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Hindawi Publishing CorporationBioMed Research InternationalVolume 2014, Article ID 121396, 7 pages Clinical StudyAlga Ecklonia bicyclis, Tribulus terrestris, and GlucosamineOligosaccharide Improve Erectile Function, Sexual Quality ofLife, and Ejaculation Function in Patients with ModerateMild-Moderate Erectile Dysfunction: A Prospective,Randomized, Placebo-Controlled, Single-Blinded Study Salvatore Sansalone,1 Rosario Leonardi,2 Gabriele Antonini,3Antonio Vitarelli,4 Giuseppe Vespasiani,1 Dragoslav Basic,5 Giuseppe Morgia,6Sebastiano Cimino,6 and Giorgio Ivan Russo6 1 Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy 2 Centro Uro Andrologico, Acireale, Italy 3 Department of Urology "U. Bracci", La Sapienza University of Rome, Rome, Italy 4 Urologia Universitaria II, Azienda Ospedaliera Policlinico Bari, Bari, Italy 5 Clinic of Urology, Clinical Center Nis, Nis, Serbia 6 School of Medicine Policlinico Hospital, Department of Urology, University of Catania, Catania, Italy Correspondence should be addressed to Giorgio Ivan Russo; [email protected] Received 18 March 2014; Accepted 1 June 2014; Published 20 July 2014 Academic Editor: Ralf Herwig Copyright 2014 Salvatore Sansalone et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly We aimed to evaluate the efficacy of oral therapy with alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide (Tradamix TX1000) in patients with erectile dysfunction (ED) at 3 months of fol ow-up. From January 2013 to September 2013, 177 patients diagnosed with mild-moderate ED (IIEF-EF< 26) were enrol ed in this multicenter, single-blinded, placebo-control ed study and randomized in Group A (Tradamix, 𝑛 = 87) and Group B (placebo, 𝑛 = 90). Penile color Doppler ultrasound measures, IIEF-15 questionnaire, male sexual health questionnaire-ejaculation disorder (MSHQ-EjD), and sexual quality of life (SQoL-M) were col ected. We observed significant changes of the IIEF-15 in Group A (mean difference: 11.54; 𝑃 < 0.05) at 3 months versus Group B (𝑃 < 0.05). PSV (𝑃 < 0.05), IIEF-intercourse satisfaction (𝑃 < 0.05), IIEF-orgasmic function (mean 𝑃 < 0.05), IIEF-sexual desire (𝑃 < 0.05), IIEF-overall satisfaction (𝑃 < 0.05), MSHQ-EjD (mean difference: 1.21; 𝑃 < 0.05), and SQoL-M (mean difference: 10.2; 𝑃 < 0.05) were significantly changed in Group A versus baseline and Group B. Patients with moderate arterial dysfunction showed significant increase of PSV (𝑃 < 0.05), IIEF-EF (𝑃 < 0.05), MSHQ-EjD (𝑃 < 0.05), and SQoL-M (𝑃 < 0.05) in Group A. Therapy with Tradamix improves erectile and ejaculation function and sexual quality of life in patients with mild-moderate ED and in particular for those with moderate arterial dysfunction.
emerged as an important indicator of men's overal health, due to the very closed relationship to concomitant comor- Al over the world, erectile dysfunction (ED) is considered bidities [1–4].
one of the most diffuse sexual disorders. The prevalence rate Several observational studies recently demonstrated that of ED increases with age and with concomitant morbidities.
ED is associated with different comorbid condition and over- To this regard, erectile dysfunction (ED) has progressively all poorer male health [5, 6], but also ED may significantly BioMed Research International increase the risk of cardiovascular disease (CVD), coronary Ministry Of Education and Science, Grant No175092). Al heart disease, stroke [7], and all-cause mortality [8–11], and patients underwent preliminary assessment including a this increase is probably independent from conventional car- detailed medical and sexual history to evaluate the presence diovascular risk factors [9] and glycometabolic control [12].
of risk factors such as diabetes mellitus, hypertension, dyslip- Based on these considerations, phosphodiesterase-5 idaemia, and smoking. Al subjects were self-administered inhibitors (PDE5-i) have become the most popular treatment the IIEF-15 item questionnaire and the Male Sexual Health and are currently the first line monotherapy for ED [13].
Ques-tionnaire-Ejaculation Disorder (MSHQ-EjD) and sex- However, it should be taken into account that some ual quality of life instrument for men (SQoL-M).
patients with complex ED may not be responders to PDE5-I The primary inclusion criteria were a minimum age of monotherapy [14]. Furthermore, this category of drugs is not 18 years, a diagnosis of nonendocrinological ED according depicted from side effects that could impair pharmacological to the National Institutes of Health statement on ED, 1 na¨ıve to treatment for ED, a stable heterosexual relationship for at The most common reported side effects are headache, least the previous 6 months, and a steady relationship with muscular pains, hot flushes, tearing, and so on that can affect the same female partner.
normal sexual intercourse [15]. It is also general y known that Exclusion criteria were as follows: severe ED (IIEF-EF < ED may be associated with serum total testosterone (TT) 11), previous medical or surgical treatments for ED, any alterations. In fact, TT in men begins to decline in the late medical treatment for sexual dysfunction before or during third or early fourth decade and diminish at a constant rate the study, congenital or acquired penile curvature or chordee thereafter [16].
with hypospadias, age >75 years, hypogonadism (total testos- In this general context, studies on natural compounds terone level of <8 nmol or serum testosterone in the range of have been conducted with the intention to limit side effects 8–11 nM and free testosterone <220 pmol, assessed at least on and to maintain efficacy [17, 18]. A new natural compound two occasions), and end diastolic velocity (EDV) >5 cm/s at made of alga Ecklonia bicyclis, Tribulus terrestris, and glu- penile color doppler ultrasound (CDU).
cosamine oligosaccharide has been diffused in order to improve male sexual function in elderly men, particularly All patients were also subjected to a thorough physical libido and possible erectile dysfunction. Ecklonia bicyclis has examination. To be able to exclude organic sexual dysfunc- radical scavenger activity 10–100 times more powerful than tions and other underlying illnesses, fasting blood glucose any other polifenol terrestris plants, which have only 3-4 level, urinalysis, complete blood count, sex hormones, and phenolic and rings that are commonly considered among prolactin levels were measured.
the most effective antioxidant molecules. The protodioscin Al measurements were conducted by a single physician is a steroidal saponin, which is about 90% of the extract unaware of the treatment status.
obtained from aerial parts of Tribulus terrestris. Thanks to Patients were randomized according to a computer gen- its particular steroidal structure it has an androgen mimetic erated random sequence with a 1 : 1 ratio in two treatment action, binding and activating the receptor of testosterone. So groups, namely, Group A and Group B. The first group this substance is able to increase the endogenous production received one tablet oral y twice a day for 3 months and one of testosterone, dihydrotestosterone, hormone luteinizing tablet consisted of 300 mg of alga Ecklonia bicyclis, 450 mg of hormone (LH), dehydroepiandrosterone (DHEA), and dehy- Tribulus terrestris and 250 mg of glucosamine oligosaccharide droepiandrosterone sulfate (DHEAS).
(Tradamix TX1000, Tradapharma Sagl, Switzerland), while glucosamine oligosaccharide acts both on nonadrenergic the second received one table twice a day for 3 months and noncholinergic system (NANC) and on endothelial cel of placebo. We monitored adverse events on the light of system as a strong nitric oxide synthetase (NOS) simulator common terminology criteria for adverse events (CTCAE) The aim of this prospective multicenter randomized, single-blinded, placebo-controlled study was to evaluate the efficacy and tolerability of the combination therapy with 2.1. Main Outcome Measures. The primary efficacy outcome alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine was the change from baseline to end point (3 months) for the oligosaccharide in patients mild-moderate erectile dysfunc- IIEF-15. Secondary outcomes were the change from baseline tion at 3 months of fol ow-up.
to end point of IIEF-15 subscore, MSHQ-EJD, SQoL-M, and PSV. Safety assessments included treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and orthostatic 2. Patients and Methods vital signs (blood pressure and heart rate).
From January 2013 to September 2013, 214 patients diagnosed with mild-moderate ED (IIEF-EF < 26) were entered in this 2.2. Study Population. The study sample of 170 was powered prospective multicenter randomized, single-blinded, pla- for an approximately 10-point difference of the IIEF-15 using cebo-controlled study. Al subjects gave written informed a two-sided type I error = 0.05 and type II error = 0.1 (90% consent before entering the study, which was conducted in power), requiring patients per group. The maximum sample accordance with the Declaration of Helsinki, and the Human size was set to 100 subjects per group, al owing for a 15% Ethics Committee approved the study protocol (Serbian dropout rate.
BioMed Research International Table 1: Baseline characteristics of patients enrol ed.
because they did not meet the entry criteria. Of the 200 patients randomized, 87 and 90 subjects in Group A and in Group B completed the study protocol. The flow chart of this study is presented in Figure 1.
Number of patients Age (yr), mean ± SD 3.1. Main Outcome Measures. Table 2 lists the mean change BMI (Kg/m2), mean ± SD differences from baseline to 3 months relative to main outcome measures. When concerning the primary endpoint Hypertension, 𝑛 (%) of this study, we observed significant changes of the IIEF-15 Dyslipidemia, 𝑛 (%) in Group A (mean difference: 11.54; 𝑃 < 0.05) at 3 months Diabetes, 𝑛 (%) versus Group B at the intergroup analysis (mean difference: Total testosterone, mean 10.22; 𝑃 < 0.05). In Group A, significant differences from Smoking habit, 𝑛 (%) baseline to last follow-up were observed relative to PSV IIEF-EF, mean ± SD (mean difference: 1.36 cm/s; 𝑃 < 0.05), IIEF-IS (mean difference: 1.72; 𝑃 < 0.05), IIEF-OF (mean difference: 2.2; IIEF-IS, mean ± SD 𝑃 < 0.05), IIEF-SD (mean difference: 1.03; 𝑃 < 0.05), IIEF-OF, mean ± SD IIEF-OS (mean difference: 2.51; 𝑃 < 0.05), MSHQ-EjD IIEF-SD, mean ± SD (mean difference: 1.21; 𝑃 < 0.05), and SQoL-M (mean IIEF-OS, mean ± SD difference: 10.2; 𝑃 < 0.05). In Group A, patients with MSHQ-EjD, mean ± SD moderate arterial dysfunction showed significant increase SQoL-M, mean ± SD of IIEF-EF (mean difference: 1.82; 𝑃 < 0.05), PSV (mean difference: 1.56; 𝑃 < 0.05), MSHQ-EjD (mean difference: 1.23; 𝑃 < 0.05), and SQoL-M (mean difference: 11.65; 𝑃 < 0.05) from baseline to 3 months. Significant differences were Normal arterial function found at the intergroup analysis when considering previous (PSV ≥ 35 cm/s), 𝑛 (%) outcome measures (Table 2) and (Figure 2). Patients with Moderate arterial dysfunction normal arterial function and with severe arterial dysfunction (PSV ≥ 25 and <35 cm/s), 𝑛 (%) of Group A did not report improvement of penile CDU Severe arterial dysfunction measures after treatment. When considering serum TT and (PSV < 25 cm/s), 𝑛 (%) EDV, both groups did not show any difference after 3 BMI = Body Mass Index; IIEF-EF = International Index of Erectile Function- months. Al subjects included in the study protocol tolerated Erectile Function; IIEF-IS = International Index of Erectile Function- treatments, and none reported adverse events.
Intercourse Satisfaction; IIEF-OF = International Index of Erectile Function- Orgasmic Function; IIEF-SD = International Index of Erectile Function- Sexual Desire; IIEF-OS = International Index of Erectile Function-Overal Satisfaction; MSHS-EJD = Male Sexual Health Questionnaire-Ejaculation Disorder; SQoL-M = sexual quality of life instrument for men; PSV = peak systolic velocity; EDV = end diastolic velocity.
Several studies have established that reactive oxygen ROS, especial y superoxide anion and hydrogen peroxide, are important signaling molecules in cardiovascular cells [19, 20].
2.3. Statistical Analysis. At baseline, the independent sample Enhanced superoxide production increases NO inactivation 2-tailed t-test was used to compare variables. For categor- and leads to an accumulation of peroxynitrites and hydrogen ical parameters, chi-square test was applied. Changes from peroxide [21]. ROS participate in growth, apoptosis, and the baseline to end of therapy were analysed using ranked migration of vascular smooth muscle cel s, in the modulation one-way analysis of variance (ANOVA) with a term for of endothelial function (including endothelium-dependent treatment group. According to the penile Doppler ultrasound relaxation and expression of a proinflammatory phenotype), analysis, patients were divided into three categories: normal and in the modification of the extracellular matrix [22– arterial function (NAF) (PSV ≥ 35 cm/s), moderate arterial 24]. All of these events play important roles in endothelial dysfunction (MAD) (PSV ≥ 25 and <35 cm/s), and severe dysfunction, suggesting that the sources of ROS and the arterial dysfunction (SAD) (PSV < 25 cm/s). Treatment group signaling pathways that they modify may represent important differences for primary and secondary end points were deter- therapeutic targets [25].
mined using post hoc analysis. Data were reported as means All these findings have determined the diffusion of ± standard deviation (SD) or median and nominal 𝑃 values several herbal extract with the intention of targeting previous were presented. For al statistical comparisons, significance was considered as 𝑃 < 0.05.
An interesting in vivo and in vitro animal investigations of a mixture of herbal extracts from T. terrestris and C.
officinalis were conducted to investigate their relaxation effects and the mechanisms of action on penile erection. T.
Table 1 lists the baseline characteristics of patients enrolled.
terrestris extract, C. officinalis extract, and the mixture of both Of the 214 patients, 14 (6.54%) were excluded from the study extracts showed concentration-dependent relaxation effects BioMed Research International Assessed for eligibility (n = 214) Excluded (n = 14) ⧫ Not meeting inclusion criteria Randomized (n = 200) Group A (TRADAMIX TX 1000) Group B (placebo) Discontinuation, n (%) Discontinuation, n (%) Perceived lack of efficacy Perceived lack of efficacy Lost to fol ow-up Lost to fol ow-up Entry criteria not met Entry criteria not met Completed 3 months Completed 3 months Figure 1: Disposition of subjects. Subject consolidated standards of reporting trials (CONSORT) diagram.
of the corpus cavernosum. Therefore, endothelium appears With the administration of the mixture of extracts, cAMP to be an important location of action of T. terrestris extract, concentration in the CC increased significantly. Based on functioning in relaxation mainly via NOS and exhibited the previous results, the extracts studied appear to exhibit relaxation effects mainly through cAMP and partly through relaxation effects on the CC mainly through cAMP and partly through cGMP.
It can be supposed that because herbal extracts do This can be explained by the multiple mechanism of not contain a single ingredient but are a combination of action of these compounds on several targets with the multiple compounds, it would not be appropriate to expect consequent therapeutical efficacy.
a mechanism of action similar to that of a single compound Based on our results and considering al subdomains of such as a PDE-5 inhibitor. C. officinalis extract appears to 15-question International Index of Erectile Function, ther- exhibit relaxation effects by acting directly on the smooth apy with multiple antioxidants was significantly superior in muscle cel s of the CC, not through the above pathway.
improving intercourse satisfaction, sexual desire, orgasmic BioMed Research International Table 2: Mean changes from baseline to 3 months for primary and secondary outcomes.
IIEF-15, mean ± SD IIEF-EF, mean ± SD IIEF-IS, mean ± SD IIEF-OF, mean ± SD IIEF-SD, mean ± SD Overal Sexual desire Orgasmic Intercourse Erectile IIEF-OS, mean ± SD function satisfaction function MSHQ-EjD, mean ± SD SQoL-M, mean ± SD PSV (cm/s), mean ± SD EDV (cm/s), mean ± SD Figure 2: Mean changes from baseline to 3 months for International Index of Erectile Function domain (a Total testosterone (nmol/L), 𝑃 < 0.05, versus baseline; b𝑃 < 0.05, versus Group B).
Normal arterial function (PSV ≥35 cm/s) subgroup IIEF-EF, mean ± SD cell system as a strong nitric oxide synthetase (NOS) stimu- PSV (cm/s), mean ± SD lator, thus improving the concentration of nitric oxide (NO) MSHQ-EJD, mean ± SD in the smooth cells inside the corpus cavernosum.
SQoL-M, mean ± SD These considerations may explain the significant changes Moderate arterial dysfunction of IIEF-EF, MSHQ-EjD, PSV, and SQoL-M in Group A for (PSV ≥25 and <35 cm/s) subgroup men with moderate arterial penile dysfunction. We can affirm IIEF-EF, mean ± SD in fact that those with severe arterial dysfunction may not PSV (cm/s), mean ± SD have benefits from therapy with natural compounds, since their ED was worse.
Penile CDU evaluation in ED has a significant role in SQoL-M, mean ± SD determining the cause of ED. Arteriogenic ED or arterial Severe arterial dysfunction insufficiency is diagnosed when PSV is <25 cm/s, with angio- (PSV <25 cm/s) subgroup graphic correlation showing that a PSV threshold of 25 cm/s IIEF-EF, mean ± SD has 92% accuracy in diagnosis of arterial integrity. Penile PSV (cm/s), mean ± SD CDU represents an accurate tool to investigate cavernous MSHQ-EJD, mean ± SD artery inflow and venous leakage frequently used for assess- SQoL-M, mean ± SD ing the efficacy of several genitourethral reconstruction sur- gical techniques, in patients who underwent urethroplasty, 𝑃 < 0.05 versus baseline; b𝑃 < 0.05 versus Group B.
peyronie's disease related surgery, or penile revascularization In this context, although the prevalence of ED before and function, and overal satisfaction. In fact, it should be noted after genitourethral reconstruction surgeries has not been that the severity of penile curvature or deformity may correctly investigated, it may affect the expectancy of these significantly contribute to man's inability to have intercourse.
techniques with failed results.
Furthermore, patients referred the improvement of ejac- Although our population study was represented by sub- ulation and quality of life, as assessed by the MSHQ-EjD and jects who did not underwent previous genitourethral recon- the SQoL-M), although there was a short fol ow-up.
struction surgeries, we may suggest with caution to use oral This new natural compound is thought to play an impor- therapy with alga Ecklonia bicyclis, Tribulus terrestris, and tant double role (therapeutic and antiaging), on cavernous glucosamine oligosaccharide with the intention to ameliorate tissue, by acting on the etiopathogenetic aspects of ED, penile CDU in patients eligible for penile surgery.
mainly the microstructural alteration of the corpus cav- However, this study is not depicted from limitations.
ernosum tissues, following inflammation and/or oxidative First of al a longer follow-up would have added more damage [16].
information about the efficacy and its maintenance over the We suppose that this combination of natural compounds time. Second, ED was assessed by questionnaire and penile may strength the efficacy of the single component, the Eck- Doppler ultrasound and ejaculation function by the MSHQ- lonia bicyclis by a radical scavenger activity, the protodioscin ED. Certainly, some more diagnostic procedures would have by binding and activating the receptor of testosterone, and the been beneficial. In conclusion, oral therapy with alga Ecklonia glucosamine oligosaccharide, by acting on the nonadrenergic bicyclis, Tribulus terrestris, and glucosamine oligosaccharide and noncholinergic system (NANC) and on the endothelial has significant advantages in patients with mild-moderate BioMed Research International ED, by improving intercourse satisfaction, sexual desire, coronary artery disease: common links," European Urology, vol.
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