutary effect to renal function, particularly in individuals whose kidneys are in a compromised state. However, the mixed character and preliminary state of the available research data suggest that sufficient evidence is lacking to support coadministration ofL-arginine as likely to offer significant definite benefit to patients undergoing cyclosporine therapy. Well-designed clinical trials comparing different dosage levels of arginine and pretreatment versus coadministration are warranted to further determine arginine's ability to mitigate adverse effects of CsA therapy and elucidate therapeutic protocols for effective integrative therapeutics.

Sildenafil and Related Phosphodiesterase-5 Inhibitors

Evidence: Sildenafil (Viagra).

Extrapolated, based on similar properties: Tadalafil (Cialis), vardenafil (Levitra).

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

The vasodilation necessary to an erection depends on NO.19The vasodilatory effect of arginine, as an enhancer of NO production, is broadly accepted. Sildenafil is generally considered to require the presence of NO for its effectiveness.20,21Other phosphodiesterase-5 (PDE-5) inhibitors, such as tadalafil and vardenafil, have exactly the same mechanism of action, varying only in pharmacokinetic parameters.

Research

Research into the therapeutic value of arginine in the treatment of men with erectile dysfunction (ED) is in preliminary stages, but the findings thus far support the hypothesis that enhancement of NO status can be efficacious, especially in men with NO deficiency or metabolic dysfunction.

In a small preliminary trial, Zorgniotti and Lizza22found that 6 of 15 men with ED demonstrated improvement after taking arginine, 2800 mg/day, for 2 weeks, versus no reported improvement with placebo. Subsequently, in a prospective randomized, double-blind, placebo-controlled trial, Chen et al.23administered arginine, 5 g/day, or placebo to 50 men with ED for 6 weeks. Plasma and urine nitrite and nitrate (designated NOx), both stable metabolites of NO, were determined at the end of the placebo run-in period and after 3 and 6 weeks. Nine of 29 (31%) patients takingL-arginine, as well as 2 of 17 controls, reported a significant subjective improvement in sexual function. However, plasma and urine NOx levels, which served as objective variables, remained unchanged. All nine patients who had subjectively improved sexual performance after being treated withL-arginine had initially demonstrated low urinary NOx, levels of which had doubled at the end of the study. Thus, these researchers concluded that arginine was particularly effective at providing significant subjective improvement in sexual function in men with organic ED who had abnormal NO metabolism, particularly decreased NOx excretion or production.

In a randomized trial involving 116 men who had undergone non-nerve-sparing radical pelvic surgery (64 prostatectomies and 52 cystectomies), Mantovani et al.19compared erectile function in those treated with sildenafil alone versus those administered both sildenafil andL-arginine. An initial 50-mg dose was inefficient in both groups (using Buckling test for evaluation), but 100-mg doses gave significant results (Buckling test >500) in both groups, especially those receiving the combined treatment.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing sildenafil for the treatment of ED are advised to discuss with patients the potential benefits of concomitant arginine therapy. Based on preliminary evidence, a beneficial interaction between sildenafil and supplemental arginine appears to be possible as a result of the additive effects of the actions of these substances on NO function, especially in individuals with abnormal NO metabolism. Such simultaneous administration could alter the effects and the dosage levels and timing appropriate to safe and effective therapeutic application of sildenafil. Of note, the effects of arginine on NO production are best produced by chronic administration, whereas the effects of sildenafil and the other PDE-5 inhibitors, occur with acute (i.e., on-demand) administration. Suggested arginine dosage levels have not been definitively established, although clinical experience suggests that 6 g daily is a reasonable target. Thus, close supervision and regular monitoring are appropriate, even though evidence is lacking to suggest a significant risk of adverse reactions. Well-designed clinical trials investigating the effects of arginine alone and together with PDE-5 inhibitors are warranted to further determine arginine's ability to complement conventional therapy, determine parameters of appropriate usage and possible contraindications, determine effective dosage levels, and elucidate therapeutic protocols for effective integrative therapeutics.

Theophylline/Aminophylline

Theophylline/aminophylline (Phyllocontin, Slo-Bid, Slo-Phyllin, Theo-24, Theo-Bid, Theocron, Theo-Dur, Theolair, Truphylline, Uni-Dur, Uniphyl); combination drug: ephedrine, guaifenesin, and theophylline (Primatene Dual Action).

Probability: XXX
Evidence Base: XXX

Effect and Mechanism of Action

Nitric oxide deficiency appears to play a major role in inducing airway hyperreactivity and other aspects of asthma pathogenesis. In particular, a relative deficiency of NO caused by increased arginase activity and alteredL-arginine homeostasis is a major factor in the pathology of asthma.24Based on research of arginine metabolism and caffeine action, the therapeutic action of theophylline (aminophylline) may be attributable, at least in part, to their effect in increasing cellular levels of cyclic adenosine monophosphate (cAMP) and thereby depressing arginase activity.25Drugs that reduce arginase activity would theoretically increase arginine's availability to be converted to NO. Administration of arginine in the context of methylxanthine therapy could create a beneficial additive or synergistic effect against pathophysiological components of asthma by enhancing NO levels.

Research

These bronchodilator drugs are primarily used in the treatment of asthma, for which arginine's central role is becoming increasingly clear within the scientific literature and medical research. Nitric oxide is a critical regulator of airway physiology, including airway and vascular smooth muscle tone.26The NOS and arginase pathways interfere with each other through substrate competition. A review of recent research indicates that a deficiency of beneficial, bronchodilating, constitutive NOS (cNOS)–derived NO is important in allergen-induced airway hyperresponsiveness, and that increased arginase activity and decreased cellular uptake ofL-arginine appear to play a key role.24Interpreting the findings of Zimmermann et al.,27based on a mouse model, Vercelli28showed that “NO inhibition resulted from substrate competition,” because expression of arginase, but not NOS, was altered in the lungs of the allergen-challenged mice. Meurs et al.29found that increased arginase activity underlies allergen-induced deficiency of cNOS-derived NO and airway hyperresponsiveness. Arginase expression appears to be controlled by Tce:section-title cytokines, central mediators of allergic asthma.30During allergic inflammation, increased IL-4 and/or IL-13 expression results in increased expression of arginase and amplification of the arginase-dependent pathway, with concomitant suppression of NO generation.28In particular, “while these enzymes are constitutively expressed, NOS-2 is an inducible enzyme independent of calcium and highly induced in inflammatory diseases such as allergic asthma, where NO may act beneficial or deleterious depending on the site … and amount of generation.”26The emerging connections between the NO pathway, inflammatory response, and collagen generation “make arginine metabolism a rising star in the asthma firmament.”28

Wechsler et al.31demonstrated an increased NO concentration in exhaled air in patients with asthma and observed an association with the asthmatic phenotype, in particular, NOS-1 genotype. Morris et al.32measured amino acid levels, arginase activity, and NO metabolites in the blood of asthmatic patients, as well as NO in exhaled breath. They found that “although levels of virtually all amino acids were reduced, asthmatic patients exhibited a striking reduction in plasma arginine levels compared to non-asthmatic normal controls.” These researchers concluded: “High arginase activity in asthmatic patients may contribute to low circulating arginine levels, thereby limiting arginine bioavailability and creating a nitric oxide deficiency that induces hyperreactive airways.”

The compiled findings could be interpreted to support the hypothesis that arginine could serve as a therapeutically efficacious component of a comprehensive strategy for the treatment of individuals with asthma, or at least some subpopulation, whether refractory to conventional care or defined by one or more genomic factors. Further, given the known and emerging knowledge of the mechanisms of action exerted by methylxanthines, a beneficial interaction appears pharmacologically plausible from concomitant administration of arginine with these agents.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing theophylline (or other methylxanthines) might consider discussing with patients the possible benefits of arginine administration, if deemed clinically appropriate. The nature of the possible interaction is variable, with possibly beneficial but also potential (although as yet unknown) adverse effects, in any given individual and likely to be influenced by such factors as dosage, timing, general health status, comorbid conditions, and pharmacogenomic variability. Close supervision and regular monitoring of such individuals for therapeutic response and potential adverse interactions are warranted.

Asthma is a disease of inherent complexity and variability that remains a major medical and scientific challenge despite intense research efforts and a growing number of affected individuals. Although inhaled corticosteroids and beta-2-agonist bronchodilators have become the mainstay of asthma therapy, a complete understanding of the pathogenetic mechanisms of the disease, as well as diverse and difficult to define factors of individual variability in susceptibility, presentation, and exacerbation, continues to elude researchers. Caution and careful management are warranted when modifying the therapeutic intervention in any patient with asthma, especially those taking bronchodilators, whether inhaled or systemic. Well-designed clinical trials investigating the effects of arginine alone and together with theophylline (or other methylxanthines) are warranted to further determine arginine's ability to complement conventional bronchodilator therapy, determine parameters of appropriate usage and contraindications, and elucidate therapeutic protocols for effective integrative therapeutics.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Estrogen-Progestin Combinations

Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)

Hormone Replacement Therapy, Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications

The concomitant use of an estrogen-progestin combination and an arginine preparation might theoretically result in increased toxicity effects because of resultant effects on GH response and glucagon and insulin effects. Although this interaction appears plausible, there is a lack of evidence from clinical trials and well-documented case reports characterizing such an interaction, defining its frequency and context of occurrence, or establishing its clinical implications.

Nitrates

Amyl nitrate, isosorbide dinitrate (ISDN, Isordil, Sorbitrate); combination drug: hydralazine and isosorbide dinitrate (BiDil); isosorbide mononitrate (Imdur, ISMN, ISMO, Isotrate, Monoket).

Members of the nitrate family of drugs are used to prevent angina. Human research has shown that arginine, as an NO precursor, also is potentially beneficial for individuals with angina or other cardiovascular conditions. An interaction between nitrate medications and arginine could potentially result from the additive effects of the similar actions of these substances if taken concomitantly. Such simultaneous administration could alter the effects and the dosage levels and timing appropriate to safe and effective therapeutic application of these agents. ³³ Evidence from clinical trials or documented case reports is lacking at this time to confirm this theoretically possible interaction or characterize its frequency, context, or severity.

Pentoxifylline

Pentoxifylline (Pentoxil, Trenta).

Based on research of arginine metabolism and caffeine action, the therapeutic action of pentoxifylline may be attributable, at least in part, to the shared effect of methylxanthines in increasing cellular levels of cAMP and thus depressing arginase activity and increasing arginine's availability for conversion to NO. ²⁵ Evidence from clinical trials or documented case reports is lacking at this time to confirm this theoretically possible interaction or characterize its frequency, context, or severity. Pentoxifylline's documented, though modest, enhancement of compromised circulation would theoretically synergize with arginine's ability to enhance endothelial function and vasodilation by optimizing NO production. Well-designed clinical trials to explore such possible synergy would seem indicated.

nutrient-nutrient interactions

Lysine

Within the world of nutritional anecdotes, the antagonistic relationship between L-lysine and L-arginine has taken on almost self-evident status, particularly within the context of preventing herpes simplex by administering lysine and reducing arginine intake. However, although the evidence supporting such conclusions is emerging, it remains inconclusive.

Arginine and lysine compete for absorption into cells, so increased intake of either amino acid can decrease levels of the other. Consequently, a diet low in lysine can enhance effects of arginine supplementation because lysine competes with arginine for absorption. Furthermore, increased arginine intake is reputed to enhance arginine status, together with the benefits and risks attendant to such an environment. This competitive relationship appears to be founded on reasonable pharmacological principles.

Anecdotal reports based on consumption of foods with a high arginine/lysine ratios (e.g., nuts, peanuts, chocolate) and in vitro research dating back to 1964 indicate that HSV has a high requirement for arginine and lysine inhibits viral replication. ⁶ Findings from several clinical trials of varying size and design have generally supported the hypothesis that lysine intake reduces the recurrence rate of HSV infections. ^34-38

Although the available evidence is strongly suggestive rather than conclusive, conservative practice warrants approaching arginine and lysine as metabolic competitors and therefore requiring that diet and supplemental intake be adjusted in accordance with clinical objectives. The immune-enhancing functions of arginine are well known, but it appears judicious to advise decreasing arginine intake and increasing lysine intake with susceptible individuals, to prevent or resolve herpes simplex outbreaks. Further research with large, well-designed clinical trials is warranted to advance and clarify the metabolic relationship between these two amino acids, define factors of individual variability in response patterns and disease susceptibilities, and develop balanced and comprehensive guidelines for evidence-based clinical application of these key nutrients.

Omega-3 Fatty Acids (Fish Oils)

In a 6-month, prospective, randomized, double-blind controlled study involving 64 HIV-infected outpatients (with CD4 lymphocyte count ≥100 × 10 ⁶ /L), Pichard et al. ³⁹ found that the addition of arginine and omega-3 fatty acids did not improve immunological parameters, compared with a group receiving only the base multinutrient oral supplement; body weight increased in both groups. The synergy between omega-3 fatty acids and arginine in supporting wound healing and tissue regeneration warrants further research and development of evidence-based clinical guidelines.

See also Parenteral and Enteral Nutritional Formulations.

Ornithine

Interest in the potentially beneficial synergy between arginine and ornithine largely derives from knowledge of arginine's function as a precursor of ornithine and their respective roles in GH secretion. Approximately 50% of arginine intake is rapidly converted to ornithine, primarily through the action of arginase. Ornithine can subsequently be metabolized to glutamate and proline, or into the polyamine pathway, under the action of ornithine decarboxylase. ⁴⁰

Coadministration of arginine and ornithine, often with other nutrients, has been suggested as a means of enhancing GH levels and thereby increasing development of muscle tissue and lean body mass, increasing gains in strength, and decreasing proportional body fat, primarily within the context of athletic training and body building.

Elam ⁴¹ reported that coadministration of arginine and ornithine (500 mg each twice daily, five times weekly) in a controlled clinical trial involving adult males, in conjunction with resistance exercise, produced a significant decrease in body fat. Subsequently, in a double-blinded clinical trial framed around a 5-week progressive strength-training program, Elam observed that a arginine-ornithine combination (1 g each, orally, five times weekly) scored significantly higher gains in total strength and enhancement of lean body mass compared to controls administered vitamin C and calcium as placebo. Elam et al. ⁴² also noted that arginine and ornithine enhanced recovery from chronic physiological stress by quelling tissue breakdown, as evidenced by lower urinary hydroxyproline levels.

However, Marcell et al. ⁴³ found that acute arginine administration (5 g orally 30 minutes before exercise) did not stimulate basal or augment exercise-induced GH secretion in either young or old adults and may actually have impaired GH secretion in young adults.

Further research comparing timing, duration, and dosage levels of combined supplementation with arginine and ornithine through clinical trials of adequate size and appropriate design is warranted to elucidate the relationship of these nutrients in building lean body mass, particularly muscle tissue, and facilitating breakdown of adipose tissue.

Parenteral and Enteral Nutrition Formulations Containing Antioxidants, Fatty Acids, and Other Nutrients

Arginine is often used with nutrients as part of multi-ingredient immunonutrition-parenteral formulas administered to patients who are recovering from injury, burns, or surgery or otherwise critically ill. Three meta-analyses found that immunonutrition results in notable reductions in infection rate and length of hospital stay, with greater benefit observed in surgical than critically ill patients. However, there was an overall lack of significant impact on outcomes, particularly mortality, and at least one study indicated significant risk of increased mortality in critically ill patients receiving immunonutrition, especially when sepsis was involved. ^44-49 “A biphasic response with an early hyperinflammatory response followed by an excessive compensatory response associated with immunosuppression” is seen in many critically ill patients. ⁴⁹ Several clinical trials have reported positive outcomes (as indicated by measures of immune function) in oncology and trauma recovery patients administered formulations containing arginine, glutamine, omega-3 fatty acids, RNA or nucleotides, and other nutrients, typically in the form of enriched enteral diets. ^50-54

In a prospective, multicenter, single-blind, randomized trial, Caparros et al. ⁵⁵ investigated the effect on nosocomial infections and outcome of early enteral nutrition in 220 critically ill intensive care unit (ICU) patients with a high-protein diet enriched with arginine, fiber, and antioxidants, compared with a standard high-protein diet. These researchers found that critically ill patients fed a high-protein diet enriched with arginine, fiber, and antioxidants had a significantly lower catheter-related sepsis rate than patients fed a standard high-protein diet. Further, although there were no differences in mortality or ICU and hospital length of stay between the two groups, the patients fed the study diet for more than 2 days showed a trend toward decreased mortality.

The preliminary nature and sometimes contradictory findings of studies thus far conducted suggest that different nutrient formulations may be appropriate for varying patient populations, Continued research into these integrative approaches to nutritional support within inpatient care settings, in general, and critical care, in particular, through large, well-designed clinical trials, is clearly warranted.

See also Omega-3 Fatty Acids (Fish Oils).

herb-nutrient interactions

Yohimbe

Yohimbe (Pausinystalia yohimbe; Corynanthe yohimbe (Corynanthejohimbe).

The major identified alkaloid in yohimbe is yohimbine, an alkaloid that blocks alpha-adrenergic outflow, thereby increasing parasympathetic tone. This can promote erectile function, as well as have blood pressure–lowering effects. Purified yohimbine is a prescription drug in the United States, but it is also found in herbal preparations at lower doses.

In a double-blind, placebo-controlled, three-way crossover, randomized clinical trial involving 45 men with ED, Lebret et al. ⁵⁶ compared the efficacy and safety of the combination of L-arginine glutamate (6 g) and yohimbine hydrochloride (6 mg) with that of yohimbine hydrochloride (6 mg) alone and that of placebo, administered orally, 1 to 2 hours before intended sexual intercourse. Based on the findings from this pilot study, these researchers concluded that “the on-demand oral administration of the L-arginine glutamate (6 g) and yohimbine (6 mg) combination is effective in improving erectile function in patients with mild to moderate erectile dysfunction,” as measured by Erectile Function Domain scores and patients’ assessment of efficacy.

Well-designed clinical trials investigating the combined effects of arginine and yohimbe derivatives are warranted to further determine safety and efficacy, determine parameters of appropriate usage and possible contraindications, determine effective dosage levels, and elucidate therapeutic protocols for effective integrative therapeutics.

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