Article

Oral L-Citrulline Supplementation Improves Erection Hardness in Men With Mild Erectile Dysfunction

Authors:
  • Ospedale della Murgia , Altamura , Italy
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Abstract

To test the efficacy and safety of oral L-citrulline supplementation in improving erection hardness in patients with mild erectile dysfunction (ED). L-arginine supplementation improves nitric oxide-mediated vasodilation and endothelial function; however, oral administration has been hampered by extensive presystemic metabolism. In contrast, L-citrulline escapes presystemic metabolism and is converted to L-arginine, thus setting the rationale for oral L-citrulline supplementation as a donor for the L-arginine/nitric oxide pathway of penile erection. In the present single-blind study, men with mild ED (erection hardness score of 3) received a placebo for 1 month and L-citrulline, 1.5 g/d, for another month. The erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded. A total of 24 patients, mean age 56.5 ± 9.8 years, were entered and concluded the study without adverse events. The improvement in the erection hardness score from 3 (mild ED) to 4 (normal erectile function) occurred in 2 (8.3%) of the 24 men when taking placebo and 12 (50%) of the 24 men when taking L-citrulline (P < .01). The mean number of intercourses per month increased from 1.37 ± 0.93 at baseline to 1.53 ± 1.00 at the end of the placebo phase (P = .57) and 2.3 ± 1.37 at the end of the treatment phase (P < .01). All patients reporting an erection hardness score improvement from 3 to 4 reported being very satisfied. Although less effective than phosphodiesterase type-5 enzyme inhibitors, at least in the short term, L-citrulline supplementation has been proved to be safe and psychologically well accepted by patients. Its role as an alternative treatment for mild to moderate ED, particularly in patients with a psychologically fear of phosphodiesterase type-5 enzyme inhibitors, deserves further research.

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... However, the fear of recurrent episode of weak erection and social embarrassment has also been identified as additional factors for increased inferiority complex and stigma in these patients [8]. Current drugs used for the treatment of sexual dysfunction and impotence have several limitations such as adverse effects, relapse and ineffectiveness in some individuals [9]. It has also been reported that most patients with sexual dysfunction and impotence in developing countries do not get proper medical attention hence depend on herbal products sought from traditional medical practitioners [10]. ...
... The health benefits of C. lanatus have been ascribed to the presence of essential phytochemical constituents such as glycosides, cucurbitacins, triterpenes, sterols, alkaloids, lycopene and quercetin [15]. Importantly, C. lanatus contains high concentration of citrulline, the precursor for nitric oxide synthesis, which plays important role as vasodilator [9]. Although studies have established the aphrodisiac activity of C. lanatus fruit and rind extracts on adult male and female wistar rats respectively [24,25]; there is lack of documented scientific literature on the activity of seed of the plant on male sexual behavior. ...
... The decreased post ejaculatory interval observed in this study, which is commonly used as tool for evaluating recovering processes following first sexual encounter [35,36] also suggests prolonged duration of coitus by the extract due to the presence of potent aphrodisiac compounds such as nitric oxide [24,33,37]. Earlier reports have stated that an increased testosterone level is directly proportional to increased sexual interest [9,38,39]. In this study, it was observed that the testosterone level was significantly increased. ...
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Background: Current drugs used for sexual dysfunction have several limitations, necessitating the search for alternative medicine. Aim and Objective: The study investigated the effect of Citrullus lanatus ethanolic seed extract (CLESE) on the sexual behavior and reproductive hormones of adult male Wistar rats. Material and Methods: Twenty-four adult male Wistar rats were randomized into four groups (n=6). Group 1 received saline (1 ml/kg, p.o.) and served as normal control, groups 2 and 3 were given CLESE (500 and 1000 mg/kg, p.o.) for 14 consecutive days. Group 4 received Sildenafil Citrate (SC) (5 mg/kg, p.o.), which served as positive control drug and this was administered 4 h before sexual behavioral test only on days 7 and 14. Sexual behavioral tests were performed in a Plexiglas copulatory arena. Male sexual behavioral parameters were evaluated following one on one exposure of experimental male rats with oestrus-induced sexual seeking female rats. Thereafter, rats were sacrificed. Results: CLESE enhanced libido by significantly (p < 0.05) increasing mounting and intromission frequencies relative to normal controls. CLESE also enhanced intromission and ejaculation latencies, but decreased mounting latency and post ejaculatory interval. Serum testosterone and luteinizing hormone were also significantly (p < 0.05) increased. The histological findings showed improved histoarchitechture of the testes and hypothalamic sections. Conclusion: The findings from this study showed that CLESE enhanced sexual behavior via
... 11 L-citrulline is converted to L-arginine in the kidney, thus setting the rationale for oral L-citrulline supplementation as a donor for the L-arginine/NO/cGMP (cyclic guanosine monophosphate) pathway of penile erection. 9 In animal experiments, administration of L-citrulline improved intracavernous pressure/mean arterial pressure (ICP/MAP), smooth muscle/collagen ratios, and serum levels of nitrogen oxides in arteriogenic ED 12 and low-testosterone ED. 13 However, few experiments have been performed on humans. 1 clinical study suggested that oral L-citrulline supplementation might improve the Erection Hardness Score (EHS) without adverse events in men with mild ED. 14 Resveratrol is a polyphenol found in grapes and wine. 15 Several studies have shown that resveratrol increases the expression of endothelial nitric oxide synthase (eNOS) 16 and improves endothelial function 17 by activation of sirtuin1 (SIRT1), which promotes endothelium-dependent vascular relaxation. ...
... All patients reporting an improvement in the EHS from 3e4 were very satisfied. 14 In animal studies, resveratrol treatment leads to SIRT1 activation, and subsequently activated eNOS leads to enhancement of cGMP synthesis via the NO/cGMP pathway for penile erection. 20 Resveratrol elicited a concentration-dependent relaxing effect on the corpus cavernosum and an increase in blood testosterone concentration in a rabbit model. ...
... The applied dosage of L-citrulline in the present study was 800 mg/day, which was the highest dosage available in Japan at the time of the study (Kyowa Hakko Bio, Ibaragi, Japan). This dosage was lower than that used in a previous study in which Lcitrulline 1.5 g/day was administered in ED patients 14 and 2% L-citrulline water (approximately 2 g/day) was used in a rat model. 12,13 Safety has been evaluated in humans and rats with ED. 12e14 No side effects have been reported from citrulline administration as an oral supplement at doses up to 15 g. ...
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Introduction: Phosphodiesterase type 5 inhibitors (PDE5i) are first-line therapy for most men with erectile dysfunction (ED). If ineffective, vacuum erection devices, intracavernous injections, and penile prosthesis implantation are suitable as second- or third-line therapies. However, very few patients select these therapies. It is critically important to improve erectile function with oral administration of effective agents. Administration of L-citrulline or transresveratrol in animal experiments has been reported to improve erectile function, but few such experiments have been performed on humans with ED. Aim: We aimed to investigate the efficacy of combination therapy of L-citrulline and transresveratrol in patients with ED despite their use of PDE5i. Methods: In this randomized, double-blind, placebo-controlled crossover pilot study, men with ED (Sexual Health Inventory for Men [SHIM] score below 16) despite on-demand use of PDE5i received a placebo for 1 month or the active treatment (L-citrulline 800 mg/day and transresveratrol 300 mg/day) for another month. Patients continued on-demand use of PDE5i. Main outcome measure: The SHIM score, Erection Hardness Score (EHS), Aging Male Symptoms Scale-sexual domain (AMS-SD), and adverse events were examined. Results: 20 patients ages 29-78 years were enrolled, and after 6 men withdrew, 13 concluded the study without adverse events. Mean SHIM score for the active treatment increased significantly (10.96 ± 1.21) compared with baseline (8.32 ± 1.21) and placebo (8.31 ± 1.23) (both P < .05). Mean EHS score for the active treatment (2.56 ± 0.26) also increased from baseline (2.31 ± 0.26), but not significantly (P = .79). Mean AMS-SD score was not significantly different in either group. Conclusion: To our knowledge, this is the first study to show that combination therapy of L-citrulline and transresveratrol is effective for ED treatment in men with added on-demand use of PDE5i. This combination supplement may be added if PDE5i is insufficient. Shirai M, Hiramatsu I, Aoki Y, et al. Oral L-citrulline and Transresveratrol Supplementation Improves Erectile Function in Men With Phosphodiesterase 5 Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Crossover Pilot Study. Sex Med 2018;XX:XXX-XXX.
... 11 Third, their cost and contraindications, as well as concerns about adverse effects have restricted their use. 17 Because of the above-mentioned reasons and the bias that "natural solutions" are safer and less invasive than pharmaceutical solutions, there seems to be a group of patients who prefer nutraceuticals. As the only physiologic substrate for NOS, arginine has been recognized as a potential alternative for ED. ...
... Cormio et al. demonstrated that all patients who reported improvement in the erection hardness score after citrulline administration continued with the same treatment rather than asking for a PDEi. 17 The results of our analysis demonstrated that patients with ED may benefit from any arginine-containing supplements, whether it is F o r P e e r R e v i e w 12 arginine alone or in combination. It is interesting to note that when arginine is combined with other substances, the combination may work synergistically and cause even greater improvement (Figs. 2 and 3). ...
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Introduction: The efficacy and safety of arginine supplements in erectile dysfunction (ED) remain debatable. Aim: To assess the potential role of arginine supplements on ED as alternatives to phosphodiesterase inhibitors. Methods: Studies published up to April 2018 that evaluated the efficacy of arginine supplements were identified from multiple databases (Google Scholar, PubMed, Medline, Embase, Kiss, DBpia, and Cochrane databases). Studies comparing arginine supplements with placebo or no treatment; focusing only on patients with mild to moderate severity of ED; and presenting outcomes such as improvement rate, International Index of Erectile Function (IIEF) score, and adverse effects were included. Subgroup analysis for arginine alone and arginine in combination with other substances was further conducted to increase interpretability. Main outcome measure: The strength of the association between arginine supplements and ED was assessed using relative odds ratios and weighted mean differences with 95% CI. Results: In total, 10 randomized controlled trials met the inclusion criteria, reporting the outcomes of 540 patients with ED. The analysis demonstrated that arginine supplements with dosage ranging from 1,500 to 5,000 mg significantly improved ED compared with placebo or no treatment (odds ratios, 3.37 [1.29, 8.77], P = .01, I2 = 44). Arginine supplements also caused significant improvements in the IIEF subdomain scores of overall satisfaction, intercourse satisfaction, orgasmic function, and erectile function, whereas the IIEF sexual desire score remain unchanged. The adverse effect rate in the arginine-treated group was 8.3%, and that in the placebo group was 2.3%, none of which were severe. Clinical implications: Arginine supplements can be recommended to patients with mild to moderate ED. Strength & limitations: The strength of this study is that it is the first meta-analysis to assess the potential role of arginine supplements in ED compared with placebo or no treatment. A limitation is that the treatment dosage and duration varied among studies, which may have contributed to study heterogeneity. Conclusion: The results of our systematic review and meta-analysis provide evidence on the effectiveness of arginine supplements for mild to moderate ED. Rhim HC, Kim MS, Park Y-J, et al. The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis. J Sex Med 2019;16:223-234.
... One clinical study reported significant improvement in EHS from 3 to 4 in 50% of men when they took L-citrulline and a significant increase in the mean number of intercourses per month compared with baseline, 2.3±1.37 versus 1.37±0.93 [19]. Resveratrol increases endothelial nitric oxide synthase expression [20] and improves endothelial function by activation of sirtuin 1, which then promotes endothelium-dependent vascular relaxation [21]. ...
... At the time of these studies, this was the highest dose available in Japan (Kyowa Hakko Bio, Ibaragi, Japan). The safety of Lcitrulline has been evaluated in patients (1.5 g/d) and rats (approximately 2 g/d) with ED [18,19]. No side effects have been reported following the administration of citrulline as an oral supplement at doses up to 15 g [27]. ...
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Purpose: Sexuality is very important for men's health. Currently, phosphodiesterase type 5 inhibitors (PDE5i) remain the first-line therapy for erectile dysfunction, and no other oral drugs or drinks are approved and used clinically to treat male libido or orgasm dysfunction. In reference to a pharmaceutical dosage document, growing health consciousness is said to have boosted yearly sales of supplement drinks to more than 170 billion yen (1.58 billion US dollars) in Japan. We have created a supplement drink comprised of testofen, L-citrulline, resveratrol, and caffeine. We hypothesized that our supplement drink would be effective for men with sexual dysfunction, and especially libido dysfunction. Materials and methods: In this study, men with sexual dysfunction received a placebo drink for 14 days or our supplement drink (testofen, 600 mg/d; L-citrulline, 800 mg/d; resveratrol, 300 mg/d; and caffeine, 40 mg/d) for another 14 days separated by a 7-day washout period. Patients continued on-demand use of PDE5i. The International Index of Erectile Function (IIEF) score and adverse events were assessed. Results: Twenty patients aged 30-47 years old were enrolled in and concluded the study with no adverse events experienced. The IIEF domains of desire frequency, erection frequency, erection firmness, erection confidence, intercourse satisfaction, ejaculation frequency, orgasm frequency, and overall satisfaction were significantly improved with our supplement drink. Conclusions: This is the first study to show that our supplement drink may not only be effective for erection but also for libido, orgasm, and ejaculation.
... Stikstofmonoxide wordt gemaakt van arginine en arginine kan worden geproduceerd door citrulline [8], waarvan de arginineconcentratie in het lichaam dus kan worden verhoogd door meer citrullinerijk voedsel te consumeren, zoals watermeloenfruit, dat vaak wordt afgedaan als niet veel waard en door deze mensen als hetzelfde wordt beschouwd als water [12]. Orale suppletie met L-citrulline verbetert de hardheid van de erectie bij mannen met milde erectiestoornissen [9] en citrulline kan in relatief hoge concentraties in watermeloen worden gevonden, hetgeen betekent dat je de dosis die ze in het onderzoek gebruikten elke dag kan eten om te proberen de resultaten te matchen met de studieresultaten die ongeveer 3,5 (drie en een halve) porties rode watermeloen per dag zijn, tenzij je gele watermeloen eet, die ongeveer 4x (vier keer) zoveel citrulline bevat [9,11] hetgeen zich vertaalt naar die ene portie per dag i.e. een schijfje dat ongeveer 1/16 (een zestiende) van een bescheiden meloen is, hetgeen is dat deze in de studie gebruikte dosis zou moeten leveren, waardoor de maandelijkse geslachtsgemeenschapsfrequentie met 68 [%] toeneemt, hetgeen uw hart ook zou moeten kunnen weerstaan gegeven hoeveel lager uw bloeddruk zal zijn bij suppletie met watermeloen [10]. Pompoen en squashzaden, beide met ongeveer 5,4/100 [g] en watermeloenzaden met ongeveer 4,9/100 [g] bevatten relatief veel arginine, dat volgens het Center of Disease Control CDC ook zou kunnen worden gebruikt om arginine in het algemeen voldoende binnen te krijgen, dit gelet op dat in de Verenigde Staten van Amerika 78 miljoen Verenigde Staten Amerikanen onvoldoende arginine binnenkrijgen [13]. ...
... Stikstofmonoxide wordt gemaakt van arginine en arginine kan worden geproduceerd door citrulline [8], waarvan de arginineconcentratie in het lichaam dus kan worden verhoogd door meer citrullinerijk voedsel te consumeren, zoals watermeloenfruit, dat vaak wordt afgedaan als niet veel waard en door deze mensen als hetzelfde wordt beschouwd als water [12]. Orale suppletie met L-citrulline verbetert de hardheid van de erectie bij mannen met milde erectiestoornissen [9] en citrulline kan in relatief hoge concentraties in watermeloen worden gevonden, hetgeen betekent dat je de dosis die ze in het onderzoek gebruikten elke dag kan eten om te proberen de resultaten te matchen met de studieresultaten die ongeveer 3,5 (drie en een halve) porties rode watermeloen per dag zijn, tenzij je gele watermeloen eet, die ongeveer 4x (vier keer) zoveel citrulline bevat [9,11] hetgeen zich vertaalt naar die ene portie per dag i.e. een schijfje dat ongeveer 1/16 (een zestiende) van een bescheiden meloen is, hetgeen is dat deze in de studie gebruikte dosis zou moeten leveren, waardoor de maandelijkse geslachtsgemeenschapsfrequentie met 68 [%] toeneemt, hetgeen uw hart ook zou moeten kunnen weerstaan gegeven hoeveel lager uw bloeddruk zal zijn bij suppletie met watermeloen [10]. Pompoen en squashzaden, beide met ongeveer 5,4/100 [g] en watermeloenzaden met ongeveer 4,9/100 [g] bevatten relatief veel arginine, dat volgens het Center of Disease Control CDC ook zou kunnen worden gebruikt om arginine in het algemeen voldoende binnen te krijgen, dit gelet op dat in de Verenigde Staten van Amerika 78 miljoen Verenigde Staten Amerikanen onvoldoende arginine binnenkrijgen [13]. ...
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The seeds of the chia salvia plant may help as nutrition for the cardiovascular system, may help as nutrition for the brain, may help as nutrition for the immune system and may help as nutrition for the reproductive system. Article: Citrullus anatus melon [Sources below] The sweet relatively often deep red to pink juicy flesh of the relatively large edible pepo berry fruits (A pepo is a type of berry formed from an inferior ovary and containing many seeds usually large with a tough outer skin, e.g. a pumpkin or cucumber) of the flowering and green lobed leaved annually growing in tropical to temperate climate regions of the world vine-like trailing water melon plant citrullus anatus (also called "citrullus vulgaris" by Carl Linnaeus in about 1753, and "watermeloen") categorizable in the citrullus genus which is in turn categorizable in the about a 1'000 species encompassing cucurbitaceae plant family (also called the "komkommerfamilie", the "cucurbits", the "gourd family" and "the cucumber plant family") are possible usable for: It may possible be usable as nutrition for the cardiovascular system in the sense that Source references:
... One of the main concerns with L-arginine is its rapid degradation by arginase I in the intestinal tract [39] and the efficacy of oral L-arginine sup- plementation remains questionable [34]. L-Citrulline pre- cludes pre-systemic metabolism [40] and efficiently converts to L-arginine, thus enhancing plasma concentra- tions [41,42]. This substance is considered as a precursor in ...
... Duration of study (weeks) BP blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure, WMD weighted mean difference, CI confidence interval, I 2 percentage score for heterogeneity the L-arginine-NO pathway [40] and some evidence has shown improvements in exercise performance [43,44] and erectile dysfunction, following its supplementation [45]. We performed quantitative analysis for all studies except for two, where there was insufficient quantitative data or unavailable full texts. ...
Article
The objective of this study was to systematically investigate the efficacy of oral L-citrulline supplementation on systolic and diastolic blood pressure. Studies were identified by a search of electronic databases from inception to April 2018, and combined and stratified analyses were used. Fifteen trials were identified, and data from 424 participants were included. Pooled analysis showed significant reductions in systolic blood pressure by −7.54 mmHg (95% confidence interval (CI): −9.44, −5.63; P < 0.001, I2 = 14%) and diastolic blood pressure by −3.77 mmHg (95% CI: −5.67, −1.86, P < 0.001, I2 = 42%) following oral supplementation of L-citrulline or a watermelon extract. No changes were detected in controls. Significant heterogeneity (I2 = 42%, P = 0.04) was found for diastolic blood pressure, and subgroup analysis showed significant improvements in systolic and diastolic blood pressure, particularly for study durations: ≥6 weeks, lower doses: ≤4 g/day, and in participants with higher baseline values: ≥130/85 mmHg. In conclusion, L-citrulline improves systolic and diastolic blood pressure and may be more efficacious in pre-hypertensive and hypertensive populations.
... Erectile dysfunction refers to the inability to achieve and maintain an erection sufficient to enable satisfactory sexual intercourse. NO is a physiological signal essential to penile erection [99], since it acts as a neurotransmitter in the penile non-adrenergic noncholinergic nerve fibers, as well as a vasodilator of smooth muscle cells of the penile arteries, sinusoids, and trabeculae [100]. Sexual stimulation releases NO to the smooth muscle of the penis, activating soluble guanylate cyclase to convert guanosine triphosphate into cyclic guanosine monophosphate (cGMP). ...
... This subsequently activates a specific protein kinase that produces phosphorylation of proteins and ion channels; cytosolic calcium is reduced because of the whole process, and penile smooth muscle is relaxed. Phosphodiesterase type 5 enzymes (PDE-5), hydrolyze cGMP to inactive GMP and, therefore, the erection of the penis ceases [99]. PDE-5 inhibitors enhance NO activity and are currently the most effective oral drugs to treat male erectile dysfunction. ...
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L-Arginine (Arg) has been widely used due to its functional properties as a substrate for nitric oxide (NO) generation. However, L-citrulline (CIT), whose main natural source is watermelon, is a non-essential amino acid but which has important health potential. This review provides a comprehensive approach to different studies of the endogenous synthesis of CIT, metabolism, pharmacokinetics, and pharmacodynamics as well as its ergogenic effect in exercise performance. The novel aspect of this paper focuses on the different effects of CIT, citrulline malate and CIT from natural sources such as watermelon on several topics, including cardiovascular diseases, diabetes, erectile dysfunction, cancer, and exercise performance. CIT from watermelon could be a natural food-sourced substitute for pharmacological products and therefore the consumption of this fruit is promoted.
... It is known that citrulline has a variety of biological actions in human (2,4,5,10,14,35). However, there have been no reports on its adjuvant activity until now. ...
Article
For a long time, many types of vaccines have been useful for the prophylaxis of many infectious diseases. Thus far, many adjuvants that enhance the effects of vaccines have been explored. However, very few adjuvants are being used for humans worldwide. In this study, we investigated the adjuvant activity of various substances, and found citrulline to have high potential as an adjuvant. Citrulline is a type of amino acid present in the body of many organisms. A number of biological activities of citrulline have been reported; however, no adjuvant activity has been reported thus far. Aluminum salts, which are commonly used as adjuvants are not water soluble; therefore, some difficulties are encountered while using them as vaccine adjuvants. Citrulline is easy to use because of its water solubility. In this study, we showed for the first time the adjuvant activity of citrulline by using viral antigens and amyloid β peptide. Water-soluble citrulline, which is present in our body, is a potential adjuvant candidate.
... l-citrulline and l-arginine supplementations have been shown to rapidly and effectively increase NO bioavailability and cyclic guanosine monophosphate (cGMP) concentrations 26 . l-citrulline supplementation has been shown to improve erectile function in rats with acute arteriogenic ED 27 and one study has shown improved erection in mild ED patients, 28 though there have been no studies in humans with l-citrulline and l-arginine combination. The advantage of l-citrulline over l-arginine is that it does not undergo first-pass metabolism nor it is metabolized by intestinal bacteria. ...
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l-arginine, being a natural precursor of nitric oxide, is one of the more commonly used adjuvants to regular medicines in the treatment of erectile dysfunction. Objectives: Here, in this review article, we aim to highlight various studies and the research studies done on l-arginine in the treatment of erectile dysfunction. Method: Reviewing the databases such as Medline (PubMed), Cochrane Library, Excerpta Medica dataBASE, Trip, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, and the British Nursing Index. Results:l-arginine has been studied alone as well as in combination with various other molecules for the treatment of erectile dysfunction, but the studies are very limited in number and have very small sample sizes. Conclusion: Positive evidence is available for the efficacy of l-arginine and its various combinations. Further research with larger sample sizes and standardized tools are required to recommend the routine use of these products in erectile dysfunction.
... Some men reported having more sex after treatment and being more satisfied. L-Citrulline supplements improved erectile dysfunction and reduced dysfunction caused by low blood pressure in rats [17] . This is likely due to an increase in nitric oxide levels. ...
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To develop an efficient method for the production of L-Citrulline, optimum conditions for the conversion of L-arginine to L-Citrulline by microbial L-arginine deiminases and for production of the enzyme were studied. A number of microorganisms were screened to test their ability to produce and accumulate L-Citrulline from L-arginine. Lacto bacillus was selected as the best organism for enzymatic method when compared to Bacillus subtilis and E. coli. The absorbance peak was obtained at 207nm. Optimum technique will be adopted based on the availability and activity of enzyme. Enzyme based involves the use of an enzyme produced by Lacto bacillus whereas the acid hydrolysis involves the chloroform extraction with the help of a strong acid. The anti-microbial and antifungal tests were done due to their potential to provide quality and safety benefits to many materials and methods.
... However, there is also high quality evidence to suggest that PDE5is do not improve unassisted erectile function following prostatectomy [6,7]. Other pro-erectogenic agents, such as L-citrulline, which increases nitric oxide synthesis, have also shown promising results, though in different patient populations [8,9]. Despite these encouraging data, the majority of men discontinue their PR program within one year [10]. ...
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To evaluate the efficacy of a novel, multi-modal, preoperative approach to postprostatectomy penile rehabilitation (PR), we performed a retrospective review of patients who underwent nerve-sparing robotic-assisted laparoscopic prostatectomy (NS-RALP). All patients were evaluated at a comprehensive, academic sexual medicine clinic between 2016 and 2017. The “prehabilitation” PR group (n = 106) consisted of men who were seen in the pre-op period and began tadalafil and l-citrulline 2 weeks prior to surgery. Vacuum erectile device (VED) therapy was started at 1-month post-op. These interventions were continued throughout the 12-month follow-up period. Individuals refractory to these therapies could start treatment with intracavernosal injections. The postprostatectomy PR group (n = 25) consisted of men who were not seen in the pre-op period and started the above therapies immediately following their first visit. A higher percentage of men in the prehabilitation group reported return of erectile function within 12 months (56% vs. 24%, P = 0.007). The prehabilitation group also showed better compliance with PR (PDE5i [96% vs. 64%, P < 0.001], l-citrulline [93% vs. 49%, P < 0.001], and VED [55% vs. 20%, P < 0.001]). Seventy-eight percent of men who attended 4–5 follow-up visits reported return of erectile function. Our results suggest that men undergoing a preoperative protocol show superior recovery of erectile function following NS-RALP. Further studies with prospective designs are warranted.
... Recently, Morita et al. (2014) showed that a combination of oral L-Cit and L-Arg effectively and rapidly augments plasma NO bioavailability and cGMP concentrations. Moreover, L-Cit supplementation improved erectile function in rats with acute A-ED (Shiota et al., 2013) and, what is more, was able to improve erection in patients with mild ED (Cormio et al., 2011). ...
Article
Nitric oxide is a physiologic signal essential to penile erection. l-citrulline (l-Cit) is converted into l-arginine (l-Arg), the precursor from which nitric oxide is generated. The level of l-Arg and l-Cit in the field of male sexual function remains relatively underexplored. The aim of the study was to evaluate the level of serum l-Arg and of l-Cit in a group of patients with erectile dysfunction. Diagnosis and severity of erectile dysfunction was based on the IIEF-5 and its etiology was classified as arteriogenic (A-ED), borderline (BL-ED), and non-arteriogenic (NA-ED) with penile echo-color-Doppler in basal condition and after intracaversous injection of prostaglandin E1. Serum l-Arg and l-Cit concentrations were measured by a cation-exchange chromatography system. l-Arg and l-Cit levels of men with A-ED were compared with those of male with BL-ED and NA-ED. Median level of l-Arg and l-Cit in 122 erectile dysfunction patients (41 A-ED, 23 ED-BL, 58 NA-ED) was 82.7 and 35.4 μmol/L, respectively. l-Arg and l-Cit levels in control patients were not significantly different (p = 0.233 and p = 0.561, respectively) than in total erectile dysfunction patients. l-Arg and l-Cit levels in control patients were significantly higher (p < 0.001 and p < 0.018, respectively) than in A-ED patients, but no difference (p > 0.50) was observed in controls and in both BL-ED and NA-ED patients. Patients with severe/complete-erectile dysfunction (IIEF-5 < 10) had l-Arg or l-Cit level significantly lower (−17%, p < 0.03; −13%, p < 0.04) and were more frequent (p < 0.01 and p < 0.04) under the respective median level (82.7 and 35.4 μmol/L) than those with mild-erectile dysfunction (IIEF-5 = 16–20). l-Arg and l-Cit levels in A-ED were significantly lower (p < 0.007 and p < 0.001, respectively) than in NA-ED patients. Penile echo-color-Doppler revealed that A-ED (peak systolic velocity ≤ 25 cm/sec) was more frequent in men with l-Arg under 82.7 μmol/L or l-Cit under 35.4 μmol/L and in the same population, the median peak systolic velocity values were lower in l-Arg deficient (29 vs. 35; p < 0.04) and also in l-Cit deficient (31 vs. 33, p > 0.3) but without reaching the statistical significance. Our study shows that a significant proportion of erectile dysfunction patients have low l-Arg or l-Cit level and that this condition is more frequent in patients with arteriogenic etiology. Low levels of these nitric oxide synthase substrates might increase the erectile dysfunction risk by reducing the concentration of nitric oxide.
... The aphrodisiac properties of watermelon is supported by the fact that flesh extract has been reported to cause a significant increase in mounting, intromission and ejaculatory frequency in laboratory rats (Munglue et al., 2014). Watermelon has also been reported to contain a high level of the amino acid Lcitrulline which has been linked to the stimulation of blood flow to the penis (Cormio et al., 2011). ...
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The popularity of watermelon, Citrullus lanatus (Cucurbitaceae) has increased in recent years in Cameroon due to the important nutrients it contains and health benefits it presents. Inspired by the ethno botanical and ethno medicinal uses of watermelon, this study was designed to evaluate its cytogenotoxic properties using the spermatogonial germ-line cells of the grasshopper Zonocerus variegatus L. (Orthoptera: Pyrgomorphidae). Fifth instar Z. variegatus individuals were treated to different concentrations of (0μg/l, 5μg/l, 10μg/l, 20μg/l, 30μg/l and 50μg/l) of aqueous extract of watermelon, C. lanatus leaves by injection into the abdomen respectively. Distilled water (0 μg/ml) was used as the control. Results revealed that C. lanatus leaf extracts exhibited cytogenotoxic effects and these were concentration dependent. Among the extracts, the 50 μg/ml recorded the highest percent aberrant cells while the 5 μg/ml showed the lowest. As regards genotoxicity, all the extract–treated cells showed different chromosomal aberrations that included bridges, laggards, vagrant chromosomes and sticky chromosomes. The 50 μg/ml extract significantly produced the highest incidences (25.83%) while the 5 μg/ml extract had the lowest incidence (1.57%) of chromosomal aberrations. The control induced only one laggard (0.95%). In general the different concentrations induced low amounts of cytogenotoxic aberrations. These results led us to conclude that C. lanatus exhibits some cytogenotoxic properties at high concentrations thus emphasizing that the fruit should be consumed by humans with caution.
... With regard to functional foods, it has been described that ingestion of pulp of watermelon, a source of L -arginine and citrulline (representing 71 % of total free amino acids) [ 30 ], was associated with improvement in vascular reactivity and NO production in obese mice [ 30 ], as well as with improvement of hemodynamic parameters in healthy individuals and individuals with hypertension or obesity [ 34 -37 ]. Together with this evidence, it has been shown that L -citrulline supplementation improved erectile dysfunction in diabetic patients [ 40 ], a phenomenon associated with endothelial dysfunction. While these studies are promising, conducting large-scale studies is necessary in order to confi rm the capacity of functional food for recovering endothelial function in patients with diabetes. ...
Article
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Functional foods are aliments that are thought to have physiological benefits and/or reduce the risk of chronic disease, beyond their basic nutritional functions, which could be produced by adding new ingredients or more of existing ingredients using food engineering techniques. In this regard, increasing health consciousness worldwide has been one of the most stimulating factors for rapid global growth of the functional food industry (Hasler, J Am Coll Nutr 19:499S–506S, 2000). Then, development of functional food products is a growing research niche worldwide.
... Supplementation of citrulline with Lb. helveticus can improve intestinal barrier functions [52]. L-arginine and L-citrulline oral intake improve erection hardness in men; both amino acids are used as a treatment of erectile dysfunction [53,54]. Lb. fermentum 28, Lb. paracasei 25 and 47, and P. acidilactici 27 accumulated lysine and tryptophan (Figure 8), and LAB enzymes involved in these pathways may have future industrial applications [55,56]. ...
Article
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Bulgarian yoghurt is associated with health benefits and longevity of consumers. The specific microflora producing bioactive metabolites is responsible for this effect. The present study examines the biodiversity in four homemade yoghurts from regions containing endemic microflora. Metagenome sequencing indicated Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus were predominant in all samples. In addition, yoghurts contained accompanying lactic acid bacteria (LAB) including Lacticaseibacillus paracasei, Lb. helveticus, Limosilactobacillus fermentum, Lb. rhamnosus, Lactococcus lactis, Pediococcus acidilactici, Leuconostoc mesenteroides, and Leuc. pseudomesenteroides. A negligible amount of pollutant strains was found. Twenty-four LAB strains were isolated from the yoghurts and identified. Lb. delbrueckii subsp. bulgaricus strains were genotyped by randomly amplified polymorphic DNA–PCR (RAPD), multi-locus sequence typing (MLST), and pulse field gel electrophoresis (PFGE), which demonstrated their uniqueness and non-commercial origin. To estimate the bioactive metabolites produced by the accompanying microflora, yoghurts fermented by single LAB strains were analyzed using liquid chromatography and mass spectrometry (LC-MS). The fermented samples contained large amounts of free essential amino acids (arginine, citrulline, tryptophan, lysine, and histidine), the neuroprotector indole-3-propionic acid (IPA), and significant quantities of the cyclic antimicrobial peptides cyclo(phenylalanyl-prolyl) and cyclo(leucyloprolyl). The disclosure of these special qualities draws attention to the accompanying microflora as a source of potential probiotic strains that can fortify the yoghurts’ content with bioactive compounds.
... Moreover, no studies have studied citrulline in people pre-determined to have high ADMA levels. Nonetheless, when administered in oral doses of 3–6 grams daily, supplemental citrulline has been shown to exert various effects suggestive of NO-mediated cardiovascular protection: Reductions in systolic and diastolic blood pressure and in arterial stiffness, improvements in endothelium-dependent vasodilation, improvements in erection hardness in patients with erectile dysfunction, increased left and right ejection fractions in patients with heart failure, and an improved clinical course in sickle cell patients [50,[55][56][57][58][59][60][61][62][63][64][65]. ...
Article
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The arginine metabolite asymmetric dimethylarginine (ADMA) is a competitive inhibitor and uncoupler of endothelial nitric oxide synthase (eNOS), an enzyme that acts in multifarious ways to promote cardiovascular health. This phenomenon likely explains, at least in part, why elevated ADMA has been established as an independent risk factor for cardiovascular events, ventricular hypertrophy, and cardiovascular mortality. Fortunately, the suppressive impact of ADMA on eNOS activity can be offset by increasing intracellular arginine levels with supplemental citrulline. Although the long-term impact of supplemental citrulline on cardiovascular health in patients with elevated ADMA has not yet been studied, shorter-term clinical studies of citrulline administration demonstrate effects suggestive of increased NO synthesis, such as reductions in blood pressure and arterial stiffness, improved endothelium-dependent vasodilation, increased erection hardness, and increased ejection fractions in patients with heart failure. Supplemental citrulline could be a practical option for primary or secondary prevention of cardiovascular events and mortality, as it is inexpensive, has a mild flavor, and is well tolerated in doses (3-6 g daily) that can influence eNOS activity. Large and long-term clinical trials, targeting patients at high risk for cardiovascular events in whom ADMA is elevated, are needed to evaluate citrulline's potential for aiding cardiovascular health.
... A combination of oral l-arginine and l-citrulline was reported to increase the plasma NO bioavailability and cGMP concentrations [27]. This was proved to improve erectile function in rats [28], and also in patients with mild ED [29]. In a recent study, Lacchini et al. assessed whether plasma levels of Arg. ...
Article
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PurposeThe purpose of the study was to compare serum level of Arginase II in patients with vasculogenic erectile dysfunction (ED) versus healthy controls and to assess if its level is affected by severity of ED. Methods This is a prospective study that compared Arginase II in 40 patients with ED versus 40 healthy controls. Patients were excluded if they had any pelvic trauma or pelvic surgery, hormonal disorders, Peyronie’s disease, smoking, drug addiction or systemic illnesses. ED was evaluated by the validated Arabic version of the abbreviated five-item form of the international index of erectile function (IIEF-5). Serum arginase II level was assayed using ELIZA. Mann–Whitney, Kruskal–Wallis and Chi-square tests and Spearman correlation were used as appropriate and confirmed by logistic regression model. Results22 (55%) patients had DM. 15 (37.5%), 7 (17%), 6 (15%) and 12 (30%) patients suffered from severe, moderate, mild to moderate and mild ED, respectively. The level of serum Arginase II was significantly higher in patients than controls (p < 0.001) and confirmed by multivariate logistic regression analysis. It also correlated significantly with age (r2 = 0.22; p < 0.001) and IIEF-5 score (r2 = 0.8; p < 0.001). Serum Arginase II increased significantly with more severe ED (p < 0.001). Arginase II was also significantly higher in diabetic patients (p < 0.001). Conclusion Serum level of Arginase II is significantly higher in patients with vasculogenic ED compared to healthy controls. It correlates significantly with age and IIEF-5 and was significantly affected by the severity of ED.
... With regard to functional foods, it has been described that ingestion of pulp of watermelon, a source of arginine and citrulline (representing 71 % of total free amino acids) [30], was associated with improvement in vascular reactivity and NO production in obese mice [30], as well as with improvement of hemodynamic parameters in healthy individuals and individuals with hypertension or obesity [34][35][36][37]. Together with this evidence, it has been shown that l-citrulline supplementation improved erectile dysfunction in diabetic patients [40], a phenomenon associated with endothelial dysfunction. While these studies are promising, conducting large-scale studies is necessary in order to confirm the capacity of functional food for recovering endothelial function in patients with diabetes. ...
... Among these, citrulline is most prominent, and watermelon remains its most important source known (27). Citrulline is used as a drug and in food supplements for its stimulating activity on protein synthesis in skeletal muscle (83), its cardioprotective and overall beneficial cardiovascular effects (84), and even for erectile dysfunction (85). In addition to citrulline, watermelon also contains high levels of glutathione and its derivatives (e.g., S-formylglutathione, glutathione disulfide, S-lactoglutathione), which show antioxidant activities (86). ...
Article
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Sweet dessert watermelon (Citrullus lanatus) is one of the most important vegetable crops consumed throughout the world. The chemical composition of watermelon provides both high nutritional value and various health benefits. The present manuscript introduces a catalog of 1,679 small molecules occurring in the watermelon and their cheminformatics analysis for diverse features. In this catalog, the phytochemicals are associated with the literature describing their presence in the watermelon plant, and when possible, concentration values in various plant parts (flesh, seeds, leaves, roots, rind). Also cataloged are the chemical classes, molecular weight and formula, chemical structure, and certain physical and chemical properties for each phytochemical. In our view, knowing precisely what is in what we eat, as this catalog does for watermelon, supports both the rationale for certain controlled feeding studies in the field of precision nutrition, and plant breeding efforts for the development of new varieties with enhanced concentrations of specific phytochemicals. Additionally, improved and comprehensive collections of natural products accessible to the public will be especially useful to researchers in nutrition, cheminformatics, bioinformatics, and drug development, among other disciplines.
... It has been reported to have tocolytic properties [6] , and as such can be used to relax the smooth muscles of the copulatory organs. It has been established that Citrullus lanatus contains high amount of citrulline which is a precursor for nitric oxide synthase; that plays an important role in vasodilation [7] . During sexual arousal there is increased blood flow to the vagina, clitoris, vestibular bulbs and labial walls [8] . ...
... In the studies where the authors have not defined citrulline as being L-citrulline, the name citrulline is used in the text below. In a single-blinded, placebo-controlled, prospective study aiming to determine whether oral L-citrulline supplementation improved erection hardness in patients with mild erectile dysfunction, 24 men (age 56.5 ± 9.8 years) were included (Cormio et al., 2011). The patients received placebo (content of placebo was not defined) for the first month and Lcitrulline, 1.5 g/day (21 mg/kg bw per day) for the second month. ...
... Oral administration of L-arginine does not signifi cantly increase its serum levels because of intestinal and liver metabolism [ 18 ]; administration of L-citrulline, on the other hand, might be useful in increasing the plasmatic concentration of L-arginine. This treatment has been proven effective in rats with arterial ED [ 53 ]; in men, administration of L-carnitine has induced some improvements in men with mild forms of ED [ 13 ], with good safety and compliance profi les. Polyphenols may also act as antioxidants: resveratrol, a polyphenol commonly found in red wine, is known to improve endothelial function by activation of NOS [ 17 ] and by suppression of apoptosis [ 59 ]; similar effects have been discovered following administration of a different polyphenol, quercetin, in animal models [ 60 ]. ...
Chapter
Besides their widely discussed role in empirical therapy of male infertility, antioxidants have been used in experimental studies also for treating male sexual dysfunctions. Oxidative stress is clearly involved in the pathogenesis of infertility: less consisting evidence has been found in regard to its involvement in erectile and ejaculatory dysfunctions. Nitric oxide (NO) is an endothelium-derived relaxing factor, acting as a vasodilator and as an antioxidant: it is also the key molecule involved in obtaining and maintaining an erection. Administration of NO has been investigated as a substitute for phosphodiesterase type 5 (PDE-5) inhibitors or an additional treatment for nonresponders to standard treatments. Furthermore, a possible role for testosterone as a free radical scavenger has been postulated: testosterone replacement therapy might help prevent oxidative stress-related dysfunctions in several organs. Oxidative stress is also involved in some forms of priapism: antioxidants might therefore be helpful in preventing recurrences or in treating vascular damage resulting from ischemia-reperfusion injury.
... Cormio et al. found that oral L-citrulline (1.5 g/day) resulted in significant improvement in EHS compared to placebo (p ≤ 0.01). They did not evaluate IIEF-5 scores [60]. Following this study, several rodent experiments were published that demonstrated NO production increased and intracavernosal pressure improved after oral L-citrulline administration [61,62]. ...
Article
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Purpose of Review To highlight and review encouraging preliminary studies behind several alternative products and interventions for erectile dysfunction (ED). Recent Findings Alternative treatments for ED are becoming more prevalent with increased consumer interest. “Natural” products are sold online, and numerous clinics offer various off-label and investigational interventions. These alternative treatments have demonstrated varying degrees of efficacy in randomized trials and meta-analyses, but none of these interventions has robust enough evidence to be considered first-line therapy. These treatments may find a role in combination with guideline treatments or may be used in novel penile rehabilitation research protocols. Summary With growing interest in alternative treatment for men’s health, an awareness of the literature is imperative for patient counsel. Alternative treatments, like l-arginine, have a growing body of evidence for efficacy in combination with PDE5i, and low-intensity shock wave therapy and stem cell therapy continue to demonstrate encouraging outcomes in ED trials.
Chapter
The purpose of this book chapter is to better understand the role of alternative nonprescription medications and their effect on sexual function. We will also discuss the prevalence of counterfeit prescription medications and their impact on health. We will discuss where these drugs are being produced and how they are regulated by the federal government. The role of the Internet as a method of obtaining these medications also will be explored. The most common alternative medicines will be reviewed based on clinical research trials in terms of efficacy and side effects.
Article
In recent years, arginine deiminase (ADI, EC 3.5.3.6) has attracted much attention as a biocatalyst that produces the functional amino acid l‐citrulline from l‐arginine and also as an anticancer enzyme. Here, we identified and characterized a putative ADI from the thermophilic bacterium Halothermothrix orenii. The H. orenii ADI (H‐ADI) protein was expressed in Escherichia coli BL21(DE3) with a specific activity of 91.8 U/mg protein at 55°C and pH 6.5. The enzyme remained at 74% relative activity after incubation at 45°C for 180 min, only 25% at 50°C. The melting temperature was 56°C. H‐ADI is not a metal‐requiring enzyme; Ni2+ slightly improved the catalytic activity. The Km and Vmax for l‐arginine were 55.5 mM and 156.8 μmol/min/mg protein, respectively. Moreover, three residues (Arg183, Arg237, and His273) were key to the formation of l‐citrulline, as analyzed by alanine‐scanning mutagenesis. Finally, the enzymatic synthesis of l‐citrulline was carried out at 50°C with a conversion ratio reaching 99.03%. Together, these findings show that H‐ADI is a promising biocatalyst for the production of l‐citrulline. A recombinant arginine deiminase from Halothermothrix orenii.
Chapter
While current treatment modalities for erectile dysfunction have become easier to administer and more scientifically based and clinically accepted, they still have their shortcomings such as inconvenience, limited efficacy, and spontaneity. These shortcomings are well recognized in the field, with many investigators exploring improved methods to meet this objective. Broadly speaking, such directions include novel pharmacotherapy, innovative technology, tissue engineering, and creative mechanical approaches. Here we provide an overview of the future of erectile dysfunction treatments.
Chapter
“Vitamin E is dangerous!” “Herbal products have no evidence!” ______ does not treat or cure advanced cancer“? “Supplements don’t do anything, so don’t waste your money!” For almost 30 years I have watched not just patients, but especially some influential clinicians generalize, embellish, and misconstrue data on dietary supplements. This type of commentary just mirrors the lack of objective education in this area, does nothing to improve the clinician and patient relationship, and arguably sends countless individuals to less credible sources for information and misguided sales pitches (as it did through the years for many of my own family members). At the same time, I have watched many in the supplement industry embellish data and supplement efficacy and promote a “we vs. them” contentious milieu that only continues to confuse the public. Again, this acrimonious dichotomy or profound polarization does nothing for overall patient care [1].
Chapter
“Heart health is tantamount to fertility and erectile health,” and “first do no harm” are the mantras of this chapter. Lifestyle changes to improve fertility and erectile function are no longer a theory, but sufficient clinical data exists to emphasize a variety of heart healthy behaviors to enhance overall male health, and specific urologic concerns such as infertility and erectile dysfunction (ED). Nutraceuticals for fertility and erectile health appear to exist or be perceived by clinicians and patients on opposite ends of the treatment validation spectrum. Numerous fertility supplements have preliminary evidence and are utilized in urology in addition to assisted reproductive technologies (ART). In fact, their ongoing use continues to be validated by meta-analyses of randomized trials examining pregnancy and live birth rates. Yet the issue with fertility nutraceuticals is the lack of discrimination over which ones to potentially recommend and discourage based on their overall safety in medicine. A plethora of nutraceuticals has been suggested to be of benefit, but one or several have not in general been recommended. Clinicians need to review the latest list of these supplements and review cost, and especially overall safety and efficacy especially outside of the urologic specialty. For example, high-dose vitamin E supplements have been found to increase the risk of prostate cancer, and regardless of their potential positive data in fertility, there are numerous other options, which could parallel the benefits of vitamin E, but without the potential harm. Erectile dysfunction nutraceuticals have arguably one of the most sordid pasts in the dietary supplement milieu, and it is rightly deserved because the FDA has removed more of these supplements from the market compared to any other type of supplement based on nefarious activities, from the addition of PDE-5 contaminants, to the promotion of a variety of benefits without adequate research. However, despite such a problem with ED nutraceuticals, it appears to have created an unnecessary bias in this category from clinicians, which is not warranted because several nutraceuticals for ED have arguably stronger methodological clinical trials compared to fertility nutraceuticals. This chapter highlights some of the most promising nutraceuticals that have the ability to be utilized with conventional options such as PDE-5 inhibitors and/or ART, and it discourages the vast majority of other ED or fertility-enhancing compounds that simply have no efficacy or are not safe.
Article
It is imperative to study the interaction of nanoparticles residuals with crop plants in agricultural soils, due to the increased application of nanotechnology in agriculture. So far, a few studies have focused on the impact of nanoparticles on fruit quality and nutritional supply. In this work, a thorough and comprehensive analysis of metabolite changes of cucumber fruits for plants under nano-Cu stress was possible through the use of both 1H NMR and GC-MS. The results of supervised partial least-squares discriminant analysis from both platforms showed that cucumber fruit extracts samples were clearly grouped based on the nano-Cu level in soil. This indicates that the fruit metabolite profile was influenced by exposure to nano-Cu. GC-MS data showed concentrations of some sugars, organic acids, amino acids, and fatty acids were increased or decreased by nano-Cu. Several metabolites, such as methylnicotinamide (MNA), trigonelline, imidazole, quinolinate were only detected and quantified by 1H NMR. Our results showed that combining the two platforms provided a comprehensive understanding about the metabolites (nutrient supply) changes in cucumber fruits impacted by exposure to nano-Cu.
Article
L-Citrulline (Cit) is a naturally occurring nonessential amino acid, present in mammals and also in every living organism. It is produced by the body naturally and found naturally in certain foods such as watermelons, cucumbers, pumpkins, muskmelons, bitter melons, squashes, and gourds. About 80% of Cit is converted in the kidney to arginine (Arg), finally converting/recycling Arg to Cit and NO and serving as a potent Arg precursor. Citrulline supplements are better for therapeutic purposes than Arg, as data show Cit supplementation elevates plasma Arg concentration and augments NO signaling in a dose-dependent manner. Citrulline has been shown to be an effective substitute to restore NO production in situations of limited Arg availability and Cit supplementation holds promise as a therapeutic adjunct in clinical conditions associated with Arg/NO deficiency and/or endothelial dysfunction. This chapter discusses the therapeutic uses and potential uses of Cit in various clinical conditions and its potential uses as a biomarker.
Chapter
It is critical to keep in mind, especially in this chapter that multiple lifestyle options exists that can improve or actually not improve and even exacerbate side effects from cancer treatments. And there are many integrative medicines, especially dietary supplements that can improve, have no impact or actually cause a side effect from cancer treatment to become worse! The purpose of this chapter just like the rest of this book is to cover all of those integrative medicines that work, have no effect or are worthless for multiple cancer treatment side effects. When applicable prescription drug treatments are mentioned and reviewed. Still, this chapter and the book is not intended to provide a summary or exhaustive list of the conventional prescription treatment options for these side effects from A to Z because it would not only create an unreadable voluminous text, but this also would not serve the purpose of this text—to simply provide a non-biased and objective review of the medical research in the area of breast cancer and integrative medicines, especially in regard to lifestyle changes and dietary supplements. This is the area of oncology that appears to have arguably the greatest current needs for more objective and educational attention to this issue.
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Many cultures throughout history have passed down knowledge rumored to enhance sexual performance of both men and women including sexual techniques, foods, and nutritional supplements. Sexual techniques can take the form of stimulating certain aspects of the female anatomy and sexual positions such as stimulation of the Grafenberg “G” spot. Other techniques focus on the psychological aspects of sex including synchronization of orgasms and ejaculation prolongation. Cultures around the world have imbued foods as aphrodisiacs, in addition to herbs, plants, and other dietary supplements, collectively known as nutraceuticals. Among the more common ones are pomegranates, antioxidant rich foods, omega-3, basil, cardamom, garlic, watermelon, oysters, l-arginine, caffeine, and dehydroepiandrosterone (DHEA). Herbs such as Chlorophytum borivilianum of the Indian subcontinent to Lepidium meyenii of the South American Andes have long been reported to have aphrodisiac qualities. Many of these products are rich in components that promote cardiovascular health, produce anti-inflammatory activity, cause vasodilatation and increase androgen levels—all important factors in sexual performance. This chapter reviews the various sexual enhancement techniques, foods, and nutraceuticals and the evidence to support their use.
Book
This book focuses on the use of various molecules with antioxidant properties in the treatment of major male genital tract disorders, especially male infertility, erectile dysfunction, and accessory gland infection. The coverage also includes discussion of pathophysiology, the molecular basis of male infertility, and the rationale for use of antioxidants, with particular attention to coenzyme Q10 and carnitine. Oxidative stress occurs when the production of reactive oxygen species, including free radicals, exceeds the body’s natural antioxidant defences, leading to cellular damage. Oxidative stress is present in about half of all infertile men, and reactive oxygen species can produce infertility both by damaging the sperm membrane, with consequences for sperm motility, and by altering the sperm DNA. There is consequently a clear rationale for the use of antioxidant treatments within andrology, and various in vitro and in vivo studies have indicated that many antioxidants indeed have beneficial impacts. In providing a detailed and up-to-date overview of the subject, this book will be of interest to both practitioners and researchers in andrology, endocrinology, and urology.
Thesis
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Tässä kandidaatintyössä on selvitetty koivumahlan ja koivusiirapin terveysvaikutuksia. Mahdolliset terveysvaikutukset on selvitetty kemiallisen koostumuksen perusteella. Työssä on keskitytty erityisesti koivusiirapin terveysvaikutuksien selvittämiseen, sillä siitä löytyy vähiten julkaistua tietoa. Vertailun vuoksi työssä on tarkasteltu myös vaahterasiirappia, ja pyritty löytämään eroavaisuuksia ja yhtäläisyyksiä koivusiirappiin. Koivumahla on 99 %:sesti vettä, joten sitä on juotava suuria määriä, jotta selviä fysiologisia vaikutuksia voitaisiin havaita. Koivusiirappia valmistetaan poistamalla mahlasta vettä. Se on 90 %:sesti sokereita, mutta sisältää myös 3,1 % omenahappoa ja 0,4 % vapaita aminohappoja, sekä hivenmääriä C-vitamiinia ja muita antioksidantteja. Terveyden kannalta tärkeimmät koivusiirapista löytyvät aminohapot ovat sitruliini ja glutamiini. Näistä erityisesti sitruliini voisi olla monien koivumahlan terveysvaikutuksista liikkuvien uskomusten takana. Myös omenahapolla on löydetty terveysvaikutuksia fibromyalgian hoitoon kun sitä käyttää magnesiumin kanssa. Molempia löytyy koivusiirapista ja koivumahlasta. C-vitamiinilla ja muilla antioksidanteilla on kykyä heikentää hapettumista, joka voi aiheuttaa syöpää. Vaahterasiirappi on 98 %:sesti sokeria, joten sen terveysvaikutukset tulevat pääosin antioksidanteista. Kehittyneissä maissa ruokavalio on nykyään monipuolista, mikä tekee koivusiirapin suorien terveysvaikutusten havaitsemisesta vaikeaa. Koivumahla, koivusiirappi ja vaahterasiirappi ovat kuitenkin luonnontuotteita, joilla on terveyttä edistäviä vaikutuksia. Terveysvaikutukset tulevat parhaiten esille varsinkin kehon puutostiloissa. Koivumahlan ja koivusiirapin terveysvaikutuksia on näin ollen tutkittava laajemmin, erityisesti antioksidanttien osalta.
Article
Purpose This paper aims to investigate the effect of L-citrulline supplementation on blood pressure (BP) in middle-aged and elderly populations. Design/methodology/approach Three electronic databases, namely, Google Scholar, PubMed and Scopus, were searched from 1990 to November 2020. Random effects model analysis was applied for quantitative data synthesis, and 6 trials with 150 participants were identified and included in the analysis. Findings Results showed an overall non-significant effect of L-citrulline supplementation on both systolic BP (SBP) and diastolic BP (DBP) in middle-aged and elderly participants. However, stratified analysis indicated a significant reduction in SBP (SMD: −0.41, 95% CI: −0.84, 0.02; p = 0.06, heterogeneity p = 0.41; I2 = 10%) but not in DBP (SMD:−0.15, 95% CI: −0.57, 0.28; p = 0.51, heterogeneity p = 0.60; I2 = 0%), following longer-term (= 8 weeks) supplementation of L-citrulline. Additionally, higher doses of L-citrulline (= 6 grams) showed a marginally significant reduction in DBP (SMD: −0.38, 95% CI: −0.78, 0.02; p = 0.06, heterogeneity p = 0.50; I2 = 0%). Originality/value In conclusion, a higher dosage and longer duration of supplementation with L-citrulline may have potential BP lowering effects in populations at an increased risk of hypertension
Article
Post-selective serotonin reuptake inhibitors (SSRIs) sexual dysfunction (PSSD) is a new clinical entity occurring after the antidepressant intake, and it is characterized by the fact that patients continue to present sexual side effects after the discontinuation of the drugs. PSSD mainly consists of hypo-anesthesia of the genital area, loss of libido, and erectile dysfunction. Although different management options have been proposed, there is no consensus on the treatment for this syndrome. Herein we report on a young man affected by PSSD who regained sexual functioning after 3-month treatment with EDOVIS, a dietary supplement containing L-citrulline and other commonly used aphrodisiacs. Clinicians should be aware about the possibility of persistent sexual side effects induced by serotoninergic antidepressants and take into considerations the use of nutraceuticals to overcome PSSD.
Article
Background and aim: Nitric oxide (NO) is the intracellular chemical responsible for initiating a penile erection. Despite conflicting clinical data, it continues to be publicized and promoted that orally administered l-arginine, the putative substrate for NO, enhances the erectile response presumably by stimulating NO production by the corporal tissues resulting in an increase in cGMP production. To shed light on this issue, an in vitro study was conducted to explore the effect of direct exogenous administration of l-arginine as well as its precursor and metabolite, l-citrulline, on the NO-cGMP pathway within the cavernosal smooth muscle (CSM) cell. Materials and methods: CSM cells obtained from 8 to 10 week old Sprague-Dawley rats were grown in Dulbecco media with 20% fetal calf serum and then incubated with or without l-arginine (L-ARG) or l-citrulline (L-CIT) in a time course and dose-response manner. Sildenafil (0.4 mM), IBMX (1 mM), l-NAME (3 μM), ODQ (5 μM) and Deta Nonoate (10 μM) were used as either inhibitors or stimulators of the NO-cGMP pathway. mRNA and protein were extracted and used for the determination of the phosphodiesterase 5 (PDE5). PDE5 activity was determined by luminometry. cGMP content was determined by ELISA. Nitrite formation, an indicator of NO production, was measured in the cell culture media by a colorimetric assay. The cationic (CAT-1) and neutral (SNAT-1) amino acid transporters for L-ARG and L-CIT, respectively, were determined by Western blot. Results: When compared to untreated CSM cells, incubation with 0.25-4.0 mM of L-ARG or 0.3-4.8 mM of L-CIT anywhere between 3 and 24 h did not result in any additional nitrite or cGMP production. The addition of l-NAME, IBMX or ODQ to these L-ARG and L-CIT treated cells did not alter these results. L-CIT but not L-ARG increased PDE5 mRNA and protein content as well as the activity of the PDE5 enzyme. Both CAT-1 and SNAT-1 were expressed in the CSM cells. Conclusions: This in vitro study demonstrates that exogenous administration of L-ARG or L-CIT failed to stimulate production of either NO or cGMP by the corporal CSM cells. A re-evaluation of the presumptive role of the exogenous administration of L-ARG in improving the synthesis of NO at least at the level of the CSM cells appears warranted.
Chapter
Erectile Dysfunction (ED) can affect males of all age groups and is often associated with an enormous decrease in quality of life. Furthermore, it is recognized as an early indicator of cardiovascular disease. Standard non-invasive therapy of ED encompasses mechanical options and pharmacological treatment with inhibitors of phosphodiesterase-5 (PDE5-i). More invasive options include local application of vasodilating agents and, in refractory cases, operative implantation of a penile prosthesis. Peyronie’s disease (PD) is caused by an inflammatory process of the penile tunica albuginea, resulting in the formation of fibrotic plaques, which may lead to penile deformity. While medical therapy can help to attain symptom relief and early plaque stabilization, different surgical approaches to correct penile curvature exist. A variety of novel treatment alternatives are available for both diseases. The following chapter sums up current treatment algorithms for ED and PD.
Chapter
L-citrulline and L-arginine are naturally occurring amino acids that are conditionally essential in periods of stress (sepsis, intestinal pathology). Previously considered to be only intermediates in the urea acid cycle, they are now found to be effective precursors of nitric oxide that are exploited in therapeutics. Its their supplementation is likely to be used in conditions like such as erectile dysfunction, male infertility, sickle cell anemia, short bowel syndrome (to restore nitrogen balance), hyperlipidemia, cancer chemotherapy, hyperoxic lung damage, uric acid cycle disorders, and intrauterine growth restriction. Other emerging uses are include immunonutrition, immunomodulation, cystic fibrosis, Alzheimer’s disease, multiinfarct dementia, T-cell dysfunction, as an antioxidant in conditions like sepsis, and for athletic training. Overall, citrulline (Cit) is a more effective precursor of arginine than arginine itself. Its role as a biomarker in intestinal pathology and diagnosis of early rheumatoid arthritis is of considerable interest. These nutraceuticals should be further explored in large-scale clinical trials in these areas. Another area of interest regarding Cit is the detection of an antibody to citrullinated peptides that serve as predictors for diseases, thus serving as biomarkers in various diseases. Cit has been used as a biomarker for diseases such as rheumatoid arthritis, intestinal pathology, and short bowel syndrome short bowel syndrome as biomarkers. It will either be proved or disproved as a biomarker in the future for other conditions such as parenteral nutrition in HIV patients, congenital anomalies, acute rejections in transplantations, intrauterine growth restriction, critically ill patients, acute kidney failure, and nitrosative stress (NO/NOS) and reactive nitrogen species (RNS) in conditions such as anticholinesterase poisoning and, kainic acid-induced neurotoxicity because oxidative stress increases RNS and reactive oxygen species reactive oxygen species (when the rate of adenosine triphosphate demand exceeds production), causing lipid peroxidation and DNA damage. Further studies are required in this regards.
Chapter
As a functional amino acid (AA), L-arginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine in mammals (including humans). NO (a major vasodilator) increases blood flow to tissues. Arg and its metabolites play important roles in metabolism and physiology. Arg is required to maintain the urea cycle in the active state to detoxify ammonia. This AA also activates cellular mechanistic target of rapamycin (MTOR) and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, promoting spermatogenesis and sperm quality, improving conceptus survival and growth, and augmenting the production of milk proteins. Although Arg is formed de novo from glutamine/glutamate and proline in humans, these synthetic pathways do not provide sufficient Arg in infants or adults. Thus, humans and other animals do have dietary needs of Arg for optimal growth, development, lactation, and fertility. Much evidence shows that oral administration of Arg within the physiological range can confer health benefits to both men and women by increasing NO synthesis and thus blood flow in tissues (e.g., skeletal muscle and the corpora cavernosa of the penis). NO is a vasodilator, a neurotransmitter, a regulator of nutrient metabolism, and a killer of bacteria, fungi, parasites, and viruses [including coronaviruses, such as SARS-CoV and SARS-CoV-2 (the virus causing COVID-19). Thus, Arg supplementation can enhance immunity, anti-infectious, and anti-oxidative responses, fertility, wound healing, ammonia detoxification, nutrient digestion and absorption, lean tissue mass, and brown adipose tissue development; ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension); and treat individuals with erectile dysfunction, sickle cell disease, muscular dystrophy, and pre-eclampsia.
Chapter
Erectile dysfunction (ED) is defined as an inability to achieve or maintain penile erection sufficiently enough for sexual performance. Sexual function involves an interplay between psychological, vascular, neurological, endocrine functions; thus the various etiologies of ED can be divided into psychosocial or organic causes. Current mainstays of treatment for ED are centered around enhancing levels of nitric oxide at the nerve terminal with pharmacologic agents such as phosphodiesterase inhibitors, followed by more invasive therapies such as intracavernosal injections and penile prosthesis. The market for supplements for ED has been growing in popularity and has warranted further investigation into mechanisms of action and efficacy. This chapter discusses several supplements that have been marketed as therapies for ED, their efficacies in clinical trials, as well as their mechanism of action on the biochemical level, safety profiles, and adverse effects.
Article
With the aim of providing a theoretical basis for the application of L‐citrulline (L‐Cit) in animal husbandry, the effects of L‐Cit on reproductive hormone levels, antioxidant capacity, and semen quality of rams were studied by feeding them varying doses of L‐Cit. A total of 32 rams were randomly divided into four groups with eight rams each. After all rams were trained to donate sperm normally, the control group was fed a basic diet, whereas the experimental groups I, II, and III were provided with feed supplemented with 4, 8, and 12 g/d of L‐Cit, respectively.The experiment was conducted for 70 days, during which blood samples were collected from the jugular vein on days 0, 15, 30, 45, and 60, and semen samples were collected on days 0, 20, 40, and 60. In the same group, 100 µL of semen was used to test for quality, The rest of the semen sample and blood samples were centrifuged at 3500 rpm for 15 min, and the supernatant and serum, respectively, were used to determine the levels reproductive hormones and antioxidant indices. Ram semen samples were also collected on day 70 and used to study sperm plasma membrane, substitution, and mitochondrial membrane potential. Compared with the control group, the groups receiving L‐Cit showed an increase in sperm concentration and number of linear motile sperm (P < 0.01); decrease in the number of dead sperm (P < 0.01); increase in sperm viability, particularly in groups II and III (P < 0.01); and increase in sperm mitochondrial membrane potential (P < 0.01). Moreover, groups I, II, and III showed significantly higher levels of serum gonadotropin‐releasing hormone (GnRH), glutathione peroxidase (GSH‐Px), and nitric oxide (NO) (P < 0.01). Luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) levels increased in groups I (P < 0.05), II (P < 0.05), and III (P < 0.01), whereas testosterone (T), catalase (CAT), and superoxide dismutase (SOD) levels increased in groups I and II (P < 0.01). Serum total antioxidant capacity (T‐A) increased (P < 0.05), whereas both hydroxyl radical (·OH) and peroxy radical (O2·−) levels decreased (P < 0.01). Compared with the control, all groups had significantly higher SOD and GSH‐Px in their seminal plasma (P < 0.01), and groups I, II (P < 0.05 for both), and III (P < 0.01) had higher levels of GnRH and FSH. LH, CAT, and NO levels increased in group I (P < 0.05), II, and III (P < 0.01 for both); malondialdehyde levels decreased in groups I, II (P < 0.05 for both), and group III (P < 0.01); and O2·− levels decreased in groups I, II, and III (P < 0.01). Under our experimental conditions, GnRH, FSH, LH, T, CAT, SOD, T‐A, GSH‐PX, and NO levels in the serum and seminal plasma of rams receiving L‐Cit increased, whereas Estradiol(E2), O2·− and ·OH levels in the seminal plasma decreased; this improved the semen quality of rams supplemented with L‐Cit. Moreover, supplementation with 12 g/d gave the best results.
Article
Patients using nutraceuticals represent a diverse patient population with a keen potential interest and/or adherence to healthy lifestyle changes. BPH nutraceuticals, including saw palmetto were as safe, but not more effective than placebo in the STEP and CAMUS clinical trials, but another high-quality saw palmetto product could be tested in a phase 3 trial. Several other BPH supplements need more recent robust clinical data, environmental oversight, or safety data. ED supplements, including Panax ginseng, and the notable nitric oxide (NO) enhancing amino acids arginine and citrulline have positive preliminary short-term efficacy data with and without PDE-5 inhibitors, but herbal quality control (QC) or safety signals with some of these agents in specific patient populations need to be resolved. "Less is more" should be the current mantra in the prostate cancer milieu, and potentially in some men with male infertility based on the FAZST trial because it is plausible some antioxidants are exhibiting prooxidant activity in some settings. Some prescription anthelmintic medications are being studied, others are being purchased over-the-counter (OTC), but their preliminary safety and efficacy against cancer have been concerning and questionable. In fairness, ongoing additional objective clinical trial data should become available soon, especially with mebendazole. DHEA or DHEA enhancing products have multiple concerns including HDL reductions, and their questionable use in men with BPH or prostate cancer based on the limited data. Some of these concerns should also be addressed in long-term robust clinical trials of prescription testosterone agents. Regardless, more attention should be directed toward heart-healthy lifestyle changes for most urologic men's health conditions, whether they are used in a preventive or synergistic setting with other acceptable clinical treatment options.
Article
Introduction: Use of supplements is common among men seeking urologic evaluation for sexual health matters. With a dizzying array of formulations available and little regulation on the dosage, purity, or ingredients found in these products, the health effects of nutraceuticals are often confusing to patients and medical practitioners alike. Aim: In this review, we set out to concisely summarize the data on ingredients found within the top-selling nutraceutical agents marketed for men's sexual health in order to provide a clinical guide for urologists. Methods: We used sales data from the most popular retail provider of men's health supplements to identify the top-selling products marketed toward improvement of men's sexual health. We summarized the available information related to the ingredients, dosage, cost, and mechanism of action for these substances and performed an extensive literature search to identify and review the current evidence available for each of the most common ingredients found in these nutraceuticals. Results: The top-selling nutraceuticals marked for men's sexual health contain a blend of multiple supplements (up to 33 in one formulation identified), the most common being ginseng, tribulus, zinc, horny goat weed, B complex vitamins/trace minerals, fenugreek, L-arginine, maca, DHEA, ginkgo, and yohimbine. The currently available medical literature evaluating the efficacy of these substances is generally of low quality. Conclusions: Despite the dearth of evidence supporting nutraceutical agents in the men's health arena, these substances are still commonly used by patients. As these products can affect the health and well-being of men presenting to a urology clinic, a familiarity with commonly used agents can help the urologist appropriately counsel their patients. Cui T, Kovell RC, Brooks DC, and Terlecki RP. A urologist's guide to ingredients found in top-selling nutraceuticals for men's sexual health. J Sex Med **;**:**-**.
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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified complex patterns of interaction among these enzymes. There is growing interest in the potential roles of the arginase isoenzymes as regulators of the synthesis of nitric oxide, polyamines, proline and glutamate. Physiological roles and relationships between the pathways of arginine synthesis and catabolism in vivo are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ (e.g. liver, small intestine and kidney) and subcellular (cytosol and mitochondria) levels, as well as to changes in expression during development and in response to diet, hormones and cytokines. The ongoing development of new cell lines and animal models using cDNA clones and genes for key arginine metabolic enzymes will provide new approaches more clearly elucidating the physiological roles of these enzymes.
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L-Arginine may be a conditionally essential amino acid in children and adolescents with sickle cell disease, particularly as required substrate in the arginine-nitric oxide pathway for endogenous nitrovasodilation and vasoprotection. Vasoprotection by arginine is mediated partly by nitric oxide-induced inhibition of endothelial damage and inhibition of adhesion and activation of leukocytes. Activated leukocytes may trigger many of the complications, including vasoocclusive events and intimal hyperplasias. High blood leukocyte counts during steady states in the absence of infection are significant laboratory risk factors for adverse complications. L-Citrulline as precursor amino acid was given orally twice daily in daily doses of approximately 0.1 g/kg in a pilot Phase II clinical trial during steady states in four homozygous sickle cell disease subjects and one sickle cell-hemoglobin C disease patient (ages 10-18). There soon resulted dramatic improvements in symptoms of well-being, raised plasma arginine levels, and reductions in high total leukocyte and high segmented neutrophil counts toward or to within normal limits. Continued L-citrulline supplementation in compliant subjects continued to lessen symptomatology, to maintain plasma arginine concentrations greater than control levels, and to maintain nearly normal total leukocyte and neutrophil counts. Side effects or toxicity from citrulline were not experienced. Oral L-citrulline may portend very useful for palliative therapy in sickle cell disease. Placebo-controlled, long-term trials are now indicated.
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In mammals, L-arginine is classified as a semiessential or conditionally essential amino acid, depending on the developmental stage and health status of the individual. It can be derived from proline or glutamate, with the ultimate synthetic step catalyzed by argininosuccinate lyase. L-arginine is catabolized by arginases, nitric oxide synthases, arginine:glycine amidinotransferase, and possibly also by arginine decarboxylase, resulting ultimately in the production of urea, proline, glutamate, polyamines, nitric oxide, creatine, or agmatine. There is considerable diversity in tissue-specific and stimulus-dependent regulation of expression within this group of enzymes, and the expression of several of them can be regulated at transcriptional and translational levels by changes in the concentration of L-arginine itself. Consequently, the interplay among these enzymes in the regulation of specific aspects of arginine metabolism can be quite complex. For example, nitric oxide production can be affected by the interplay between nitric oxide synthases, arginases, and argininosuccinate synthetase. This metabolic complexity can pose challenges for analyses of arginine metabolism not only because L-arginine is a substrate for several different enzymes but also because ornithine and citrulline, key products of arginine metabolism, can each be produced by multiple enzymes. This overview highlights key features of the arginine metabolic enzymes and their interactions.
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To explore relationships between erection hardness and other outcomes in men with erectile dysfunction (ED). Pooled analyses were conducted on 27 randomized, double-blind, placebo-controlled trials and six open-label trials from the worldwide sildenafil database. Outcomes included erection hardness graded subjectively, hardness and sexual satisfaction questions from the International Index of Erectile Function, general and sexually-specific emotional well-being from the self-esteem and relationship questionnaire, and the erectile dysfunction inventory of treatment satisfaction. Hardness outcomes improved (with a possible dose-response relationship for the achievement of fully hard and rigid erections) and correlated positively with the other outcomes. Sildenafil 100 mg produced optimal erection hardness (fully hard and rigid erections) in a substantial proportion of men with ED. Because optimal erection hardness correlated positively with some emotional well-being and satisfaction outcomes, sildenafil 100 mg may be the most appropriate dosage for treatment of ED for most men.
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A metabolic relation exists between glutamine and arginine, 2 amino acids with properties that enhance the recovery of seriously ill patients. It is possible that glutamine exerts part of its beneficial effects by enhancing the availability of arginine. We aimed to quantify under postabsorptive conditions the metabolic pathway of plasma glutamine into arginine via the intermediate citrulline and to establish the contribution of the kidneys to the synthesis of arginine. The study was conducted in patients during surgery. The metabolism of glutamine, citrulline, and arginine was studied by using intravenous administration of stable isotope tracers of the amino acids. Results were interpreted by using established equations. Parametric tests were used to test and correlate results. P < 0.05 was regarded as significant. Mean (+/-SE) whole-body plasma turnover rates of glutamine, citrulline, and arginine were 240 +/- 14, 6.2 +/- 0.6, and 42 +/- 2.9 micromol x kg(-1) x h(-1), respectively (P < 0.01). Plasma turnover of citrulline derived from glutamine was shown to be 5.1 +/- 0.7 micromol x kg(-1) x h(-1), and arginine derived from citrulline was shown to be 4.9 +/- 0.9 micromol x kg(-1) x h(-1) (P < 0.01). The contribution of plasma glutamine to plasma arginine derived from plasma citrulline was calculated to be 64%. The kidneys were observed to take up >50% of circulating plasma citrulline and to release equimolar amounts of arginine into plasma. This study shows that glutamine is an important precursor for the synthesis of arginine in humans. It also provides a firm basis for future studies exploring the effect of a treatment dose and the route of administration (enteral or parenteral) of glutamine.
Article
Introduction. Erection hardness is a fundamental component of erectile function, and is a very specific and easily monitored outcome. The Erection Hardness Score (EHS) is a single-item, patient-reported outcome (PRO) for scoring erection hardness. Aims. The aim of this article is to report the psychometric validation of the EHS. Methods. The dataset (N = 307) was from a multinational sildenafil trial (efficacy in the treatment of erectile dysfunction [ED]) with a 2-week screening phase, a 6-week double-blind, placebo-controlled treatment phase, and a 6-week open-label extension. Main Outcome Measures. Test–retest reliability (intraclass correlation coefficient), quality and distribution of responses, known-groups validity (ability to differentiate between ED severity groups defined by the International Index of Erectile Function [IIEF] questionnaire), convergent validity (Pearson correlation coefficients with domain scores of the IIEF and the Quality of Erection Questionnaire [QEQ]), treatment responsiveness, and clinically important difference. Results. The EHS demonstrated good test–retest reliability, acceptable quality and distribution of responses, known-groups validity against the IIEF (including clear differentiation between normal and impaired erectile function), moderate-to-strong convergent validity against the prespecified domains of the IIEF and QEQ, and high treatment responsiveness. Conclusion. The EHS has desirable measurement properties, including being highly responsive to treatment. This one-item PRO is robust and easy to use for evaluating erection hardness. Psychometric analysis supports the use of the EHS as a simple, reliable, and valid tool for the assessment of erection hardness in clinical trials research. Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC, and Hvidsten K. Validation of the Erection Hardness Score. J Sex Med 2007;4:1626–1634.
Article
The Erection Hardness Score (EHS), a validated single-item patient-reported outcome (PRO), may provide a simple method to capture erectile dysfunction (ED) symptoms and to monitor treatment outcome. To map the relationship between the EHS, which was used as the anchor, and other validated PROs: International Index of Erectile Function (IIEF), Quality of Erection Questionnaire (QEQ), Sexual Experience Questionnaire (SEX-Q), and Self-Esteem and Relationship questionnaire (SEAR). Methods. Data were from a trial of flexible-dose sildenafil (50 or 100 mg) in 209 men with ED. A mixed-effects repeated-measures model with EHS as a categorical explanatory variable and each of the other PROs, as a separate dependent variable, was applied to analyze the longitudinal data from randomization to the end of the 10-week, double-blind, placebo-controlled phase and the 6-week open-label phase. EHS data, which were generated at each sexual encounter (event), were averaged per patient over the same recall period that preceded administration of the other PRO questionnaires. Scores on all domains of the IIEF and SEX-Q, as well as the SEAR total score and SEAR Sexual Relationship domain, discriminated on all EHS categories. The QEQ total score discriminated on all EHS categories except EHS 1 and EHS 2. Although the model did not impose any functional relationship between PRO score and EHS, an approximately linear relationship existed between the EHS and all other PROs, which was especially pronounced for those PROs that were more directly related to erectile quality or function. The relationship between discrete EHS categories and PRO scores demonstrates the close correspondence of erectile hardness with erectile function (IIEF), erection quality (QEQ), overall sexual experience (SEX-Q), and ED-related psychosocial factors (SEAR) in men with ED.
Article
Nitric oxide (NO) is a cytotoxic agent of macrophages, a messenger molecule of neurons, and a vasodilator produced by endothelial cells. NO synthase, the synthetic enzyme for NO, was localized to rat penile neurons innervating the corpora cavernosa and to neuronal plexuses in the adventitial layer of penile arteries. Small doses of NO synthase inhibitors abolished electrophysiologically induced penile erections. These results establish NO as a physiologic mediator of erectile function.
Article
To determine, in a prospective randomized, double-blind placebo-controlled study, the effect of 6 weeks of high-dose (5 g/day) orally administered nitric oxide (NO) donor L-arginine on men with organic erectile dysfunction (ED). The study included 50 men with confirmed organic ED who were randomized after a 2-week placebo run-in period to receive L-arginine or placebo. A detailed medical and sexual history, O'Leary's questionnaire, a specially designed sexual function questionnaire and a sexual activity diary were obtained for each patient. All participants underwent a complete physical examination including an assessment of bulbocavernosus reflex and penile haemodynamics. Plasma and urine nitrite and nitrate (designated NOx), both stable metabolites of nitric oxide, were determined at the end of the placebo run-in period, and after 3 and 6 weeks. Nine of 29 (31%) patients taking L-arginine and two of 17 controls reported a significant subjective improvement in sexual function. All objective variables assessed remained unchanged. All nine patients treated with L-arginine and who had subjectively improved sexual performance had had an initially low urinary NOx, and this level had doubled at the end of the study. Oral administration of L-arginine in high doses seems to cause significant subjective improvement in sexual function in men with organic ED only if they have decreased NOx excretion or production. The haemodynamics of the corpus cavernosum were not affected by oral L-arginine at the dosage used.
Article
Nitric oxide (NO) is a physiologic signal essential to penile erection, and disorders that reduce NO synthesis or release in the erectile tissue are commonly associated with erectile dysfunction. NO synthase (NOS) catalyzes production of NO from L-arginine. While both constitutively expressed neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms mediate penile erection, nNOS is widely perceived to predominate in this role. Demonstration that blood-flow-dependent generation of NO involves phosphorylative activation of penile eNOS challenges conventional understanding of NO-dependent erectile mechanisms. Regulation of erectile function may not be mediated exclusively by neurally derived NO: Blood-flow-induced fluid shear stress in the penile vasculature stimulates phosphatidyl-inositol 3-kinase to phosphorylate protein kinase B, which in turn phosphorylates eNOS to generate NO. Thus, nNOS may initiate cavernosal tissue relaxation, while activated eNOS may facilitate attainment and maintenance of full erection.
Article
The study sought to determine whether citrulline supplementation, a precursor to nitric oxide synthesis, is safe and efficacious in increasing plasma citrulline concentrations and decreasing the risk of postoperative pulmonary hypertension. Forty children, undergoing cardiopulmonary bypass and at risk for pulmonary hypertension, were randomized to receive 5 perioperative doses (1.9 g/m2 per dose) of either oral citrulline or placebo. Plasma citrulline and arginine concentrations were measured at 5 time points. Measurements of systemic blood pressure and presence of pulmonary hypertension were collected. Median citrulline concentrations were significantly higher in the citrulline group versus the placebo group immediately postoperatively (36 micromol/L vs 26 micromol/L, P = .012) and at 12 hours postoperatively (37 micromol/L vs 20 micromol/L, P = .015). Mean plasma arginine concentrations were significantly higher in the citrulline group versus the placebo group by 12 hours postoperatively (36 micromol/L vs 23 micromol/L, P = .037). Mean systemic blood pressure did not differ between groups (P = .53). Postoperative pulmonary hypertension developed in 9 patients, 6 of 20 (30%) in the placebo group and 3 of 20 (15%) in the citrulline group (P = .451), all of whom had plasma citrulline concentrations less than age-specific norms. Postoperative pulmonary hypertension did not develop in patients who demonstrated plasma citrulline concentrations in excess of 37 mumol/L (P = .036). Oral citrulline supplementation safely increased plasma citrulline and arginine concentrations compared with placebo after cardiopulmonary bypass. Postoperative pulmonary hypertension did not occur in children with naturally elevated citrulline levels or elevations through supplementation. Oral citrulline supplementation may be effective in reducing postoperative pulmonary hypertension.
Article
Oral supplements of arginine and citrulline increase local nitric oxide (NO) production in the small intestine and this may be harmful under certain circumstances. Gastrointestinal toxicity was therefore reviewed with respect to the intestinal physiology of arginine, citrulline, ornithine, and cystine (which shares the same transporter) and the many clinical trials of supplements of the dibasic amino acids or N-acetylcysteine (NAC). The human intestinal dibasic amino acid transport system has high affinity and low capacity. L-arginine (but not lysine, ornithine, or D-arginine) induces water and electrolyte secretion that is mediated by NO, which acts as an absorbagogue at low levels and as a secretagogue at high levels. The action of many laxatives is NO mediated and there are reports of diarrhea following oral administration of arginine or ornithine. The clinical data cover a wide span of arginine intakes from 3 g/d to>100 g/d, but the standard of reporting adverse effects (e.g. nausea, vomiting, and diarrhea) was variable. Single doses of 3-6 g rarely provoked side effects and healthy athletes appeared to be more susceptible than diabetic patients to gastrointestinal symptoms at individual doses>9 g. This may relate to an effect of disease on gastrointestinal motility and pharmacokinetics. Most side effects of arginine and NAC occurred at single doses of >9 g in adults (>140 mg/kg) often when part of a daily regime of approximately>30 g/d (>174 mmol/d). In the case of arginine, this compares with the laxative threshold of the nonabsorbed disaccharide alcohol, lactitol (74 g or 194 mmol). Adverse effects seemed dependent on the dosage regime and disappeared if divided doses were ingested (unlike lactitol). Large single doses of poorly absorbed amino acids seem to provoke diarrhea. More research is needed to refine dosage strategies that reduce this phenomenon. It is suggested that dipeptide forms of arginine may meet this criterion.
Article
Oral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects. In a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (C(max), T(max), C(min), AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects. L-Citrulline dose-dependently increased AUC and C(max) of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the C(min) of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 +/- 8 (baseline) to 278 +/- 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 +/- 10 to 125 +/- 15 micromol mmol(-1) creatinine (P = 0.01, 95% CI 8, 58) and from 38 +/- 3.3 to 50 +/- 6.7 nmol mmol(-1) creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD. Our data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.
Article
We investigated the relaxant effects of repetitive administration of L-arginine, the substrate for nitric oxide, at hourly intervals and elucidated its mechanism of action in human corpus cavernosum. Samples of human corpus cavernosum were suspended in an organ chamber for measurements of isometric tension. After precontraction with phenylephrine (10 microM), concentration-response curves were performed for L-arginine at 2-hour intervals (1 to 10 hours). Underlying mechanisms of relaxation were evaluated by inhibitory and stimulatory agents. After a brief incubation period of 1 to 4 hours L-arginine (0.1 to 1,000 microM) but not D-arginine induced minor changes in HCC. In contrast, when incubation time was increased to 6 to 10 hours L-arginine evoked detectable human corpus cavernosum relaxation proportional to concentration and time. Relaxation was significantly attenuated by the nitric oxide synthase inhibitor L-NAME, the blocker of soluble guanylyl cyclase ODQ and the blocker of small conductance Ca2+ activated K+ channels apamin, and partially by the inducible nitric oxide synthase inhibitor aminoguanidine and the cyclic guanosine 5'-monophosphate dependent protein kinase G inhibitor Rp-8-pCPT-cGMPS. Relaxation was potentiated in the presence of the membrane permeable cyclic guanosine 5'-monophosphate analogue 8-bromo-cyclic guanosine 5'-monophosphate, the Rho-kinase inhibitor Y-27632 and the phosphodiesterase-5 inhibitor sildenafil. These observations demonstrate that L-arginine induces slow and prolonged relaxation of human corpus cavernosum. This may occur by restoring the endogenous amino acid pool for nitric oxide synthesis and by nitric oxide-soluble guanylyl cyclase-protein kinase G signaling involving the activation of KCa channels or by inhibiting the up-regulated RhoA/Rho-kinase pathway. The use of sildenafil combined with L-arginine further facilitates erections and it may benefit men with more severe erectile dysfunction.
Article
Introduction: Vascular smooth muscle cells express endothelial nitric oxide synthase (eNOS) and produce nitric oxide (NO). Recently, increased NO production has been reported to induce the synthesis and secretion of vascular endothelial growth factor (VEGF) via the NO/cyclic guanosine 3',5'-monophosphate (cGMP) pathway. L-arginine (L-arg), the precursor of NO, and selective phosphodiesterase type 5 (PDE-5) inhibitors that increase levels of intracellular cGMP may complementarily enhance VEGF synthesis in corpus cavernosal smooth muscle cells (CCSMCs), and may consequently restore impaired endothelial function. Expression of eNOS in corpus cavernosal smooth muscle has also been reported. However, it is unclear whether CCSMCs can generate NO. Aim: To elucidate whether CCSMCs can synthesize NO and whether NO synthesis enhances VEGF synthesis via the NO/cGMP pathway. Methods: Corpus cavernosal cells were cultured and characterized by immunocytochemistry and immunoblotting. CCSMCs were treated with L-arg. CCSMCs were also incubated with L-arg and with vardenafil, an inhibitor of PDE-5. Main outcome measures: Release of NO from cells was confirmed by assay of NO metabolites (NOx). Intracellular cGMP concentration and VEGF concentration in the medium were measured. Results: Isolated cells were determined to be CCSMCs. The expression of eNOS by CCSMCs was also identified. NOx and cGMP levels in the L-arg-treated group were significantly greater than those in the control group. VEGF and cGMP levels in the L-arg-treated group were also significantly greater than those in the control group. VEGF and cGMP levels in the L-arg + vardenafil-treated group were significantly greater than those in the L-arg-treated group and the control group. Conclusions: CCSMCs express eNOS and synthesize NO. NO synthesis leads to enhancement of VEGF synthesis via the NO/cGMP pathway. Combined L-arg and vardenafil treatment, which can enhance VEGF production, may provide a novel therapeutic strategy for the treatment of erectile dysfunction as well as endothelial dysfunction in general.
Arginine metabolism: nitric oxide and beyond.
  • Wu G.
  • Morris Jr, S.M.