Original Article

International Journal of Impotence Research (2008) 20, 173–180; doi:10.1038/sj.ijir.3901597; published online 16 August 2007

Improvement of erectile function with Prelox: a randomized, double-blind, placebo-controlled, crossover trial

R Stanislavov1, V Nikolova1 and P Rohdewald2

  1. 1Department of Obstetrics and Gynecology, Medical University Sofia, Faculty of Medicine, Sofia, Bulgaria
  2. 2Institute of Pharmaceutical Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany

Correspondence: Professor Dr P Rohdewald, Institute of Pharmaceutical Chemistry, Westfälische Wilhelms-Universität Münster, Hittorfstr. 58–62, Münster, Germany. E-mail: rohdewa@uni-muenster.de

Received 17 April 2007; Revised 26 June 2007; Accepted 26 June 2007; Published online 16 August 2007.



In a randomly allocated, double-blind, placebo-controlled, crossover design, 50 patients with mild to moderate erectile dysfunction (ED) were treated for 1 month with placebo or a combination of L-arginine aspartate and Pycnogenol (Prelox). Patients reported sexual function from diaries. Testosterone levels and endothelial NO synthase (e-NOS) were monitored along with routine clinical chemistry. Intake of Pycnogenol for 1 month restored erectile function to normal. Intercourse frequency doubled. e-NOS in spermatozoa and testosterone levels in blood increased significantly. Cholesterol levels and blood pressure were lowered. No unwanted effects were reported. Prelox is a promising alternative to treat mild to moderate ED.


erectile dysfunction, Prelox, L-arginine, Pycnogenol, endothelial nitric oxide synthase (e-NOS)



In the process of penile erection, nitric oxide (NO) is involved in two mechanisms: In the first instance, it acts together with acetylcholine and prostaglandins as a neurotransmitter within the process of sexual stimulation.1 In the second step, NO is produced from L-arginine by endothelial nitric oxide synthase (e-NOS) to start the process of vasodilatation.

The hypothesis that erectile dysfunction (ED) may be overcome by high doses of L-arginine, thus providing e-NOS with abundant substrate, has been tested in several clinical trials. Five grams of L-arginine per day improved ED in 31% of patients, whereas 1.5 per day had no better effect than placebo.2, 3 In combination with yohimbine, 3.25g L-arginine produced only marginal additional improvement.4 So the effect of L-arginine seems to be weak and dose-dependent.

Another attempt has been made by stimulating e-NOS with a standardized extract from the bark of the French maritime pine (Pycnogenol, marketed by Horphag Research Ltd, London, UK), as shown in endothelium of isolated aortic rings from rats.5 This extract improved ED significantly in a double-blind, placebo-controlled study.6 The special pine bark extract consists of a concentrate of polyphenols, mainly procyanidins and is listed in the US Pharmacopoeia 28 as Maritime Pine Extract.7, 8

An open clinical trial showed that the combination of stimulation of e-NOS by pine bark extract (PBE), together with supply of L-arginine, leads to a very significant improvement of ED.9 Three grams of L-arginine aspartate daily for 1 month normalized erection in only 5% of patients. The addition of 80mg PBE per day to L-arginine treatment for 1 month resulted in an 80% success rate, which increased to 92% after treatment with 120mg PBE per day for 1 month more.

In an open study with 37 men, 70% of patients reported improved ED after treatment with a fixed combination of 750mg L-arginin aspartate with 20mg PBE (Prelox, Horphag Research Ltd, London, UK), four tablets daily.10

To objectivate the findings from open studies, the following double-blind, placebo-controlled, crossover study was initiated.


Patients and Methods

Study objective

The primary outcome measure was improvement of erectile function, scored from the questionnaire of the international index of erectile function (IIEF).11

The secondary outcome measure was improvement of sexual wellness by evaluating patients' diaries. e-NOS activity was followed in spermatozoa, and testosterone levels were monitored.


From 210 patients visiting the Seminological Laboratory of the Medical University of Sofia, Bulgaria, 50 men were recruited meeting the criteria for inclusion. Patients gave written informed consent and were informed that they could leave the study any time. The sample size of 50 patients was chosen on the basis of the previous study, with 40 patients showing significant improvement of ED.9 Patients were examined for medical history and were undergoing physical and seminological examination. Blood was taken for routine clinical chemistry and determination of testosterone concentration.

Physical examination

Patients were examined at the first visit for infertility, signs of hypogonadism, normal development of musculature, decrease of testicular volume, anatomical changes of penis, fat distribution, voice, height, weight, vital signs (including blood pressure and heart rate).

After 18 weeks, the patients' vital signs were examined again.

Medical history

Patients were asked for impairment of general performance, diminution of beard growth, decrease in erection frequency, lessening of sexual desire and fantasies, recurrent bronchitis or sinusitis in childhood, infections with or without orchitis or epididymitis, harmful occupational or environmental influences, drug or narcotics abuse and chronic diseases.

Inclusion criteria

Age between 30 and 50 years.

Stable sexual partnership for the last 6 months.

ED: Score of IIEF from 11 to 17 (moderate ED).

Exclusion criteria

Testicular maldescent, varicocele, orchitis, globozoospermia, infections, disturbances of semen deposition (hypospadias), severe cardiovascular disease, severe hypertension dgreater than or equal to90mm/Hg; sgreater than or equal to150mm/Hg, renal failure, hepatic insufficiency, endocrine hypogonadism abnormality, psychiatric disorders, testicular tumors, treatment of ED with any drugs during the last 4 weeks, severe ED caused by anatomic abnormalities.

Random allocation

Patients received numbers according to the order of their enrollment. Patients with even numbers started the first treatment period with medication B, and those with odd numbers with medication A.


Prelox and placebo tablets were prepared by the same producer (Manhattan Drug Company Inc., New York, NY, USA). Tablets were indistinguishable in color, size, shape and weight. Tablets were dispensed by the American producer in identical plastic boxes marketed as A and B. Investigators were not informed about the identity of A and B tablets until after evaluation of the study results. Patients were instructed to take two tablets between 7 and 9am and two tablets between 7 and 9pm with 200ml of water. The daily dose of Prelox corresponds to an intake of 80mg of Pycnogenol and 3g of L-arginine aspartate.



Seminological analysis

Patients were provided with a diary card in Bulgarian, that covered a period of 31 days. Patients were asked to note sexual activity in the diary each day and to score sexual desire, erectile function, orgasmic function, intercourse satisfaction and overall satisfaction according to the IIEF questionnaire. Patients had been instructed how to score the items listed in the diary card using the Bulgarian translation of the IIEF questionnaire given together with the diary card at each visit.

Additional information was obtained by asking the following ‘Yes’ or ‘No’ questions at each visit with answers.

  • Did treatment improve your erections?
  • Have you had an increase in morning erections?
  • Have you had an increase in sexual dreams?
  • Have you had an increase in sexual fantasies?
  • Has it been easier to initiate erections?
  • Has it been easier to sustain an erection?
  • Has your partner noted any change in your sexual interest?
  • Has your partner noted any change in your sexual performance?

Collection of semen samples

Semen samples were obtained following sexual abstinence for 2 to 7 days by masturbation. Semen samples were delivered in plastic containers from the nearby privacy room. Samples were kept warm; examination was done at the latest 1 hour after ejaculation. Analyses for e-NOS activity were made by the authors (RS and VN) using the radial enzyme diffusion method.

Semen samples were obtained at the end of the run-in period, the end of the first treatment period, the end of the wash-out period and at the end of the second treatment period. Two pre-study samples were obtained during the recruiting period.

Activity of e-NOS in spermatozoa

Spermatozoa were tested for e-NOS activity using a radial enzyme diffusion method, based on the conversion of L-arginin into citrulline and the accompanying pH change.12 The 1% agar gel contained 0.1mmol L-arginine and 0.1% thymolphthaleine as an indicator of the conversion of the alkaline L-arginine to the neutral citrulline. A quantity of 3μl spermatozoa lysate (20 million cells), lysed by 0.1% Triton X-100, was applied to the gel. NOS activity is expressed as pmoles of citrulline produced per minute per milligram of protein.

Clinical chemistry

Fasting blood samples were taken at visit 0 before the start of the study and at visit 5 after the termination of the study, using standard procedures. Hematology comprised hemoglobin, leukocytes, erythrocytes, hematocrit and thrombocytes. Standard assays were used to quantify glucose, cholesterol, uric acid, albumin, aspartate/amino transferase, alanine/aminotransferase and γ-glutanyltranspeptidase.

Total testosterone in plasma was quantified using the ACS 180 testosterone immunoassay produced by Bayer Health Care, Leverkusen, Germany. Samples for analysis had been obtained between 0800 and 1000 hours.


Differences between groups were evaluated statistically by using the two-sided t-test. As the primary and secondary outcome variables were obtained by comparison of four pairs of visits, significance is given for P-values of 0.05/8=0.00625.

Study design

The study was designed as a randomly allocated, double-blind, placebo-controlled, crossover study. The study was approved by the committee for approval for clinical trials from the Ministry of Health, Republic of Bulgaria, and was monitored by the authorized clinical research officer V Damianova. The study was conducted at the Seminological Laboratory of the University Hospital Maichin Dom, Sofia, Bulgaria. Study was performed in accordance with the declaration of Helsinki between spring 2005 and summer 2006.

During the 4-week run-in period, data for sexual activity and ED were collected as base-line information from patients' IIEF diaries and by answering additional questions at the end of the run-in period. Patients received blinded medication, group A placebo, group B Prelox, for the first treatment period of 4 weeks.

At the end of the first treatment period, tablet boxes were controlled for tablets taken. IIEF diaries and questionnaires were collected and new diaries and questionnaires were given for the wash-out period of 4 weeks.

Following the wash-out period, IIEF diaries and questionnaires were collected and new diaries and questionnaires were given for the second treatment period of 4 weeks. Patients received blinded medication, group A Prelox, group B placebo.

After the second treatment period, tablet boxes were controlled for remaining tablets. IIEF diaries and questionnaires were collected and new diaries and questionnaires were given for the last wash-out period of 4 weeks. Patients were thoroughly investigated by physical examination and clinical chemistry.

At the end of the last wash-out period, patients returned diaries and questionnaires to the investigator.

At each visit, patients were asked about concomitant medication and for unwanted effects. e-NOS activity tests were performed at each visit.

All data were collected in case report forms.



The two groups enrolled in the crossover study did not differ in mean age (36.8/37.2), BMI (26.2/25.9), mean ED before treatment (scores 11–14: 18/16, 15–17: 7/9 patients) and mean intercourse frequency (4.4/4.6 per month). Group A had slightly more patients with ED scores of 11–14; however, the difference is not statistically significant. All patients were normogonadotropic and were diagnosed as idiopathic infertile.

All enrolled patients completed the study and compliance to intake of medication was excellent, and all tablets had been taken.

Figure 1 demonstrates the highly significant improvement of erectile function for each group following treatment with Prelox, doubling the IIEF scores. At the end of the treatment period, patients treated with Prelox achieved normal IIEF scores exceeding 25. Treatment with placebo had no significant effect. The scores dropped clearly after treatment periods; however, the scores for the months following verum treatment were significantly higher compared to placebo, signaling a longer lasting effect of Prelox.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mean IIEF scores and standard deviations for erectile function over the period of the clinical trial. *Differences of IIEF scores after treatment with Prelox to placebo, run-in and wash-out periods were highly significant (P>0.001).

Full figure and legend (38K)

The onset of action of Prelox was evaluated from the diaries. The earliest improvement of erectile function was reported after just 1 day, latest response was after 9 days, mean response was 4.9 days.

Parallel to the increase of erectile function, the mean number of intercourse more than doubled during treatment (10.7/11.2) compared to the pretreatment period (4.4–4.6).

The detailed IIEF scores for orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction and percent sexual response (Table 1) also show nearly doubled values. The values for treatment with placebo are very low, demonstrating a small placebo effect. In contrast, group B showed an improvement of all scores even 4 weeks after treatment at the end of the wash-out period, a sign of a longer lasting effect.

The improvement of sexual wellness was further confirmed at visits by ‘Yes’ or ‘No’ answers to questions regarding sexual activity in the preceding 4 weeks. Results in Table 2 underline the findings made by the evaluation of the IIEF questionnaire. The positive answers accumulate unequivocally in the treatment periods with Prelox for groups A and B.

e-NOS activity in lysate of spermatozoa

Tests in lysate of spermatozoa collected from both groups following the run-in period were analyzed for e-NOS activity using an assay quantifying the conversion of L-arginine to citrullin, catalyzed by e-NOS. There is a clear decrease in e-NOS activity with the age of the participants (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Dependence of e-NOS activity on age of patients and influence of Prelox on e-NOS activity. Black bars: before treatment, grey bars: after treatment.

Full figure and legend (39K)

Treatment with Prelox produced a steep increase of e-NOS activity in most patients with just one exception. It is obvious that the amount of e-NOS contained in spermatozoa is more than double in patients over 35 years. The older the patients, the larger the increase of e-NOS production.

Intake of placebo had no effect on e-NOS activity (Table 3).

Total testosterone in plasma

Patients had normal testosterone levels at the start (Table 4). Placebo produced a small, but significant, increase in group A after the first treatment, Prelox a highly significant increase in group B. The second treatment with verum elevated testosterone levels in group A to about the same extent as before in group B. Testosterone levels remained slightly higher in the second treatment period under placebo in group B.

Blood pressure and clinical chemistry

Mean blood pressure was slightly elevated at the start (Table 5) At the end of the study following the last wash-out period, systolic as well as diastolic blood pressure was significantly lowered (P<0.001).

Data for routine clinical chemistry were collected at the start and the end of the last wash-out period. Data for albumin, hemoglobin and erythrocytes were slightly but significantly elevated (Table 5).

Total cholesterol decreased slightly but significantly by 3.1% (Table 5). All other data of clinical chemistry remained unchanged after the wash-out period and were normal at start (data not shown).

Adverse effects

Patients were asked at each visit to report any unwanted effects. No unwanted effects were reported.



The results of this double-blind, placebo-controlled, crossover study verify findings from previous clinical trials on a broader, controlled basis.9, 10, 12

The synergy between e-NOS stimulation by Pycnogenol and the simultaneous supply with the substrate of e-NOS, L-arginine, establishes the basis for an enhanced production of NO. NO is the non-adrenergic/non-cholinergic neurotransmitter of primary importance for controlling relaxation of penile smooth muscle, together with acetylcholine and prostaglandins.13 These erectogenic neurotransmitters act in concert with vasodilators produced by the endothelium, predominantly NO. NO diffuses to the smooth muscle layers to stimulate guanyl cyclase, initiating intracellular production of cyclic GMP (cGMP), which subsequently triggers muscle relaxation as a second messenger.

Whereas 5-phospho-diesterase inhibitors increase erectile function by blocking the degradation of cGMP, thus prolonging its action, Prelox provides more NO to stimulate guanylcyclase, to produce more cGMP.

Thus, both treatment principles enhance the quantity of cGMP—Prelox by providing more NO to stimulate its production, 5-phosphodiesterase inhibitors by blocking its enzymatic degradation.

The treatment with Prelox in this investigation increased IIEF scores from 11–17 to 26–30. According to an analysis of erectile function scores, scores above 25 no longer represent ED, but normal erectile function.14 The doubled frequency of intercourse after verum shows the success of treatment.

Patients selected for this study corresponded very closely to the group of patients in our first open study in terms of age—36.6 versus 37 years—and ED.9 Patients at this age respond best to treatment, whereas the treatment period for patients with an age of around 50 years and disturbed ED had to be extended to 11 months to produce a 76% rate despite additional testosterone treatment.12

The response rate in this study is higher than the 80% success rate found previously in the open study, with the combination of Pycnogenol and L-arginine aspartate.9 This could be caused by the tight control of intake in our study and/or by the convenience of taking one preparation (Prelox) instead of the two medications, L-arginine aspartate and Pycnogenol separately in the previous study.

The treatment effect with Prelox lasts for a couple of weeks, as can be seen by the mean IIEF scores for group B, getting Prelox in the first treatment period (Table 1). IIEF scores for orgasmic function are going down from 9.2 to 6.1 after the following wash-out period, go further down to 5.2 after the end of the placebo treatment and end up with 5 after last wash-out period. Further investigations are needed to show whether a longer period of treatment is able to produce a longer persisting effect.

Analysis of e-NOS activity in lysed spermatozoa showed a surprisingly clear dependence of e-NOS formation on the age of our patients. Similar effects of age on NO-mediated effects had been observed in animal experiments.15, 16 Loss of e-NOS activity in aging rats is reported to be caused by an altered phosphorylation of e-NOS.16

Further studies are needed to identify the mechanism by which Pycnogenol or its metabolites activate e-NOS or, alternatively, block its inactivation. Pycnogenol, reinforced by L-arginine supply, may overcome an inhibition of e-NOS activity by interfering with its abnormal phosphorylation in aged organisms. An other possibility is that Pycnogenol enhances not only the activity of e-NOS, but its synthesis. It has been demonstrated in cell culture systems that incubation with Pycnogenol doubled synthesis of antioxidative enzymes (superoxidedismutase and catalase).17 Therefore, a stimulation of synthesis of e-NOS is another option for the mode of action of Pycnogenol.

e-NOS has been detected in human seminal vesicles; it is not solely confined to endothelial cells as previously assumed. In the testis, e-NOS was found in Leydig cells and Sertoli cells and in the epidymis and vas deferens, illustrating the important role of NO—and e-NOS—for the human male reproductive system.18 Decreasing amounts of e-NOS in spermatozoa with increasing age correspond to the general effect of aging on fertility.

The increase of testosterone levels in treatment periods could be caused by the mutual relationship between testosterone levels and sexual stimuli. There is a positive feedback, as testosterone is released by sexual stimulation.19, 20, 21, 22 The enhanced ability of patients to perform sexual intercourse stimulates sexual wellness. Sexual wellness, in turn, overcomes depression, which is often associated with ED. Depression leads to lower testosterone levels so more frequent sexual stimulation, enhanced sexual wellness, and fewer depressive episodes may cause positive feedback to testosterone production.23, 24

The normalization of blood pressure after treatment is in accordance with studies showing a normalization of blood pressure in slightly hypertensive patients by administration of pine bark extract.25 Supplementation with Pycnogenol lowered endothelin-1 in blood of hypertensive subjects and increased prostacyclin levels, thus reducing blood pressure.26

The slight lowering of cholesterol, observed in this study as well as in clinical trials with Pycnogenol, may contribute to an anti-atherosclerotic effect.6, 27, 28 All other parameters of routine clinical chemistry remained in the normal range. The small, but significant increase in the number of erythrocytes and in the concentrations of albumin and hemoglobin remained well within the reference ranges for male adults.

As the treatment with Prelox was very well tolerated—none of the patients reported adverse effects and none of the patients left the study—Prelox has a very favorable risk/benefit ratio.



Continuous treatment of moderate ED for 1 month with Prelox normalized erectile function in a group of men with a mean age of 37 years, physiological as well as psychological sexual wellness was restored.

Restoration of erectile function was accompanied by a slight anti-hypertensive action. Both effects can be related to the enhanced production of endothelial nitric oxide, reflected in the increased activity of e-NOS in spermatozoa.

Treatment with Prelox seems to offer a safe and very effective alternative to existing medications. Further studies with large collectives of patients, a longer period of treatment and follow-up are needed to substantiate our findings on a broad basis.



Competing Interests

Dr Stanislavov received a grant from Horphag Research Ltd to perform this study. Dr Rohdewald is a consultant for Horphag Research Ltd and holds a patent for the method of increasing sexual wellness with a combination of proanthocyanidins and L-arginine.



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We thank Dr J Gerß from the Institute of Medical Informatics and Biomathematics of the University Clinics Münster, Germany, for statistical evaluation of data. This study was funded by Horphag Research Ltd, UK.

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