Phosphodiesterase Inhibitors PDE5 natural, do they work? by
Ray Sahelian, M.D.
October 1 2015
A phosphodiesterase (PDE) is an enzyme that catalyzes the hydrolysis of phosphodiester bonds. There are 11 families of phosphodiesterases, namely PDE1-PDE11. These enzymes are responsible for the degradation of the cyclic nucleotides cAMP and cGMP. They are therefore important regulators of signal transduction mediated by these molecules.
Phosphodiesterase and impotence, natural inhibitor
The oral phosphodiesterase type 5 (PDE5) inhibitors have become quite popular for the treatment of erectile dysfunction. Phosphodiesterase type 5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, phosphodiesterase type 5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of phosphodiesterase type 5 inhibitor failure. A substance found in horny goat weed herb, called icariin, has been shown to inhibit phosphodiesterase type 5 activity.
Natural phosphodiesterase inhibitors
Consider an herbal sexual enhancement.
Potent inhibition of human phosphodiesterase-5 by icariin derivatives.
J Nat Prod. 2008. Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Plant extracts traditionally used for male impotence (Tribulus terrestris extract, Epimedium brevicornum, Ferula hermonis, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Only E. brevicornum extract and its active principle icariin were active. To improve its inhibitory activity, icariin was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin, where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil. Thus, 3,7-bis(2-hydroxyethyl)icaritin was 80 times more potent than icariin, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make 3,7-bis(2-hydroxyethyl)icaritin a promising candidate for further development.
Phytomedicine. 2006. FRS 1000, an extract of red onion peel, strongly inhibits phosphodiesterase 5A (PDE 5A). As part of our ongoing search for flavonoids that are bioactive in humans, it was determined that FRS 1000, a beverage containing flavonoids extracted from onion peel, showed unexpected improvement of male sexual function. An in vitro enzyme assay clearly showed that FRS 1000 has a strong phosphodiesterase 5A (PDE 5A) inhibitory activity, which is considered to be important for treatment of erectile dysfunction. Detailed assays of each major ingredient indicated that the antioxidative flavonoid quercetin was responsible for the activity. Results also suggested that PDE 5A inhibition is not directly related to the free radical scavenging activity of flavonoids.
Andrology (Los Angeles). 2015. Treatment with a combination of ginger, L-citrulline, muira puama and Paullinia cupana can reverse the progression of corporal smooth muscle loss, fibrosis and veno-occlusive dysfunction in the aging rat. Aging associated erectile dysfunction is characterized within the corpora by a progressive apoptosis of the smooth muscle cells and their replacement by collagen. Nitric oxide from iNOS has been shown to inhibit these histological changes in the corpora while PDE5 inhibitors as well as certain nutraceuticals such as ginger, paullinia cupana, muira puama and L-citrulline are known to enhance the effects of NO. We evaluated whether the daily oral administration for 2 months with a combination of ginger, paullinia cupana, muira puama and L-citrulline (COMP-4) can effectively delay the ongoing corporal fibrosis, smooth muscle cell apoptosis and cavernosal veno-occlusive dysfunction (CVOD) seen in middle aged rats similar to that seen with tadalafil. 10 Month old Fisher 344 rats were treated or not for two months with COMP-4, tadalafil or a combination of tadalafil plus COMP-4. CVOD was determined by dynamic infusion cavernosometry. Penile sections of the corpora cavernosa were subjected to Masson trichrome staining to evaluate fibrosis and immunohistochemistry for desmin as a marker of smooth muscle content and inducible nitric oxide synthase (iNOS) followed by image analysis. Oxidative stress levels were determined by GSH/GSSG ratio in whole blood. A decline in the non-treated rat's erectile function is evident by 10-12 months of age and is accompanied by a decrease in the corporal smooth muscle content determined by desmin expression and an increase in corporal fibrosis. The daily treatment for two months with COMP-4 reverses this process by reducing systemic oxidative stress and increasing desmin and iNOS expression, similar to that seen with tadalafil or the combination of COMP-4 plus tadalafil. An oral combination of ginger, muira puama, Paullinia cupana and L-citrulline seems to be as effective as daily PDE5 inhibitor therapy in either delaying or reversing the onset of the histological and functional characteristics of aging related erectile dysfunction.
and some available by prescription
Choosing a Phosphodiesterase Inhibitor
Of the current options available to treat erectile dysfunction, oral phosphodiesterase type 5 (PDE5) inhibitors are the recommended first-line treatment. There are currently licensed PDE5 inhibitors: sildenafil citrate, vardenafil HCl and tadalafil. All three phosphodiesterase type 5 (PDE5) inhibitor drugs have similar efficacy and toxicity profiles. Sildenafil and vardenafil have similar molecular structures, but tadalafil is structurally different. With regard to the onset of action, achievement of an erection that leads to successful intercourse has been reported for 35% of patients treated with sildenafil within 14 min, 21% of patients treated with vardenafil within 10 min and 16% of patients treated with tadalafil within 16 min. Sildenafil and vardenafil both have half-lives of approximately 4 h but the half-life of tadalafil is 17 h. Another difference between the PDE5 inhibitors is that food, especially fatty food, affects the pharmacokinetic profiles of sildenafil and vardenafil, but not that of tadalafil. These pharmacokinetic differences among the PDE5 inhibitors may underlie patient preference, an important and emerging aspect of ED therapy.
Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of
erectile dysfunction; Expert Opinion on
Investigational Drugs Nov 2010. Erectile Dysfunctiono sildenafilo tadalafilo
vardenafil. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil
and vardenafil) are currently the first-line treatment option presented to
patients with ED. There exists a significant number of men who remain
dissatisfied with the available therapies and are either unable to achieve their
therapeutic goals or unwilling to tolerate adverse side effects. Therefore,
development of novel PDE5 inhibitors with enhanced selectivity, faster onset of
action, increased potency and improved tolerability is desirable. Preclinical
and clinical studies of avanafil, a new oral PDE5 inhibitor being investigated
for the treatment of ED. Data were obtained by searching for all English
peer-reviewed articles on Medline and any related abstracts presented on
avanafil at major international congresses. We propose that avanafil, which
displays enhanced selectivity, faster onset of action, and a favorable
side-effect profile relative to currently available PDE5 inhibitors, may offer
an alternative first line treatment option for men with ED.
An erectile dysfunction drug that reduces by half the time patients need to take the pill before sexual activity has been approved by the U.S. Food and Drug Administration. Developed by Auxilium Pharmaceuticals and Vivus, the drug, Stendra, is the first FDA-approved erectile dysfunction drug that can be taken about 15 minutes prior to sexual activity. Pfizer's blockbuster erectile dysfunction drug, Viagra, can be taken about an hour before sex. Stendra, first approved in 2012, is available in multiple dosages (50 mg, 100 mg and 200 mg tablets) and may be taken with or without food and moderate alcohol consumption (up to three drinks). It belongs to a class of drugs called phosphodiesterase type 5 inhibitors, which are used to help increase blood flow to the penis. Vivus owns the worldwide development and commercial rights to Stendra for use in sexual dysfunction, with the exception of certain Asian countries in the Pacific Rim.
Mirodenafil is newer than the other ED meds.
vardenafil have similar molecular structures, but tadalafil is structurally
Indian J Biochem Biophys. 2013. Serum homocysteine levels and sildenafil 50 mg response in young-adult male patients without vascular risk factors. The results indicated that measurement of serum homocysteine levels could be used as a marker for the evaluation of efficacy of phosphodiesterase 5 inhibitor and the selection of efficacious alternative therapies.
Tadalafil may have an untoward effect on hearing.
Udenafil is a potent novel phosphodiesterase-5 inhibitor approved for use in Korea.
Erectile dysfunction drug
Factors associated with preference for sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy: post hoc analysis of data from a multicentre, randomized, open-label, crossover study.
BJU Int. 2007. Eardley I, Montorsi F, Mirone V, Chan ML, Loughney K, Vail GM, Beardsworth A. Pyrah Department of Urology, St. James University Hospital, Becket Street, Leeds, UK.
To determine if baseline characteristics, treatment efficacy, psychosocial outcomes or tolerability were associated with patient preference for sildenafil citrate or tadalafil for treating erectile dysfunction in men naive to phosphodiesterase 5 inhibitor therapy. In an open-label, crossover study of sildenafil (25, 50 or 100 mg) and tadalafil (10 or 20 mg) erectile dysfunction drugs dosed as needed, after a 4-week baseline assessment, men with erectile dysfunction were randomly assigned to sildenafil followed by tadalafil or vice versa. Patients completing both periods chose which treatment they preferred for an 8-week extension phase. Of patients completing both treatments and indicating a preference, 85 (29%) preferred sildenafil and 206 (71%) preferred tadalafil. Patient differences in time concerns, dosage choice, intercourse satisfaction, treatment tolerability, number of sexual attempts and satisfaction with erection hardness were the set of factors most significantly associated with erectile dysfunction drug treatment preference.
Tolerance to Phosphodiesterase Inhibitors
Tolerance is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Phosphodiesterase inhibitor treatment failure may cause considerable distress.
I am an italian
doctor, I wish to know what is the therapeutic proposal when PGE5 inhibitors
tolerance occurs in patients with ED.
The standard medical treatment is with other types of drugs, but I prefer trying libido boosting herbal products.
Alternative treatment to Phosphodiesterase Inhibitors
These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Another option is to use natural sexual enhancement herbs.
Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of phosphodiesterase type 5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of phosphodiesterase type 5 inhibitors may be maintained.
Early phosphodiesterase inhibitor use after brachytherapy
aids erectile function
After brachytherapy for prostate cancer, use of a phosphodiesterase inhibitor such as sildenafil within a year, rather than later, may restore and preserve erectile function. Dr. Jonathan D. Schiff and colleagues from Mount Sinai Medical Center, New York studied 210 men who underwent brachytherapy and subsequently used a phosphodiesterase inhibitor ( sildenafil or vardenafil ) -- 85 within 1 year of treatment (mean 191 days) and 125 who started after 1 year (mean 595 days). Baseline and 12-month Sexual Health Inventory for Men (SHIM) scores were not significantly different between the two groups. However, SHIM scores at 18-36 months after brachytherapy were significantly different. The men in the early group had earlier and sustained improvements in erectile function that were not apparent in the late group. The researchers say, "We think that using oral phosphodiesterase inhibitors after brachytherapy helps to preserve the endothelium of the erectile tissue, and to preserve penile blood flow," the investigators write. "This should decrease the corporal fibrosis that is often seen after radiotherapy. Preventing fibrosis should lead to better erectile function, as was apparently the case in the present patients." BJU Int 2006;98:1255-1258.
Comments: It is possible that the use of natural herbs for erectile function may also provide such benefits.
Phospodiesterase inhibitors may not work well after
prostate cancer surgery
After the introduction of oral therapy for erectile dysfunction there were some changes in the cause of refractory ED; ED after radical prostatectomy is gaining acceptance as the main reason for a penile implant since Viagra, Levitra, and Cialis may not work well in men who have had radical prostatectomy.
Oxytocin release in rats?
Viagra, made by Pfizer Inc., is an inhibitor of an enzyme called phosphodiesterase type 5. Related drugs such as Eli Lilly and Co.’s Cialis, known generically as tadalafil, and Levitra or vardenafil, sold by GlaxoSmithKline, Bayer AG and Schering-Plough, are also PDE-5 inhibitors. They block this enzyme, which in turn breaks down other compounds. This increases blood flow in the muscles but it also affects a brain structure known as the posterior pituitary. This, in turn, boosts oxytocin in rats.
Pulmonary hypertension treatment
Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. Endothelial cell dysfunction playa an important role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are approved PDE-5 inhibitors in PAH treatment. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors.
Blurred vision, fatigue, muscle aches or pain, headache, stuffy nose, closed nasal passages, difficulty in breathing, easily tired, low motivation, hearing loss are some of the untoward reactions that are common with the use of these impotence meds.
Loss of hearing
Braz J Otorhinolaryngol. December 2013. Phosphodiesterase Type 5 Inhibitors and sudden sensorineural hearing loss. Increased occurrence in clinical practice and scientific reports in the literature suggest that the phosphodiesterase type 5 inhibitors are considered a risk factor for sudden deafness. Further studies with larger samples and control groups are needed for better assessing this association.
Drugs to treat erectile dysfunction need stronger warnings on their packaging about the risk of blindness, U.S. consumer group Public Citizen said in 2005, in a petition filed with health regulators. The U.S. Food and Drug Administration should "immediately add a black box warning regarding the risks of drug-induced blindness for the three phosphodiesterase 5 (PDE5) inhibitors that are prescribed for the treatment of erectile dysfunction," Public Citizen's Health Research Group wrote. Pfizer Inc.'s pulmonary hypertension drug Revatio, which has the same active ingredient as its impotence drug Viagra, should also carry a similar black box warning. Earlier drugmakers agreed to put information on their impotence drug labels about the possible vision loss, called non-arteritic anterior ischemic optic neuropathy. Viagra, Cialis, sold by Eli Lily & Co. and Icos Corp., and Levitra, sold by GlaxoSmithKline , Bayer AG and Schering-Plough Corp., now carry the new labels, which say the condition "has been reported rarely."
Q. I'm a risk analyst preparing a submission banning of herbs containing PDE5 inhibitors in New Zealand on the basis that they are analogues of Viagra. I came across your website and wonder if you are able to provide scientific references regarding herbs such as horny goat weed and any other herbs with such activity.
A. I don't see any reason to ban a natural herb from use unless there is clear evidence that it causes significant harm to users. As such, I have not seen any reports of horny goat weed supplement users to have a high risk of safety problems. Why would anyone even consider banning these natural herbs? Why not focus your attention on banning acetaminophen which causes many deaths and thousands of cases of liver damage each year? Unless your motivation is to make drug companies more profitable?
I was doing some research on PDE5 inhibitors and happened to read your comment to the risk analyst researching a herb ban. I cheered your use of acetaminophen as an example of what the real motivation for a ban on Horny Goat Weed might be. As an HIV treatment advocate, and liver health advocate of 13 years, I just wanted to share that it is refreshing read candid comments that focus on patient health and less on big pharma profits. I bookmarked you web and will come back often to get your perspective during my research.
FEBS Lett. 2013. Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis. Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.