L-arginine – Latest Research Included

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Objective

L-arginine is an amino acid semi-essential that serves as the base for the production of nitric oxygen by immune and vascular endothelial cells. The production of nitric oxide by immune cells is vital for blood pressure regulation and the regulation of immune function. There is, however, a lot of divergence in the literature regarding randomized controlled trials, and that's why this review of all published meta-analyses was done to determine the effectiveness of l-arginine's function as an agent of treatment.

Methods

The overall search of the literature between 1 January 1980 and December 31st, 2015., in three databases: PubMed, Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature–using the following method of searching: (arginine) AND (meta-analysis OR systematic review). Only English publications in the English language were found that offered quantitative analysis of immunity and blood pressure.

Results

The seven meta-analyses included in this review showed significant positive results in reducing diastolic and systolic blood pressure in adults with hypertension in the 2.2 to 5.4 millimeters, respectively. 2.7 to 3.1 millimeters, decreasing diastolic blood pressure for pregnant women suffering from high blood pressure during pregnancy by 4.9 millimeters and reducing the duration of hospitalization for patients undergoing surgery. In addition, two of the three meta-analyses showed an increase of 40% in hospital-acquired infections. However, these positive findings will be taken with a pinch of salt due to the statistically significant heterogeneity in five of the seven meta-analyses.

For example, if the image was linked to the study on the effects of supplementing with l-arginine, it could show changes in blood pressure, the prevalence of hospital-acquired illnesses, or the diversity among the studies included during the meta-analysis. It could also evaluate the quality or bias of the studies reviewed.

Simplified Summary of Meta-Analyses on l-Arginine

  • Dong et al. (2011)

      • Participants: 387 adults (72 percent hypertension)
      • Dose 10g/d, orally every day for five weeks
      • Findings: Decrease in SBP by 5.4 mm Hg and DBP by 2.7 mm Hg
      • Qualitative: Some high, others low, some low
      • Consistency: Moderate for SBP, low for DBP
  • Zhu et al. (2013)

      • Participants: 296 pregnant women
      • Dose Orally, 8 grams orally. IV over 10 days.
      • Results: Minor decrease in SBP, but a more significant decrease in DBP
      • Qualitative: Mostly high
      • Conformity: Very high, very little variation
  • Gui et al. (2014)

      • Participants: 204 pregnant women
      • Dosage: 8g/d orally or 25g/d IV for 10 consecutive days.
      • Results: Decrease in SBP and significant reduction in DBP
      • High-quality: Mostly high, one study did not include
      • Consistency: Moderate for SBP, low for DBP
  • Bai et al. (2009)

      • Participants: 493 adults
      • Dose Dosage of 10g/day orally over 18 days.
      • Results: Improvement in flow-mediated dilation
      • Quality: High
      • Congruency: Very high
  • Drover et al. (2011)

      • Patients: 2780 surgical patients
      • Dose: Not reported
      • Results: Reduced infection rates and shorter hospital stay
      • Quality: Above average
      • Consistency moderate for infections High for duration of stay
  • Vidal-Casariego et al. (2014)

      • Participants: 348 patients with cancer of the neck and head.
      • Dose 11.7g/L intravenous for 7.5 days
      • Results: Mixed outcomes for infections and significant reductions in fistulas after surgery.
      • High Quality Most of the time high. certain exclusions
      • Consistency: Moderate
  • Kang et al. (2014)

      • Participants: 168 hospital patients
      • Dose 16.g/d for 16 days
      • Results: Reduced infection rates and slight increase in albumin levels, significant growth in CD4 count
      • Qualitative: Mostly high
      • Consistency The CD4 counts are high and moderate for albumin, Very high in terms of infection rates.

This summary summarizes the findings of various studies that have examined the effects of l'arginine on different conditions and demographics.

Conclusions

A few studies suggest the benefits of supplementing with l-arginine to reduce diastolic and systolic blood pressures in hypertensive adults, the risk of hospital-acquired infections, and the time spent in hospitals treating surgical patients. Because of the limitations of the studies that were included, the conclusions must be taken with care.

Introduction

L-arginine is a semi-essential amino acid high in certain foods like meats and nuts. L-arginine serves as the substrate for the enzyme nitric oxygen synthase (NOS), which creates Nitric oxide. Nitric oxide produced by the vascular endothelium through endothelial NOS is the reason for the relaxation of smooth muscle cells and is vital for reducing blood pressure. Any improvement in the function of the endothelial system helps prevent cardiovascular diseases. L-arginine is also utilized by the immune system's cells, where the enzyme inducible NOS creates nitric oxide to aid in cell signaling and antioxidant bactericidal effects. Thus, l-arginine can help reduce the infection rate, especially in circumstances that affect immune function, like surgery or disease.

Various clinical trials have been conducted to assess the function of L-arginine in blood pressure control for preeclampsia and hypertensive populations. However, the sample sizes used in most of these studies were insignificant, and the results were often inconsistent and negligible. Additionally, clinical studies of l-arginine supplementation, hospital or surgical patients' infection rates, and duration of stay in the hospital have utilized smaller sample sizes, and some outcomes didn't reach statistical significance. The research has concluded that the efficacy of arginine in higher doses than standard diet methods has not been proven in clinical studies, and they have been hampered by a lack of the statistical power required, heterogeneity of patients, and randomization errors.

Due to the inconsistent nature of the literature available and the lack of statistical power resulting from the lack of small sample sizes, collecting information from individual studies may provide an accurate and precise estimation of the effect of arginine supplementation on blood pressure and immunity. Most researchers have shifted to a highly effective statistical procedure called meta-analysis to accomplish this. Meta-analyses are essential to provide the highest quality of evidence needed to inform healthcare decision-making.

This article presents the research evidence from various studies to assess the effectiveness of l-arginine's function as an agent for healing. It was decided to carry out an umbrella study to achieve this objective. An umbrella review offers an overview of the research synopsis and evaluates whether the authors who tackle similar review issues independently see identical results and come to similar conclusions.

Methods

The systematic search using PubMed and the Cochrane Library, and Cumulative Index through Nursing and Allied Health Literature from January 1st, 1980 until the 31st of December, 2015, was carried out by using the following search strategy: “(arginine) AND (meta-analysis OR systematic review)”. Only English publications in English were found that offered quantitative analysis of immunity and blood pressure. Systematic reviews or meta-analyses which did not provide study-specific summaries using at least 4 randomized controlled trials were not considered.

For all papers published that were accepted for inclusion in this study, the following data was extracted and entered into the Excel spreadsheet: the number of articles that were included in the meta-analysis, the number of participants in total, as well as the dose and method used for L-arginine supplementation, combined results of treatment for clinical endpoints like diastolic and systolic blood pressure, relative rates of infection and the length of hospitalization in days. Since the review is descriptive of meta-analyses, the analysis was not statistical.

The papers were also evaluated for transparency of the quality assessment, statistical variability (Cochran Quantitative Test (Q test) and I2 statistics), and bias in publication (visual examination of funnel plots and Egger and Begg regression tests).

Results

The initial search resulted in an impressive 93 citations. Of those, 84 were discarded, and after further examination, two meta-analyses were rejected since they both were based on statistical analysis of just two clinical trials (one examined the effect of l-arginine supplementation in determining the outcome of patients with acute myocardial infarction and the second one looked into the role of l-arginine supplementation to prevent the development from necrotizing enterocolitis among premature infants).7 8 The remaining seven meta-analyses have been retrieved to be included in this comprehensive review. A flow diagram of the process used to select the meta-analyses can be seen in Figure 1. Table 1 gives a detailed analysis of the seven meta-analyses that were reviewed.

Regarding quality assessments, each of the seven meta-analyses carried out such evaluations, and 2 meta-analyses excluded studies due to poor quality.11 14 Gui and Al11 did not exclude one study, and Vidal-Casariego excluded 5 research studies from their meta-analyses due to their low score on Jadad's quality assessment scale. Of the seven meta-analyses that did quality assessments, 3 utilized 3 scales based on the Jadad qualitative assessment scale. 3 utilized the 0-5 quality measure, while one employed a 0 to 14 scale. None of the seven meta-analyses did not report their findings. On average, half of the studies incorporated into these meta-analyses were judged as high-quality. The top-quality studies included in these meta-analyses are listed in Table 1.

The major findings of this review are that the l-arginine supplementation has significantly reduced diastolic and systolic blood pressures in a mostly hypertensive group (hypertensive participants comprising 72 percent of all participants); however, only diastolic blood pressure was significantly decreased in pregnant women. L-Arginine supplementation significantly increased vascular endothelial functions according to flow-mediated dilation (FMD). L-Arginine administered via the intravenous route to surgical patients reduced the incidence of infections and duration of stay in the hospital. However, the infection rate was not significantly reduced in patients who underwent surgery for neck cancer. Patients receiving intravenous l-arginine therapy showed significant increases in CD4 T-cells (increased T-helper cells' development). For all seven meta-analyses, the results were derived using a fixed-effects model, but only where there was significant variability, and then the random-effects model was employed.

All seven meta-analyses conducted heterogeneity testing. All 7 using the Cochran test. Six of them employ I2 statistics. I2 statistic. For the Cochran test, P-values and the I2 statistic percentages are listed in Table 1. A significant amount of heterogeneity was seen within the results for systolic blood pressure for both adults and the pregnant women population. FMD, duration of hospitalization in surgical patients, and the CD4 count in hospital patients.

Seven of the meta-analyses examined for bias in publication, using visual inspections of funnel plots to determine asymmetry. Five used or used the Egger and Begg regression tests; however, neither test identified statistically significant bias in publication within any study examined. Table 1 displays the Egger and Begg regression tests.

Discussion

For adults with hypertension, L-arginine supplementation can significantly lower diastolic and systolic blood pressures between 2.2 to 5.4 mm Hg and 2.7 to 3.1 millimeters and 2.7 to 3.1 mm Hg, respectively. The results are only a little better than results from vitamins C, Vitamin D as well as magnesium supplements meta-analyses that showed a reduction in diastolic and systolic blood pressures of 3 to 4 millimeters Hg and 1.5 to 3 millimeters Hg and 1.5 to 3 mm Hg, respectively. Extending from a review that was based on more than 600 000 people with these results, the modest reductions of blood pressure can be clinically significant since 5 mm Hg decrease in systolic bloodpressure is linked to a reduction of 14% in risk of stroke, and a reduction of 9% in coronary heart diseases risk.19 The overall decrease in diastolic and systolic blood pressure in this review of the umbrella could have been higher because four of the eleven studies included in the meta-analysis of Dong and co. Employed normotensive adult subjects in which there was little room for improvement. Although there was no bias in publication identified in this meta-analysis, significant heterogeneity was observed in the results for systolic blood pressure. Some possible reasons for the high variations in blood pressure that go beyond the apparent distinction between normotensive and hypertensive populations could be due to differences in diet, exercise prescriptions, medications, and the duration of trials. Also, the participants in the different trials possessed different comorbidities, such as diabetes, hypercholesterolemia, coronary artery disease, and gestational hypertension. Regarding the mechanism of action, L-arginine is the main base for the enzyme endothelial NOS. It is located in endothelial vessels and plays a role in the generation of nitric oxide, which is then released from the endothelial cells and initiates the relaxation of smooth vascular muscle cells.

The improvement in the function of the endothelial cells through l-arginine supplementation could be assessed using the FMD method. FMD is the capacity of the brachial arterial artery to dilate when ischemia causes hyperemia. The dilation depends on the creation of nitric oxide in the vascular endothelium. The meta-analysis included in this comprehensive review of the effects of l-arginine on FMD has shown significant benefits; however, these results are constrained by the discovery of substantial heterogeneity.

In both meta-analyses of pregnant women suffering from gestational hypertension, the supplementation of l-arginine led to substantial reductions in diastolic blood pressure; however, no significant decreases in systolic blood pressure. There was no evidence of bias in the publication; however, one of the two meta-analyses showed considerable heterogeneity in systolic blood pressure. This significant heterogeneity can be explained by different methods of supplementation with l-arginine (oral as opposed to intravenous) and the different doses utilized by other studies. Regarding the mechanisms of action, l-arginine concentrations are reduced significantly for women suffering from preeclampsia or gestational hypertension. Significantly decreased levels of circulating nitric oxide are also observed. It has been discovered that in women who are pregnant and suffer from preeclampsia, levels of superoxide rise, and then it reacts with nitric oxygen, resulting in a significant decrease in circulating nitric Oxide and, consequently, a rise in blood pressure. So, boosting your nitric Oxide production through supplementation with l-arginine can counteract the effects of superoxide's oxidative production and drastically lower blood pressure.

For patients who are hospitalized or undergoing surgery In the 3 meta-analyses showed that l-arginine supplementation decreased the likelihood of contracting a hospital-related illness by up to 40%, and infections included abdominal abscess, pneumonia fasciitis, septic shock as well and urinary tract infections. There was no evidence of bias in the publication; however, significant heterogeneity was noted in the first of three meta-analyses. L-arginine is utilized for immune cell production to create Nitric oxide (via inducible NOS) to improve immune cell function by stimulating cytokine production and the proliferation of lymphocytes and differentiation.2 This is observed in the meta-analysis of hospitalized patients with an increase of CD4 count, however the results is countered by the fact that there is significant variation.

The two meta-analyses of surgical patients, as well as patients suffering from cancer of the neck and head, found a significant reduction in the length of stay at the hospital. However, the largest of the two analyses noted that there was statistically significant variation. The high degree of heterogeneity in this meta-analysis can be because all 28 studies used in the meta-analysis consisted of hospital patients who weren't a homogenous group. The authors did not show bias in their publications in these two meta-analyses. Regarding its mechanism of action, L-Arginine can stimulate the synthesis of proteins and speed up wound healing.22 l-Arginine is a powerful agent that speeds up the healing process of damaged tissues and thus decreases healing time through two mechanisms. In the first, arginine is the precursor to proline synthesis, essential for collagen production and wound healing, and Secondly, it is also a precursor to polyamine synthesizing, which is believed to stimulate cell proliferation, growth, and differentiation.23, 24 l-Arginine functions as a secretagogue since it triggers the release of various anabolic hormones such as growth hormone, insulin, as well as insulin-like growth factors 1.25

Seven of the meta-analyses dealt with adverse effects that could result from the l-arginine supplementation. Four of the five meta-analyses reported adverse side effects relating to diarrhea complaints and nausea. However, it only comprised 7 of 33 individual papers that registered complaints. This is in line with the idea that daily dosages of greater than 9 grams of l-arginine per day may cause gastrointestinal nausea, discomfort, and diarrhea for some patients.26

Limitations

One drawback of this review of the umbrella is that only three indexing systems were examined, which means that it's possible that no specific meta-analyses were found. Another issue is that only one author conducted the research and selected the included meta-analyses. As with every literature review, the quality of this review is directly correlated to how well the meta-analyses are.

Conclusions

The meta-analyses included in this review suggest that the l-arginine supplement provides substantial advantages in reducing systolic as well as diastolic blood pressures for hypertensive adults while reducing diastolic blood pressure among pregnant women who suffer from gestational hypertension and reducing time spent in hospitals for surgical patients. Two of the 3 meta-analyses revealed an increase of 40% in the frequency of infections acquired in hospitals. However, these results should be used cautiously as significant statistical heterogeneity was found in five of the seven meta-analyses. This can weaken the conclusions that could be drawn from these results.

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