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November 2009

A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea.

The efficacy and safety of sildenafil was evaluated in a randomiSed, double-blind, placebo-controlled, flexible-dose study in Korean men aged 28-78 y with erectile dysfunction (ED) of broad-spectrum aetiology and more than 6 months duration. A total of 133 patients were randomised at six centres in Korea to receive either sildenafil (50 mg initially, increased if necessary to l00 mg or decreased to 25 mg depending on efficacy and tolerance) (n=66) or matching placebo (n=67) taken on an ‘as needed’ basis l h prior to anticipated sexual activity for a period of 8 weeks. At the end of this time, the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse, and the secondary efficacy variables, which included: (1) the five separate domains of sexual functioning of the International Index of Erectile Function (IIEF) scale, (2) the percentage of successful intercourse attempts, and (3) a global assessment of erections, were all statistically significantly improved by sildenafil in comparison with placebo (P&<0.0001). Treatment-related adverse events occurred in 56.1% of patients receiving sildenafil and 20.9% receiving placebo. The most common adverse events with sildenafil were vasodilatation (flushing), headache and abnormalities in colour vision (31.8, 22.7 and 6.1% of patients, respectively), and most were mild in nature. The efficacy and safety of sildenafil in this population of Korean men appears similar to that reported in other studies in western populations.

Int J Impot Res. 2003 Apr;15(2):80-6

Viagra—the first oral treatment for impotence that is not lacking in fatal effects.

Impotence, a common problem especially among older men, can now be treated with Viagra, This oral pill, unlike previous approved treatments mostly involving local injections, does not directly cause penile erection, but increases response to sexual stimulation. It acts by enhancing the relaxant effects of nitric acid on smooth muscle, and thus increases blood flow to certain areas of the penis, leading to erection. It has been evaluated in many randomized trials and in all was more successful in inducing erection than placebos. The most common side-effects include headache, flushing and indigestion, but there have also been reports of fatalities. We describe a 75-year-old man who had an acute myocardial infraction in the past and who had maturity-onset diabetes and hypertension. In the week prior to admission he had a cardiac scan following a few weeks of exacerbation of anginal pain for which he had been taking nitrites. He took a Viagra pill without prescription or medical advice and 2 hours later, during intercourse with his wife, developed audible respiratory distress and lost consciousness. His wife started cardiac massage but not mouth-to-mouth breathing. The emergency team found ventricular fibrillation and gave 5 electrical shocks and amines and atropine. He remained unconscious, but his pulse returned and he was hospitalized. He then had several generalized convulsions treated with i.v. valium. 20 minutes after admission there was asystole and all attempts at resuscitation failed. Cardiovascular status must be considered prior to prescribing Viagra, and the associated risk evaluated.

Harefuah. 1998 Jul;135(1-2):1-2, 88

Sildenafil citrate for erectile dysfunction in men with diabetes and cardiovascular risk factors: a retrospective analysis of pooled data from placebo-controlled trials.

OBJECTIVE: Cardiovascular (CV) risk factors are associated with an increased risk of erectile dysfunction (ED). In men with diabetes mellitus (DM), pooled from clinical trials of sildenafil treatment for ED, this retrospective analysis determined efficacy and safety, overall and in subgroups with additional CV risk (i.e., hypertension, dyslipidemia, and smoking). RESEARCH DESIGN AND METHODS: From the manufacturer’s database of worldwide research, 12-week data from men with DM were pooled from randomized, double-blind, placebo-controlled trials of flexible-dose sildenafil (25, 50, or 100 mg, PRN) for ED. MAIN OUTCOME MEASURES: Question 3 (achieving an erection), question 4 (maintaining an erection), and the Erectile Function domain of the International Index of Erectile Function; percentage of successful intercourse attempts according to patient event logs; and response to a global efficacy question (GEQ). Differences between groups were determined using logistic regression (percentage of responders according to GEQ) and analysis of covariance (all other outcomes). RESULTS: Inclusion criteria were met by 11 trials and by 974 men with DM and ED who were randomized to placebo (n = 482) and sildenafil (n = 492) within the selected trials. For all outcomes, overall and regardless of additional CV risk, the benefit was greater for sildenafil versus placebo (p < or = 0.0001), including 3-fold more men responding that sildenafil treatment improved their erections (62% vs. 18%) and a more than doubling of the mean +/- standard error percentage of successful sexual intercourse attempts (52.6 +/- 5.0 vs. 22.4 +/- 5.1). Adverse events were mild to moderate and included (sildenafil vs. placebo) headache (5% vs. 2%), flushing (7% vs. 2%), and dyspepsia (4% vs. 0%), which is consistent with the profile in the general population of men treated with sildenafil for ED. CONCLUSION: This retrospective analysis of pooled data showed that sildenafil was well tolerated and improved erectile function and intercourse success in men with ED and DM, regardless of additional CV risk factors.

Curr Med Res Opin. 2006 Nov;22(11):2111-20

Update on the relationship between sexual dysfunction and lower urinary tract symptoms/benign prostatic hyperplasia.

PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is a condition that commonly affects older men and is often associated with sexual dysfunction. Recent evidence of an association between LUTS/BPH and sexual dysfunction will be reviewed, as well as the effects of pharmacological treatment options for symptomatic LUTS/BPH on sexual function. RECENT FINDINGS: Large-scale epidemiological studies conducted worldwide have provided strong evidence for an association between LUTS, erectile dysfunction and ejaculatory dysfunction. In multivariate analyses controlling for age, comorbidities, and lifestyle factors, LUTS have been clearly demonstrated to be an independent risk factor for erectile and ejaculatory dysfunction. Various pathophysiological mechanisms have been proposed for the association between LUTS and male sexual dysfunction. These include autonomic hyperactivity, alterations in Rho/Rho kinase pathway, endothelial (nitric oxide synthase/nitric oxide) dysfunction, pelvic ischemia, and age-related hormone imbalances. Owing to the link between LUTS/BPH and male sexual dysfunction, patients presenting with one of these conditions should be routinely screened for the other condition. In addition, because medical and surgical treatments for LUTS/BPH are commonly associated with sexual side effects, patients with LUTS/BPH should be monitored for treatment-related sexual outcomes. SUMMARY: LUTS/BPH is an independent risk factor for sexual dysfunction in aging men. Further studies are needed to define the mechanism(s) underlying the link between LUTS/BPH and male sexual dysfunction. Additional studies of combination therapy for LUTS/BPH, sexual dysfunction, and other age-associated comorbidities are needed to establish new approaches to the optimal management of these conditions in aging men.

Curr Opin Urol. 2006 Jan;16(1):11-9

Effects of long-term oral administration of L-arginine on the rat erectile response.

PURPOSE: Nitric oxide (NO), the neurotransmitter responsible for mediating penile erection in the rat, is synthesized from L arginine by nitric oxide synthase (NOS) in a reaction blocked by L-NAME (N-omega-nitro-L-arginine methyl ester). To determine whether dietary supplementation of L-arginine can stimulate penile erection and whether ancillary pathways for penile erection may exist, a series of experiments were conducted in the Fischer 344 rat. MATERIALS AND METHODS: Adult male (5 month old) and aged (20 month old) rats were fed L-arginine (2.25%) and L-NAME (0.7%) dissolved in tap water for 8 weeks. Animals (n = 6) underwent electrical field stimulation (EFS) of the cavernosal nerve to induce erection and both maximal intracavernosal pressure (MIP) and mean arterial pressure (MAP, mm. Hg +/- SEM) were measured. Tissue and serum levels of L-arginine were measured by an automated amino acid analyzer. Penile eNOS (endothelial) and nNOS (neuronal) content were measured by western blot densitometry. Total penile NOS enzyme activity was measured by the L-arginine to L-citrulline conversion assay. RESULTS: The L-arginine fed animals demonstrated a significant increase in EFS-induced MIP when compared to the controls in both the adult (104 +/- 4 vs. 86 +/- 6, p = 0.04) and aged (87 +/- 5 vs. 66 +/- 4, p = 0.02) animals, without changes in MAP. L-NAME virtually abolished the MIP in adult rats (8 +/- 3, p < 0.0001), while increasing the MAP (186 +/- 8, p < 0.0001). Serum and penile tissue levels of L-arginine were increased by 64-148% in all groups compared to control animals. Penile eNOS and nNOS content remained unchanged in control and treated animals. Penile NOS activity was increased nearly 100% in the L-arginine treated groups vs. controls. CONCLUSIONS: Long-term oral administration of supra-physiologic doses of L-arginine improves the erectile response in the aging rat. We postulate that L-arginine in the penis may be a substrate-limiting factor for NOS activity and that L-arginine may up-regulate penile NOS activity but not its expression. The blockade of penile erection by EFS with L NAME suggests that if ancillary corporeal vasodilator mechanisms develop, a basal level of NO synthesis is still required for activation and relaxation of the corporeal smooth muscle. These data support the possible use of dietary supplements for treatment of erectile dysfunction.

J Urol. 1997 Sep;158(3 Pt 1):942-7

Treatment of erectile dysfunction with pycnogenol and L-arginine.

Penile erection requires the relaxation of the cavernous smooth muscle, which is triggered by nitric oxide (NO). We investigated the possibility of overcoming erectile dysfunction (ED) by increasing the amounts of endogenous NO. For this purpose, we orally administered Pycnogenol, because it is known to increase production of NO by nitric oxide syntase together with L-arginine as substrate for this enzyme. The study included 40 men, aged 25-45 years, without confirmed organic erectile dysfunction. Throughout the 3-month trial period, patients received 3 ampoules Sargenor a day, a drinkable solution of the dipeptide arginyl aspartate (equivalent to 1.7 g L-arginine per day). During the second month, patients were additionally supplemented with 40 mg Pycnogenol two times per day; during the third month, the daily dosage was increased to three 40-mg Pycnogenol tablets. We obtained a sexual function questionnaire and a sexual activity diary from each patient. After 1 month of treatment with L-arginine, a statistically nonsignificant number of 2 patients (5%) experienced a normal erection. Treatment with a combination of L-arginine and Pycnogenol for the following month increased the number of men with restored sexual ability to 80%. Finally, after the third month of treatment, 92.5% of the men experienced a normal erection. We conclude that oral administration of L-arginine in combination with Pycnogenol causes a significant improvement in sexual function in men with ED without any side effects.

J Sex Marital Ther. 2003 May-Jun;29(3):207-13

Sperm parameters in male idiopathic infertility after treatment with prelox.

The diagnosis of male infertility is determinate after assessment of sperm quality and clinical study. In nearly 30% of the cases nevertheless detailed clinical and laboratory study it can’t be discovered the cause and on the bases of exclusion criteria set the diagnosis idiopathic infertility. The object of our study was investigation of the group patients (n=50) with idiopathic infertility treated with Prelox and to be studied its effects on spermatozoa parameters. MATERIAL AND METHODS: The study design was double-blind, placebo-controlled, cross-over, randomized study, including introduction period (1 month), two therapeutic periods (each one of 1 month) separated with 1 month wash out period and concluding period of 1 month. There was applied a new method for treatment with mechanism of action stimulation the production cGMP of spermatozoa endothelial nitric oxide synthase (eNOS). This is not surprising achieving results show improvement of sperm quality. The methods of the study were: 1. Assessment of the conventional semen analysis (according the criteria of WHO, 1999). 2. Spermatozoa function tests. 3. Spermatozoa-cervical mucus penetration tests. RESULTS: The obtained results showed improvement of sperm quality, in the middle-aged men the therapeutic answers was better than in younger. In conclusion the therapy with Prelox improve sperm parameters in men with idiopathic infertility. Pycnogenol (one of the constituents of Prelox) has powerful antioxidative influence ameliorating spermatozoa function.

Akush Ginekol (Sofiia). 2007;46(5):7-12

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

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.

Int J Impot Res. 2008 Mar-Apr;20(2):173-80

Improvement of seminal parameters with Prelox: a randomized, double-blind, placebo-controlled, cross-over trial.

In a randomly allocated, double-blind, placebo-controlled, cross-over design, 50 infertile patients were treated for 1 month with placebo or a combination of l-arginine aspartate and Pycnogenol (Prelox). Semen samples were examined at 4 week intervals according to WHO criteria. Treatment with Prelox increased significantly the semen volume, concentration of spermatozoa, percentage of motile spermatozoa and percentage of spermatozoa with normal morphology compared with placebo. The placebo had no influence on the parameters of seminological analysis. Intake of Pycnogenol for 1 month improved the fertility index to normal values. After treatment, the fertility index decreased again to infertile status. No unwanted effects were reported. Prelox seems to be a promising alternative to treat patients with mild infertility.

Phytother Res. 2009 Mar;23(3):297-302

Nitric oxide and penile erectile function.

The discovery of nitric oxide (NO) as an intercellular messenger or neurotransmitter opened a new era for identifying the important mechanisms underlying physiological and pathophysiological events in autonomically innervated organs and tissues; it also provided the way for development of new therapeutics based on a novel concept of molecule and cell interaction. Endothelium-derived relaxing factor (EDRF) discovered by Furchgott and Zawadzki has been proved to be NO, a labile gaseous molecule, that modulates vascular tone, platelet aggregation and adhesion, and vascular smooth muscle proliferation. Later, NO was determined to act as a non-adrenergic, non-cholinergic (NANC) neurotransmitter of postganglionic parasympathetic nerve fibers, innervating a variety of smooth muscles including the penile corpus cavernosum (CC). The nerve is called “nitrergic” or “nitroxidergic”. Although CC sinusoidal endothelial cells also produce and liberate NO in response to chemical and possibly physical stimuli, roles of neurogenic NO in penile erection appear to be more attractive and convincing. NO is formed from L-arginine via catalysis by NO synthase (NOS) isoforms, neuronal (nNOS), endothelial (eNOS), and inducible NOS. NO from nerves and possibly endothelia plays a crucial role in initiating and maintaining intracavernous pressure increase, penile vasodilatation, and penile erection that are dependent on cyclic GMP synthesized with activation of soluble guanylyl cyclase by NO in smooth muscle cells. Erectile dysfunction (ED) is caused by a variety of pathogenic factors, particularly impaired formation and action of NO. Thus, replenishment of this molecule or intracellular cyclic GMP is expected so far to be the most promising therapeutic measures for patients with ED. This article includes recent advances in research on physiological roles and pathophysiological implications of NO in penile erection and on novel therapy for ED in reference to NO.

Pharmacol Ther. 2005 May;106(2):233-66

Ocular safety in patients using sildenafil citrate therapy for erectile dysfunction.

Sildenafil citrate improves erectile function in men with erectile dysfunction (ED) by selectively inhibiting cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), which is present in all vascular tissue. Sildenafil also has a weaker inhibitory action on PDE6, located in the rod and cone photoreceptors. Modest, transient visual symptoms, typically blue tinge to vision, increased brightness of lights, and blurry vision, have been reported with sildenafil use and occur more frequently at higher doses. Visual function studies in healthy subjects and in patients with eye

disease suggest that sildenafil does not affect visual acuity, visual fields, and contrast sensitivity. Transient, mild impairment of color discrimination can occur around the time of peak plasma levels. Spontaneous postmarketing reports of visual adverse events, including nonarteritic anterior ischemic optic neuropathy (NAION), have been reported during the 7 years that sildenafil has been prescribed to more than 27 million men worldwide. However, because men with ED frequently have vascular risk factors that may also put them at increased risk for NAION, a causal relationship is difficult to establish. No consistent pattern has emerged to suggest any long-term effect of sildenafil on the retina or other structures of the eye or on the ocular circulation.

J Sex Med. 2006 Jan;3(1):12-27

Penile arteries and erection.

Alterations in the flow of blood to and from the penis are thought to be the most frequent causes of male erectile dysfunction and, therefore, the present review focuses on the penile vasculature. In the flaccid state, tonic noradrenaline release from the sympathetic nerves contracts penile arterial and corporal smooth muscle through activation of postjunctional alpha(1)-adrenoceptors, both by increasing intracellular calcium and by enhancing the sensitivity of the contractile apparatus for calcium. In addition, noradrenaline inhibits vasodilatatory neurotransmitter release by prejunctional alpha(2)-adrenoceptors. The exact role of the sympathetic neurotransmitters, neuropeptide Y and adenosine 5’-triphosphate, in erection is largely unknown. Penile vasodilatation during erection is mediated by nitric oxide (NO) through activation of guanylyl cyclase in the smooth muscle layer, followed by increases in cyclic guanosine monophosphate lowering of intracellular calcium and desensitisation of the contractile apparatus for calcium. Acetylcholine, vasoactive intestinal peptide as well as peptides in sensory nerves probably also play a role in penile vasodilation. Increased flow through the penile arteries stimulates the endothelium leading to release of NO, prostanoids and a non-NO non-prostanoid factor, and as such enhances the vasodilatation, while the role of endothelium-derived contractile factors in penile vasoconstriction is not clear. Erectile dysfunction shares arterial risk factors with ischaemic heart disease, and diabetes, age, and hypercholesterolaemia are associated with impairment of both neurogenic and endothelium-dependent vasodilator mechanisms in corpus cavernosum. Only few studies have investigated the impact of these risk factors on the penile vasculature, although recent evidence suggests that arterial insufficiency precedes changes in corpus cavernosum leading to erectile dysfunction.

J Vasc Res. 2002 Jul-Aug;39(4):283-303