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Herbal Aphrodisiac

Herbal Aphrodisiac

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Herbal Viagra and nitric oxide: how hard is the evidence?

John P. Cooke

*Address Correspondence to: John P. Cooke, MD, PhD Professor and Associate Director, Stanford Cardiovascular Institute Stanford University, Stanford, CA; 300 Pasteur Drive, Stanford, CA 94305-5406 Email: john.cooke@stanford.edu

Word Count: 7578 Key words: impotence, endothelium, cyclic GMP; soluble guanylyl cyclase,
vasodilation

Abbreviations:

asymmetric

dimethylarginine

(ADMA);

cyclic

guanosine

monophosphate (cGMP); dimethylarginine dimethylaminohydrolase (DDAH); endothelial nitric oxide synthase (eNOS); nitric oxide (NO); nitric oxide synthase (NOS); soluble guanylyl cyclase (sGC); coronary artery disease (CAD); peripheral arterial disease (PAD); phosphodiesterase (PDE)

Abstract
A central role of endothelium- and neuronal-derived NO in erectile function is strongly supported by pre-clinical studies and human data. This endogenous vasodilator

increases penile blood flow and tumescence. An impairment of NO synthesis and/or bioactivity plays a major role in erectile dysfunction in many patients. Indeed, effective pharmacotherapy for impotence augments the action of endogenous NO; sildenafil (Viagra®) was the first of these drugs to market. By increasing the stability of cyclic

GMP (the ‘second messenger’ of NO) phosphodiesterase-5 inhibitors such as sildenafil enhance NO-induced penile blood flow. A number of dietary supplements are purported to be herbal equivalents of sildenafil, by enhancing NO synthesis and/or bioavailability. This review examines the evidence for these claims.

Etiology of erectile dysfunction
Erectile dysfunction is the inability to maintain a penile erection that is sufficient for sexual intercourse. There are multiple etiologies, both psychological and physical. With respect to the latter, erectile dysfunction may be the manifestation of neuropathy (such as that associated with the autonomic neuropathy of diabetes mellitus, or with surgical or radiological treatments of pelvic pathology); with structural alterations in the penis (as with Peyronie’s disease); hormonal disturbances (as with low testosterone levels);

adverse effects of certain medications (such as hormonal therapy for prostate cancer) or vascular disease (as with atherosclerotic obstruction of the internal iliac arteries, or with vascular dysfunction). Of these, vascular dysfunction may be the most common cause of erectile dysfunction. Vascular dysfunction is commonly observed in individuals with hypertension, diabetes mellitus, insulin resistance, hypercholesterolemia, aging or tobacco use, and with atherosclerosis. Notably, impotence may be the first indication

which produces cGMP from GTP. The PDE-5 inhibitors increase penile blood flow by inhibiting the degradation of cyclic guanosine monophosphate (cGMP) by its phosphodiesterase (Figure). Self-treatment with over-the-counter remedies. cGMP is the ‘second messenger’ of nitric oxide. It does so by activating protein kinases that phosphorylate proteins that reduce cytosolic calcium levels. However. As can be seen from the figure. These drugs include sildenafil. and vardenafil (Levitra®). without the evaluation of a physician. Individuals with low testosterone levels benefit from testosterone replacement therapy. Thus. and be evaluated for serious underlying diseases often associated with this condition. Pharmacotherapy for erectile dysfunction There are a number of effective drugs to treat impotence. The PDE-5 inhibitors prevent the degradation of cGMP. Injection of this vasodilator prostanoid into the base or shaft of the penis increases penile blood flow to induce tumescence. An alternative approach is the intraurethral application of alprostadil. Nitric oxide and other nitrovasodilators activate soluble guanylate cyclase.that an individual is at serious risk of cardiovascular disease. Other treatments include the self-injection of vasodilators. these approaches have been overtaken by the phosphodiesterase-5 inhibitors (PDE-5 inhibitors). This molecule relaxes vascular smooth muscle. such as alprostadil. and this symptom may be a harbinger of stroke or heart attack. Other vasodilators for injection include papaverine and phentolamine. or that dephosphorylate the myosin light chains of vascular smooth muscle(2). men that are having difficulty with sexual function should seek early medical attention. which are very effective as oral therapy in the treatment of impotence (1). thereby . places the individual at serious risk. tadalafil (Cialis®). because of its implications for the physical and mental well-being of the individual.

Their effect to reduce systemic vascular resistance (and thereby reduce blood pressure) was modest. which cannot induce vasodilation. increasing penile blood flow and tumescence. Soluble guanylate cyclase converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) to stimulate other kinases that induce vasodilation and increase blood flow. so as to increase blood flow. The action of this enzyme is blocked by phosphodiesterase inhibitors. but a rather positive effect on erectile dysfunction was observed. or provided by other nitrovasodilators to stimulate soluble guanylate cyclase. the primary phosphodiesterase is PDE-5. This serendipitous observation was made possible by the fact that NO is a major mediator of penile blood flow.increasing and prolonging its effect to relax vascular smooth muscle. thus PDE-5 inhibitors such as sildenafil primarily enhance cGMP levels in the penis. In the penis. Figure 1. Nitric oxide (NO) is released by nitroglycerin. by NO synthase. . This signaling pathway is inhibited by cGMP phosphodiesterase. The PDE-5 inhibitors were initially developed to treat hypertension. The action of this enzyme is inhibited by the endogenous NOS inhibitor. which cleaves the high energy phosphate bond of cGMP to produce GMP. ADMA (asymmetric dimethylarginine). Endogenous NO is produced by the metabolism of L-arginine to NO (and L-citrulline).

the gas nitric oxide (NO). macrophage. it is now known that NO can be made by neurons. traumatic or metabolic injury to the cavernous nerve reduces nNOS activation.The central role of NO in penile tumescence In 1998. Penile blood flow increases. secondary to phosphorylation and activation of eNOS (9. and by the neuronal isoform (nNOS) in the nitrergic nerves. In response to sexual stimulation. nNOS in the nerve terminals of penile autonomic nerves (pelvic plexus. Any alteration in either of these NO signaling pathways can attenuate penile blood flow and cause erectile dysfunction. NO released by the endothelium induces vasodilation and In the penile circulation. Endothelial shear stress is known to induce vasodilation. Robert Furchgott and Louis Ignarro) for their discovery and characterization of a unique signaling molecule. First discovered to be a vasodilator produced by the endothelium lining the blood vessels. The NOS enzymes metabolize L-arginine to NO and L-citrulline (Figure). In the case . Penile tumescence is achieved by a collaboration of these two NOS signaling pathways (8). NO synthesized by the endothelial isoform of NO synthase (NOS) in the endothelium. Endothelium-derived NO then amplifies and sustains the increase in penile blood flow (11). For example. creating a tractive force (shear stress) on the endothelium. and has diverse functions in the body (3). this function of the endothelium is increases blood flow. cavernous and dorsal nerves) and eNOS in the endothelium of the cavernosal cisternae and arteries (5-7). the nitrergic nerves are activated. the Nobel Prize was awarded to three US pharmacologists (Drs Ferid Murad. Both isoforms are present in the penis. and other cells. supplemented by release of NO from nitrergic nerve terminals within the penis(4).10). In the vasculature. and causes erectile dysfunction. releasing NO to induce vasodilation.

The importance of NO in vascular homeostasis is supported by a large number of studies revealing that an impairment of endothelial vasodilator function is an independent risk factor for cardiovascular morbidity and mortality (24-26).16). NO is a potent inhibitor of platelet adhesion and aggregation (15. . or tobacco exposure (13. hypertension. sildenafil is capable of enhancing the action of eNOS to preserve erectile function (12). In addition to relaxing vascular smooth muscle.of cavernous nerve injury model.29). However. that derangements of the NO synthase pathway can cause erectile dysfunction. Similarly.14). This has been attributed to impaired eNOS protein expression and activity and increased oxidative stress (28. hypercholesterolemia. enhancement of NO synthesis (as with L-arginine administration or overexpression of eNOS protein) has been shown in animal models to reduce the progression of atherosclerosis and myointimal hyperplasia (21-23). In addition. and in the corpora cavernosa from patients with diabetes mellitus. In the penile tissue of animals with experimentally induced hyperglycemia. NO suppresses vascular inflammation by reducing the expression of leukocyte adhesion molecules and inflammatory cytokines (17-20). Because of these powerful effects of NO on vascular homeostasis. An impairment of endothelial NOS not only reduces the ability of a blood vessel to relax. and to induce relaxation of the underlying vascular smooth muscle. there is an impairment in NO synthesis (27). The ability of the endothelium to respond to shear stress or other stimuli. and those with diabetes. there is strong evidence from pre-clinical studies and clinical investigation. but also broadly disrupts vascular homeostasis. is impaired in older individuals. the major cause of NOS impairment in the western world is dysfunction of endothelial NOS. and that therapy to augment NO signaling is therapeutic.

diabetes mellitus favors the production of advanced glycosylation endproducts (AGEs) which can also disrupt eNOS activation. Hypercholesterolemia enhances the inhibitory interaction of caveolin-1 with eNOS. by oral or intravenous administration of L-arginine supplementation. 49). it appears that the endothelial vasodilator dysfunction observed in these conditions can be reversed. alterations in the phosphorylation and activation of eNOS is observed in experimental animals (33). 48. (29. In a rather broad range of cardiovascular disorders. Because L-arginine exists in the plasma at concentrations of about 100uM. our observations were confirmed by a number of other groups (52-57). hypercholesterolemia. But despite the calculations of enzymologists.Diabetes mellitus is associated with mitochondrial dysfunction and oxidative stress (30) that can accelerate the degradation of NO (31). an effect that can be reversed by sildenafil (34). the ability of the endothelium to induce vasorelaxation is impaired (14). diabetes. With aging. at least in the short-term. and in humans with endothelial vasodilator dysfunction (21. Initially our findings faced significant skepticism (50). the Km of NOS for L-arginine is in the range of 2-3 uM (51). Furthermore. an effect that can be may be reversed by diet and exercise (35). the concentration of L-arginine should not be rate-limiting. Our group was the first to provide evidence that administration of L-arginine could restore endothelial vasodilator function and enhance NO synthesis in animal models of disease. 32). and in apparent contradiction of Michaelis-Menton kinetics. the improvements in endothelial vasodilator dysfunction have been associated with . The major criticism was that in vitro. as with formation of N-acetylglucosamine (OGlcNAc) adducts with serine phosphorylation sites on eNOS. hypertension). Furthermore. L-arginine: rationale for its use in vascular diseases In a number of cardiovascular disorders associated with erectile dysfunction (eg.

66) which is expressed ubiquitously as two isoforms (67). ADMA is elevated in all of the conditions associated with cardiovascular . These include monomethylarginine (MMA). The plasma concentration of ADMA and MMA are increased in renal failure. The methylarginines are methylated analogues of L-arginine. congestive heart failure. There have been several explanations proffered for the arginine paradox. In humans. We have shown that the enzyme activity is impaired with a number of disorders associated with cardiovascular disease including hypercholesterolemia. their antagonism of NOS can be reversed by increasing the concentration of L-arginine (14). The discrepancy between the in vitro calculations and the in vivo observations has been termed the arginine paradox (63). asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). About 20% of the clearance of these compounds is due to renal excretion. and improvements in symptoms in patients with coronary artery disease. The remaining 80% of clearance is largely due the action of the cytoplasmic enzyme dimethylarginine dimethylaminohydrolase (DDAH. Patrick Vallance and colleagues demonstrated the existence of endogenous antagonists of the NOS pathway (64). Sometime after our observation that arginine restored NO signaling. The methylarginines are metabolites of the hydrolysis of proteins containing methylated arginine residues (65). This enzyme is exquisitely sensitive to oxidative stress because it expresses a sulfhydryl group in its catalytic site (68). diabetes mellitus. Both ADMA and MMA are capable of competing with L-arginine for binding to the NOS enzyme. The arginine paradox and ADMA. whereas SDMA does not.increased NO synthesis. Since ADMA and MMA are competitive inhibitors of NOS. but one of the most compelling is the existence of an endogenous NOS inhibitor. and hyperhomocysteinemia (69-71). and peripheral artery disease (58-62).

in a time.disease (14). it is theoretically possible that the efficacy of these agents could be enhanced by the administration of L-arginine. oral administration of L-arginine for 8 wk to aged rats resulted in an increase in penile tissue levels of L-arginine. In one of these. even after adjusting for the usual CV risk factors (77). Of relevance to this review ADMA is increased in patients with erectile dysfunction. Because the PDE-5 inhibitors do not appear to restore normal plasma levels of ADMA (78).and dose-dependent fashion (81). than in those without CAD (77). L-arginine: an herbal Viagra? In a model of atherosclerosis in Sprague-Dawley rats. and an impairment in NO synthesis (79). On the strength of the pre-clinical studies and clinical investigations. an increase in NOS activity and a complete reversal of age-related erectile dysfunction (80). there is a strong scientific foundation for clinical trials to assess L-arginine supplementation as a method to improve NO signaling in cardiovascular disease. Cavernosal ADMA was negatively correlated with the intra-cavernosal pressure (79). supporting the use of supplemental L-arginine for erectile function. which cannot be . in humans ADMA is a predictor of the severity and progression of atherosclerosis and myointimal hyperplasia. and is an independent predictor of cardiovascular morbidity and overall mortality (72-75). and its utility in promoting sexual function. cavernosal ADMA was increased in association with a decline in DDAH activity. D-arginine. Plasma ADMA levels are higher in ED patients with CAD. Park and colleagues found that by comparison to control animals. ADMA remains a strong and independent predictor for CAD in patients with ED. Gur and co-workers found that L-arginine could relax strips of isolated human corpus cavernosum. In addition. and levels correlate with the severity of erectile dysfunction (76). These findings may explain the observations of others.

Not all studies have been positive. Several small clinical trials are supportive of L-arginine supplementation for erectile function. This beneficial effect was not reported during the placebo phase (82). There was no subjective improvement in erectile function (84). Nine of 29 (31%) patients taking L-arginine and two of 17 controls reported a significant subjective improvement in sexual function using a validated questionnaire. The level of urinary NOx in this subgroup had doubled by the end of the study. In a small randomized clinical trial with cross-over design. which may have been ineffective at increasing plasma L-arginine levels (85). L-arginine administered orally (2. crossover design. 32 patients with impotence were administered L-arginine (1. In one small clinical study of 20 impotent men using a placebo controlled. as L-NAME (a NOS inhibitor) and ODQ (an antagonist of cGMP synthesis) blocked the effect of L-arginine. In a subsequent randomized clinical trial. had no effect. The effect of L-arginine was due to its conversion to NO.metabolized to NO by NOS. All nine patients treated with L-arginine who improved were noted to have low urinary NOx at the initiation of the study. L-arginine 5g/day was administered for 6 weeks (83). .8 g/d for 2 wk) subjectively restored erectile function as well as vaginal penetration ability in 6 of 15 patients completing the study. These observations demonstrated that supplemental L-arginine (in addition to the endogenous levels of L-arginine in the tissue) could induce relaxation by increasing NO synthesis. whereas sildenafil potentiated the arginine induced relaxation. suggesting that patients with low levels of NOS activity may be particularly benefited by L-arginine supplementation (83).5 g/day) or placebo. The major difference between this trial and the others was the smaller dose of L-arginine in the negative trial.

placebo-controlled. crossover design. double-blind. the group receiving vardenafil alone manifested an increment of 4 points on the IIEF5. Erectile function was estimated with the International Index of Erectile Function (IIEF5) questionnaire. the group receiving placebo showed no change in the IIEF5. Lebret and co-workers (86) studied the combination of yohimbine (6mg) and Larginine (6g) daily in a randomized clinical trial with cross-over design (n=45. Gentile and colleagues assessed in 40 diabetic patients a dietary supplement product containing a combination of propionyl-L-carnitine. n=10). n=10) was compared to those receiving vardenafil 20 mg twice weekly (Group B. L-arginine and nicotinic acid (87). In a randomized placebo controlled study. or the combination of vardenafil with the dietary supplement(group C. allocated. There was a tendency of the group receiving both vardenafil and the supplement to have a slightly better outcome. and increased frequency of intercourse. Patients reported sexual function from diaries. One month of treatment was associated with subjective improvement. n=10). The group receiving the dietary supplement had 50% of the improvement of the vardenafil group. Another recent study assessed a dietary supplement product that contained L-arginine aspartate and pycnogenol (88). or double placebo (Group D n=10). 50 patients with mild to moderate erectile dysfunction (ED) were administered for 1 month a placebo or the combination of L-arginine aspartate and pycnogenol. . Pycnogenol is derived from pine bark extract and In a randomly contains oligomeric proanthocyanidins that have anti-oxidant effects. treatment periods of two weeks). At the end of treatment. Erectile function was modestly but significantly improved by comparison to placebo for the primary endpoint of change in the Erectile Function Domain of the International Index of Erectile Function (IIEF). By contrast. The group receiving the dietary supplement product (group A.Several studies have examined the use of L-arginine in combination with other nutritional agents.

because of the small numbers and short duration of treatment. in the short-term after a myocardial infarction. there was a strong tendency toward a reduction in cardiovascular morbidity (89).i. More importantly. for 30 days) or placebo in addition to standard of care. Furthermore.d p. Furthermore. The end point was the composite of 30 day cardiovascular death. p=0. resuscitation. The clinical trials have been conducted in small groups of patients.02. improvements in exercise tolerance. in the largest study of short-term arginine therapy. safety concerns have not been addressed. Although L-arginine is a component of the diet (about 3-5 g/day in the western diet).63. penile plethysmography). shock/pulmonary edema or recurrent myocardial ischemia. Proper dose-ranging studies were not performed. These major adverse cardiovascular events occurred in 24% patients treated with L-arginine and 27% with placebo (OR 0. . Thus. and relief of symptoms (58-62).39-1. A number of studies have indicated benefit of L-arginine supplementation in patients with coronary artery disease and congestive heart failure. In this randomized clinical trial. No serious adverse effects were observed during L-arginine supplementation. the clinical evidence is weak for the utility of L-arginine as a therapeutic adjunct in the treatment of erectile dysfunction.0 t. reinfarction. 792 patients with acute myocardial infarction (with ST segment elevation) were randomized to oral Larginine (3. with improvements in endothelial vasodilator function. 95% CI 0. there was a tendency for a shortterm benefit. and little pharmacokinetic or pharmacodynamic information has been obtained.06). and for the most part have used subjective indices of erectile function without objective assessments (eg.How hard is the evidence? What is apparent from the discussion above is that though the pre-clinical foundation is strong. L-arginine was well tolerated. little is known regarding the long-term consequences of supplementing dietary arginine.o.

in a subsequent study. In a pilot study. 3. Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. This pilot study provided data for safety. patients (n=150) patients with acute myocardial infarction were randomized to placebo or L-arginine supplementation for a longer term of therapy (6 months) following acute myocardial infarction. This trial was terminated early by the data and safety monitoring board when 8 deaths occurred in the arginine treated group (90). 6 or 9 g of L-arginine daily in three divided doses for 12 weeks (85).However. In 220 patients with peripheral arterial disease (PAD) we studied the potential benefit of L-arginine supplementation on endothelial vasodilator function and functional capacity. a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily. one long-term study suggests that chronic administration of Larginine can induce a form of tolerance (91). However. The difference between these studies may be related to the duration of therapy. The study drug was well tolerated. patients with PAD and intermittent claudication (n = 80) were randomly assigned to oral doses of 0. . Although abundant evidence indicates that short-term administration of L-arginine is beneficial for endothelial vasodilator function and symptoms in patients with cardiovascular disease. and there was a trend for an improvement in walking speed in patients treated with L-arginine. There was no significant difference observed in absolute claudication distance between the groups. for power calculation and for dosing for the subsequent definitive trial. with no significant adverse effects of Larginine administration.

Nobel laureate Louis Ignarro has given his imprimatur to a product . However. Although absolute claudication distance improved in both L-arginine. and increases plasma L-arginine levels to a greater extent than does L-arginine supplementation (92). long-term administration of L-arginine does not appear to be useful in patients with intermittent claudication and PAD.and placebotreated patients. Administration of L-citrulline (the precursor of Larginine) escapes this degradation pathway. oral L-arginine (3 g/d) versus placebo for 6 months was assessed in subjects (n= 133) with intermittent claudication due to PAD. Thus. Furthermore. In this study.In the definitive study. long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. The study suggests that an ‘arginine tolerance’ or tachyphylaxis to the effects of chronic administration of L-arginine could even induce dysfunction of the NO synthase pathway. L-citrulline 3g bid increased urinary nitrate and cGMP by 30% (reflecting increased NO synthesis and bioactivity). Indeed. This latter study raises questions about the long-term efficacy and safety of L-arginine supplementation.05). plasma and urinary nitrogen oxides. L-arginine undergoes extensive first-pass metabolism by arginase in the small intestine and liver. and plasma citrulline formation) were reduced or not improved compared with placebo. L-arginine supplementation significantly increased plasma L-arginine levels. measures of nitric oxide availability (including flowmediated vasodilation. As opposed to its short-term administration. vascular compliance. the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28% versus 12%. in patients with PAD. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. It is possible that other methods to enhance plasma L-arginine levels would be more effective. p<0. the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group.

. issue a warning or require that the product be removed from the market). particularly for the many ED patients that also have known or occult coronary artery disease. studies need to be done to validate this use. These regulations require that the product meets purity specifications. It is important to know that the regulation of supplements is not as rigorous as for pharmaceuticals. Some of these agents may be hazardous.containing L-citrulline (Niteworks®) that is said to increase NO production and enhance physical and sexual functioning. Some of these may be of modest benefit. It is possible that intermittent administration of L-arginine may avoid the problem of ‘arginine tolerance’ and maintain efficacy as an enhancer of penile NO synthesis. Once the product is on the market. Manufacturers are obliged to follow good manufacturing practice (GMP) regulations promulgated by the US Food and Drug Administration (FDA). such that the risk of hypotension is increased. but the evidence is weak. However. The Food and Drug Administration has banned several of these products. Herbal Viagra and NO There are a number of other dietary supplements that purport to improve sexual function. However. some of which have contained PDE-5 inhibitors (36). Whether this adverse interaction might occur with L-arginine has not been definitively studied. and if necessary can take remedial action (eg. particularly during coadministration of pharmaceutical agents for erectile dysfunction. manufacturers don't need FDA approval before going to market with their product. there are no long-term randomized clinical trials assessing the safety and efficacy of this dietary supplement for its intended use. the FDA is responsible for monitoring its safety. There is a known interaction of exogenous nitrates with PDE-5 inhibitors. In which case.

as one can imagine. But because they do not support research. ginkgo and L-arginine. yohimbe. Small studies of ginseng suggest that the herb is safe and has modest benefit for individuals with erectile dysfunction (37). folate and zinc). and the limitations of the FDA budget. Epimedium is another traditional Chinese medicine for erectile dysfunction that contains an active principle (icariin) with PDE-5 inhibitory activity (38).The claims made by the distributors of the dietary supplement are regulated by the Dietary Supplement Health Education Act (DSHEA) of 1994. Yohimbe is derived from the bark of a West African . Because they don’t perform their own research. and they generally do not subject their products to rigorous testing. However. Epimedium (horny goat weed). which is one of the reasons that the medical community is skeptical of dietary supplements. a precursor of testosterone). Ginseng is an herb often brewed as a tea. no randomized clinical trials have assessed safety or efficacy. it is difficult to provide thorough oversight regarding the safety of these products once on the market. which permits the distributor to make structure or function claims. Finally. these companies can sell their products at a lower cost (which is good for the consumer). frequently scientists at universities not affiliated with or supported by the health food companies. Dietary supplements for sexual function include Korean red ginseng (Panax ginseng). they generally do not develop substantially new or more effective therapies (which is not good for the consumer). For example. and has been employed as a traditional Chinese remedy for diverse disorders. a manufacturer of a calcium supplement can maintain that the product promotes bone health. but prohibits claims regarding treatment of a disease. because of the number of products on the market. but cannot claim that it is useful for the treatment of osteoporosis. anti-oxidants (Vitamin E. They must also include a disclaimer that the FDA hasn't evaluated the claim. DHEA (dehydroepiandrosterone. The claims that health food companies make about their products are usually based on research performed by other parties.

Furthermore. an alpha 2 adrenergic antagonist. For that matter. yohimbine can increase heart rate and blood pressure (42). However. which is of particular concern for individuals with cardiovascular disease (common in men with erectile dysfunction). Conclusion There is compelling evidence that the NOS pathway is critical for erectile function. and some clinical experience indicating that yohimbine can enhance sexual function (3941). the literature supporting the use of pharmaceutical testosterone for erectile dysfunction is mixed (1). There is pre-clinical evidence. The rationale for the use of DHEA is that this chemical is a precursor to testosterone. The antioxidant vitamins may reduce oxidative stress. The level of evidence that a dietary supplement can enhance NO production is arguably the strongest for L-arginine. However. The major active moiety is yohimbine. providing a rationale for its administration in erectile dysfunction. The nutritional product with . Similarly. Therefore herbal supplements that enhance NO synthesis or reduce its degradation could be useful for enhancing erectile function. gingko may preserve NO from oxidative degradation (45) to improve vascular reactivity. For more information regarding the other dietary supplements.evergreen containing a variety of pharmacologically active chemicals. there is little evidence for the efficacy of DHEA (43). yet questions remain regarding efficacy and safety. and that a derangement of neuronal and endothelial NO signaling is a major contributor to erectile dysfunction in a majority of patients. bolstering the NOS pathway with PDE-5 inhibitors has been a very effective pharmacological approach to treating impotence. L-arginine is the precursor for NO.47). and thereby preserve NO from oxidative inactivation so as to improve endothelium dependent vasodilation (44). good sources of information include the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (46.

Garritty C. However. Cooke is a consultant for NiCox. there is no evidence of long-term efficacy and safety. self-treatment with herbal remedies. Finally. has been shown to enhance NO synthesis. and The Wallace H. 1U01HL100397). Dr. Daniel R. Cooke is the inventor of patents owned by Stanford University for diagnostic and therapeutic applications of the NOS pathway from which he receives royalties. Fox S. the California Tobacco Related Disease Research Program of the University of California (18XT-0098). Tsertsvadze A. Fink HA. R21 HL085743. Individuals with erectile dysfunction should be evaluated by their physician for cardiovascular disease. which in pre-clinical studies and in small clinical studies of short duration. is risky. Oral Soares-Weiser K. A few randomized clinical trials of short duration in small groups of patients suggest modest benefit. Ansari MT. with respect to the notion that L-arginine or other dietary supplements may safely and effectively improve erectile function. Wilt TJ. as definitive trials of chronic L-arginine administration have not been done in patients with erectile dysfunction. Acknowledgements and disclosures This work was supported by grants from the National Institutes of Health (RO1 HL75774. in the absence of physician supervision. However. Bella AJ. RC2HL103400. P50HL083800. there is scant information regarding potential interactions with other medications. because erectile dysfunction is often associated with cardiovascular disease. Moher D. . K12 HL087746. the evidence is soft. Furthermore. and offered effective pharmacotherapy for sexual function.the strongest rationale for this use is L-arginine. MacDonald R. Dr. Coulter Translational Research Grant Program. Sampson M. Yazdi F. References: 1.

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