Arginine becomes essential when your body is compromised due to conditions like infection and trauma, and your arginine needs significantly increase due to physiologic demands. Under these circumstances, your body can no longer fulfill your arginine needs, which must be met through external sources.
Arginine depletion during critical illness or after surgery leads to serious adverse effects, including impaired immune function and blood flow. To avoid these potential complications, arginine supplements are used frequently in the clinical setting to treat a variety of conditions. For example, oral or IV arginine is commonly used to treat serious infections like necrotizing enterocolitis in infants, cases of sepsis, burns, chronic disease, and wounds, as well as in pre- and post-surgical and trauma patients 5 , Research shows that L-arginine may benefit those with diabetes by improving glucose metabolism and insulin sensitivity L-arginine is needed for the production of nitric oxide.
Therefore, increasing nitric oxide availability may help enhance the function of cells that secrete insulin and help your body use blood sugar more efficiently. Some research has shown that long-term treatment with L-arginine supplements may prevent diabetes in at-risk populations A study in people with impaired blood sugar regulation found that treatment with 6. In addition to the potential benefits listed above, some research suggests that L-arginine supplements may be helpful when used in the following ways:.
This list is not exhaustive, and L-arginine has been studied for its potential beneficial effects on various conditions, including obesity, heart disease, cancer, polycystic ovary syndrome PCOS , infertility, and anxiety, either used on its own or in combination with other supplements.
However, research on the effects of L-arginine in people with these and many other conditions is limited and inconclusive, highlighting the need for future studies In addition to the potential benefits and uses above, many people take L-arginine supplements for a variety of other reasons, including reducing the risk of the common cold and boosting weight loss.
Overall, research has shown that L-arginine is safe and generally well tolerated when taken in supplement form, even when taken daily over long periods of 1 year or more However, it can cause unpleasant side effects, including bloating , abdominal pain, nausea, and diarrhea, especially when taken in large doses of 9 grams or more per day 1.
Yet, one day study in adults demonstrated that a daily dose of up to 30 grams was well tolerated and not associated with any adverse effects, suggesting that even very high doses of L-arginine are usually safe, at least in the short term Even though they have a strong safety profile, arginine supplements should be avoided by certain populations.
For example, those with asthma, cirrhosis of the liver, kidney disease, low blood pressure, and guanidinoacetate methyltransferase deficiency — an inherited disorder that affects arginine metabolism, should avoid L-arginine due to the potential for adverse effects For example, studies investigating the effects of L-arginine on blood pressure have used doses of 6—30 grams per day for 2—24 weeks 22 , In those with erectile dysfunction, research has suggested that supplementing daily with 1.
L-arginine may also be given intravenously to pregnant women with high blood pressure in the clinical setting 22 , This is explained in greater detail later in this article.
L-arginine may interact with certain medications, including 22 :. Additionally, L-arginine may interact with certain supplements and substances, including 22 :. Keep L-arginine supplements in a cool, dry area.
Avoid exposing the supplement to heat or moisture. L-arginine supplementation during pregnancy is typically prescribed and monitored by a healthcare provider for a specific reason, such as preeclampsia or the risk of preeclampsia and intrauterine growth restriction IUGR 22 , This increased need may not be met through diet, especially in women living in low-resource settings without access to protein-rich foods Additionally, although the increased demand for arginine during pregnancy can be provided through diet, protein or individual amino acid supplements may be necessary under certain circumstances.
This may include women who follow restrictive diets or are experiencing severe nausea and vomiting during pregnancy , rendering them unable to meet demands through dietary intake. However, supplements during pregnancy should always be approved and monitored by a healthcare provider. If you are pregnant and interested in taking supplemental L-arginine, consult your healthcare provider for advice.
L-arginine supplements have not been researched in breastfeeding women. The safety of L-arginine has been demonstrated in many populations, including pregnant women and older adults. L-arginine is also found in most protein-rich foods, including fish, red meat, poultry, soy, whole grains, beans and dairy products.
As a supplement, L-arginine can be used orally and topically. It can also be administered intravenously IV. Because L-arginine acts as a vasodilator, opening dilating blood vessels, many people take oral L-arginine to treat heart conditions and erectile dysfunction. L-arginine is considered to be generally safe. It might be effective at lowering blood pressure, reducing the symptoms of angina and PAD , and treating erectile dysfunction due to a physical cause.
L-arginine isn't recommended for people who have had a recent heart attack due to concerns that the supplement might increase the risk of death. L-arginine can worsen allergies or asthma. Use the supplement with caution if you have these conditions. Be careful about taking L-arginine if you've had cold sores or genital herpes. Too much L-arginine in your system can potentially trigger the virus that causes those conditions. There is a problem with information submitted for this request.
Sign up for free, and stay up-to-date on research advancements, health tips and current health topics, like COVID, plus expert advice on managing your health. Error Email field is required. On the basis of these important and diverse metabolic effects, a number of studies have suggested that Arg may be an effective nutriceutical to treat obesity and the associated metabolic prequelae and sequaelae of adiposity in adults.
Despite the plethora of beneficial effects discovered to date, a full understanding of the relative benefits and potential adverse effects of Arg on human metabolism is warranted and should include the recognition of differences between animal and human pathophysiology 7 , 8. The purpose of this review is to summarize the current knowledge with regard to the safety of Arg, especially noting data from recent studies in animals and humans pertinent to the effects of Arg on adipose tissue and the metabolic derangements associated with adiposity.
Overview of Arg metabolism in humans. Arg in the plasma derives from dietary intake of Arg, whole-body catabolism of protein, and endogenous synthesis of Arg from citrulline. The latter is formed from the catabolism of glutamine, glutamate, and proline in the small intestine. In addition to serving as a precursor of protein synthesis, Arg is utilized to generate many low-molecular-weight molecules including NO, polyamines, creatine, agmatine, homoarginine, and urea in a tissue-specific manner.
Adapted from reference 5 with permission. Dietary sources include protein-rich foods such as nuts e. Arg is metabolized extensively in the small intestine and extraintestinal tissues 3.
Castillo et al. Thus, substantial amounts of dietary Arg are not available to tissues other than those in the digestive system. Future research is required to provide data on Arg catabolism by the human small intestine.
Pharmacokinetics studies have found that intravenous or orally administered Arg is rapidly utilized by adult humans. For example, data from Tangphao et al. There was no renal excretion observed after an oral dose, whereas this is the primary pathway of excretion with an intravenous dose.
Arg concentrations in the plasma declined but did not return to baseline even after 8 h. Evans et al. Schwedhelm et al.
They did not specify if these increases were significant. The discrepancies between studies suggest that the absorption of arginine is dependent on known factors form and concentration of Arg, mode and timing of dosing, small sample sizes and factors difficult to account for e.
The terminology used to describe safety with respect to medication use is inconsistent among studies 17 , and there is no universally agreed-upon definition among various international drug regulatory bodies. In general, however, adverse events are distinguished from adverse drug reactions and side effects. For the purposes of IND, or investigational new drug, safety reporting, reasonable possibility means there is evidence to suggest a causal relation between the drug and the adverse event.
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug That is, the former adverse event, also referred to as an adverse drug event does not require a causal link between the drug and the event, whereas the latter adverse reaction, also referred to as an adverse drug reaction does. An example of an adverse drug reaction would be an allergy to the drug. For example, Schulman et al.
They reported more adverse events death, myocardial infarction, and hospitalization for heart failure in the Arg group than in the placebo group, including 6 deaths in the Arg group compared with none in the placebo group, and the study was stopped prematurely because of these adverse events despite the fact that the number of deaths was lower than the expected mortality risk 21 , Adverse reactions primarily gastrointestinal problems were equal in both groups.
Although it has been pointed out that there was no evidence to support a causal effect of Arg in the active treatment group, the excess mortality was accurately characterized as an adverse event and the trial was appropriately stopped.
Animal models provide important data to establish mechanisms of action for a drug, as well as drug safety, but there are recognized limitations.
Clinical trials in humans are more complex because of genomic and pharmacogenomic diversity, resulting in different concentrations of key metabolic enzymes and their isozymes and patterns of tissue-specific expression 8. In addition, there are dissimilarities, minor and major, between mammalian species with respect to metabolic pathways and overall organ function. For example, no single animal species is a perfect model of the gastrointestinal anatomy, physiology, and biochemistry in humans The longevity of humans compared with animals also contributes to potential long-term drug toxicities that may occur after acute or chronic drug administration, soon or long after exposure to the drug, as evidenced by the ongoing discussions concerning statin therapy Because of greater human longevity as well as genetic and environmental factors, animal models may therefore not fully evaluate the risk of developing various malignancies that involve abnormalities in key enzymes of Arg metabolism and that result in Arg auxotrophy.
Several large-animal models have provided genetic, metabolic, and physiologic data for a multitude of human diseases 25 — Pigs are a particularly good model for assessing human risk because of similarities to humans with respect to digestion, metabolism, and physiology A limitation of animal models is that dose-limiting adverse reactions may go undetected in animals, including gastrointestinal symptoms such as dyspepsia, abdominal cramping, bloating, etc.
However, as animal models for establishing the maximal recommended starting dose with respect to safety considerations, pig, sheep, and rat models provide robust, supportive data for the safety and efficacy of Arg, as described in the review by Wu et al. Based solely on the animal data summarized in that review, the observed safe level OSL for oral Arg supplementation in healthy pigs and rats was 0. Arg deprivation chemotherapy has been used to treat several types of cancers i.
Paradoxically, only a few studies have shown that Arg supplementation may stimulate tumor growth and none of the studies concerned malignancies that respond to Arg deprivation therapy 34 , Therefore, the safety of supplemental Arg in people who may be predisposed to or who have undiagnosed malignancies remains to be established.
In rare situations, such as Arg-dependent malignancies, reducing the Arg concentration pharmaceutically as well as by decreasing dietary Arg may be beneficial, but most often the impact of supplementing Arg on human health and diseases is beneficial 1 , 2 , 9. For example, supplemental Arg has been shown to be favorable in human studies that evaluate fertility, fetal growth and development, preeclampsia and preterm birth, prevention of necrotizing enterocolitis in preterm infants, endothelial function, wound healing, immune function, arterial pressure, dental caries, and tumor growth.
Evidence also shows that Arg has favorable effects on fat mass reduction, IR, and type 2 diabetes T2D , which are discussed in greater detail below 2. The OSL and the Tolerable Upper Intake Level for oral Arg reported in the literature also differ widely, likely due to different experimental conditions e.
More long-term studies are needed to fully address the issue of Arg safety in humans. We previously reviewed the safety and beneficial effects of Arg in youth 37 and we limited the current review to data from the adult population.
Shao and Hathcock 36 published an extensive, comprehensive, and highly detailed review of 38 clinical trials of Arg in adults from to , including studies in medically fragile populations such as the elderly and individuals with renal, pulmonary, and cardiovascular diseases, among others. They excluded studies in patients with certain gastrointestinal diseases, malignancies, severe burns, trauma, and other hypercatabolic states.
One error we wish to correct in the Shao and Hathcock review 36 pertains to the highest dose studied [i. However, patients with CF have a markedly lower weight, especially in the young, predominantly female subjects included in this particular study mean age was 22 y, with a range of 14—37 y. In addition, the OSL estimated from this singular study was based only on pulmonary function data rather than any metabolic survey data.
Studies carried out in pregnant women, a potentially more vulnerable population, also have not raised any safety concerns.
Gui et al. They found that Arg was more effective in reducing preeclampsia or eclampsia incidence OR: 0. Three of 12 studies reported adverse reactions, primarily associated with common gastrointestinal effects of Arg, including nausea, dyspepsia, and diarrhea, although palpitations, headache, and numbness were also reported in some cases.
The data from human studies, although limited, show similar positive effects on insulin sensitivity and fat mass reduction, although it should be noted that the same Italian group who enrolled a more homogenous population and used a similar methodology published several studies.
The most notable study, published by Monti et al. After treatment was stopped, the subjects were followed for an additional 12 mo. During the mo treatment phase, there were significant changes including an increase in the plasma fasting Arg concentration in the Arg-treated group compared with placebo At the end of the extended period, only Clinical studies involving oral administration of Arg to adult humans with obesity, insulin resistance and T2D 1.
The number in parentheses refers to the number of study subjects in the Arg treatment group. No information was provided on the frequency of dosing for oral Arg supplementation by study subjects. Lucotti et al. The subjects were given either Arg 8. There was a significant increase in the Arg plasma concentration from Although this type of intervention is not clinically feasible, it showed a clear metabolic advantage of Arg.
As in the study by Monti et al. In a third study, Lucotti et al. Compared with the placebo group, there was a significant increase in the plasma Arg concentration from baseline There was no effect on fasting glucose or the glycated hemoglobin concentration, but the authors did find a substantial increase in NO concentration and total antioxidant status plasma Arg concentrations were not reported.
More recently, Hurt et al. The 13 women who completed the study showed a significant 5. There was a significant increase in Arg concentrations from baseline at both 6 and 12 wk.
Because this was an open-label study no placebo and because it also incorporated considerable lifestyle counseling, it is difficult to attribute the reduction in adiposity entirely to Arg.
Some studies reported a beneficial effect of Arg on blood pressure. On the basis of animal studies, Arg has beneficial effects on adipocyte metabolism and has been shown to reduce weight and white fat mass while increasing brown fat and skeletal muscle mass. Such experiments are still lacking in humans, but given the relatively high OSL, this nutriceutical alone or in combination with pharmaceuticals that can reduce adiposity and IR may offer an inexpensive therapeutic option worthy of exploration given the worldwide epidemic of obesity and the associated metabolic sequelae.
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