List, how they work, foods, and more

We include products we think are useful for our readers. If you buy through links on this page, we may earn a small commission Here’s our process.

Medical News Today only shows you brands and products that we stand behind.

Our team thoroughly researches and evaluates the recommendations we make on our site. To establish that the product manufacturers addressed safety and efficacy standards, we:

• Evaluate ingredients and composition: Do they have the potential to cause harm?
• Fact-check all health claims: Do they align with the current body of scientific evidence?
• Assess the brand: Does it operate with integrity and adhere to industry best practices?

We do the research so you can find trusted products for your health and wellness.

Read more about our vetting process.

Was this helpful?

Phosphodiesterase 5 (PDE5) inhibitors are a type of drug that can affect blood flow and how cells communicate in the body. PDE5 inhibitors can also appear in some foods and supplements.

Share on PinterestKaempferia parviflora is a plant that naturally contains PDE5 inhibitors.

People may take PDE5 inhibitors to manage conditions such as erectile dysfunction (ED) or pulmonary hypertension.

In this article, we explain how PDE5 inhibitors work and the potential risks and side effects of taking them. We also provide a list of drugs and substances that contain them.

Please note that the writer of this article has not tried these products. All information presented is purely research-based and correct at the time of publication.

Medical News Today follows a strict product selection and vetting process. Learn more here.

Was this helpful?

PDE5 is an enzyme in the walls of blood vessels. It affects blood flow and how cells signal within the body.

PDE5 inhibitors block the PDE5 enzyme to prevent it from working. This inhibition relaxes the blood vessels and increases blood flow.

People may take PDE5 inhibitors to treat ED or pulmonary hypertension.

In people with ED, PDE5 inhibitors increase blood flow to the penis, improving erectile function.

In people with pulmonary hypertension, PDE5 inhibitors can help by:

• controlling blood flow to the arteries in the lungs
• increasing blood flow to the lungs
• lowering blood pressure

Research also suggests that PDE5 inhibitors may help treat heart disease, diabetes, and cancer.

Current research looks into whether PDE5 inhibitors are also effective in treating cognitive disorders like dementia.

Read more about the best pills for ED here.

Various PDE5 inhibitor drugs are available, and people usually take them in tablet form.

In the United States, the following prescription PDE5 inhibitors are available:

Avanafil (Stendra)

Avanafil, brand name Stendra, is a relatively new ED medication. An older study reports that this drug takes effect quicker than other ED treatments, taking effect around 15 minutes after ingestion, and does not last as long, with a maximum duration of 6 hours.

Additionally, a 2016 study states that avanafil has fewer side effects than some other ED medications, and the shorter onset time allows people to have more spontaneous sex.

Vardenafil (Levitra)

Vardenafil, brand name Levitra, achieves maximum effect around 60 minutes after ingesting. It lasts for a maximum of 12 hours inside the body.

Learn more about vardenafil here.

Tadalafil (Cialis, Adcirca)

Tadalafil, which has the brand names Cialis and Adcirca, has the slowest onset of ED medications, achieving maximal effect around 120 minutes after ingesting. However, it lasts for a maximum of 36 hours in the body.

Learn more about tadalafil here.

Sildenafil (Viagra)

Sildenafil, brand name Viagra, takes effect around 60 minutes after ingestion. It lasts for around 12 hours in the body.

Learn more about sildenafil here.

People can only receive ED medication through prescription. A healthcare professional must write a valid prescription that a pharmacy must fill.

Was this helpful?

However, several telemedicine companies offer prescription ED medications. Some companies also offer online doctor appointments to receive prescriptions if a person does not already have one.

Options include:

Hims

Hims is a telehealth company specializing in male health conditions, including erectile dysfunction.

This company offers sildenafil (Viagra), tadalafil (Cialis), and avanafil (Stendra). It also offers online appointments with healthcare professionals.

Learn more about Hims here.

Price: The cost of ED medication starts from $3 per dose.

LEARN MORE

Roman

Roman is a telehealth company also specializing in male health conditions, including treatment for ED.

It offers sildenafil (Viagra) and tadalafil (Cialis). Similar to Hims, Roman also offers online appointments with healthcare professionals.

Learn more about Roman here.

Price: The cost of ED medication starts from $2 per dose.

LEARN MORE

There are also several other substances and supplements that are PDE5 inhibitors. However, a person should not take any supplements that claim to treat ED without first seeking the advice of a healthcare professional.

The FDA warns that many ED supplements contain undeclared prescription medication that can cause harm.

Phentolamine (Regitine)

Phentolamine (Regitine) is a prescription medication for hypertension.

However, healthcare professionals may inject this medication if a person does not respond to any prescription PDE5 inhibitors.

Individuals should contact a doctor and discuss whether phentolamine is the right medication for their circumstances.

L-arginine

L-arginine is a type of amino acid available in many foods.

A 2020 study suggests that combining L-arginine with tadalafil may increase the effectiveness of the ED medication. The researchers also found that L-arginine had a smaller beneficial effect on ED when the participants only took this supplement.

Yohimbine (Yocon)

Yohimbine is a compound in a tree native to central and western Africa. Traditional medicine uses the bark to increase sexual arousal and performance.

The National Center for Complementary and Integrative Health states that there is not enough evidence to say that yohimbine is effective for erectile dysfunction. Additionally, yohimbine has an association with heart attacks and seizures and interacts negatively with antidepressants.

Due to safety concerns, several countries have banned yohimbine.

Black ginger

Black ginger, or kaempferia parviflora, may have a slight PDE5 inhibiting effect.

A small 2018 study of 14 participants found that ethanol extract from this plant may improve erection function. However, more research on larger sample sizes is necessary to determine the safety and effectiveness of this plant.

Tongkat ali

Eurycoma Longifolia, or tongkat ali, is a plant native to Indonesia and Malaysia.

There is some evidence that Tongkat ali may increase testosterone levels and arousal, which may help improve ED.

Tribulus terrestris

According to a 2013 study on rodents, this substance has a relaxing effect on arterial pressure, which may help improve ED.

There is slight evidence that this plant may help improve a person’s libido, however, there needs to be more research on this tribulus terrestris’ effect on humans.

Horny goat weed

Horny goat weed contains icariin, an extract from the Epimedium plant.

An older study on rats found that horny goat weed extract may benefit ED. However, there have been no clinical trials on humans.

The following table compares the PDE5 inhibitors in this article.

People who are taking nitrate medication should avoid taking PDE5 inhibitors. The combination of both medications can cause a severe decrease in blood pressure, which can potentially be fatal.

People may be taking nitrate medications for chest or heart issues. These drugs include:

• nitroglycerin (Nitrostat)
• isosorbide dinitrate (Dilatrate-SR, Isordil) or isosorbide mononitrate (Imdur, Monoket)
• amyl nitrate, or “poppers”

PDE5 inhibitors can also potentially be harmful to people with certain conditions. Before taking these medications, a person should make their doctor aware if they:

• have a history of heart attack, severe arrhythmia, or stroke in the last 6 months
• have hypotension or hypertension
• have a history of heart failure or angina
• are currently using alpha-blockers

Common, and usually mild, side effects of PDE5 inhibitors can include:

• headaches
• flushing
• symptoms resembling those of the common cold
• stomach upset
• muscle and back pain

Rare side effects may include:

• changes in vision, or sudden loss of vision, for which people with heart disease or diabetes are more at risk
• sudden loss of hearing
• prolonged or painful erections that will require treatment to prevent lasting damage

PPDE5 inhibitors may interact negatively with grapefruit juice and alcohol. They can potentially also interact with other medications, so people should make their doctor aware if they are taking other drugs or supplements.

Some herbs contain PDE5 inhibitors, so people may find them in certain supplements or herbal remedies.

However, herbs and supplements may contain additional unlisted ingredients, cause adverse side effects, or interact with other drugs.

The FDA warns that herbal or natural remedies for conditions such as ED may contain active ingredients that are also present in prescription drugs.

It is advisable to speak to a doctor before taking substances and supplements that contain PDE5 inhibitors or promise results equivalent to those of PDE5 inhibitor prescription drugs.

A person may wish to contact a doctor if they are finding it difficult to have and maintain an erection.

Doctors may ask questions about a person’s sexual history, such as:

• the frequency and length they have erections for
• whether any factors make it harder to have an erection, such as stress
• how often the person has sex
• whether the person is already trying treatments
• if the person has a partner, whether they would be willing to be involved with treatment

Healthcare professionals may also ask questions about certain risk factors, such as whether a person has type 2 diabetes or high blood pressure. They may also ask if the person smokes, drinks, uses drugs, or does regular activities.

These questions help doctors determine the best treatment option for each person. They may recommend prescription medication, such as sildenafil, to help people maintain their erection for longer.

Here we answer some common questions.

Can you mix caffeine and Viagra?

Currently, there are no known interactions between caffeine and Viagra or sildenafil.

However, people may wish to contact their doctor or another healthcare professional for advice if they intend to have beverages with high caffeine content alongside PDE5 inhibitors.

What everyday foods contain PDE5 inhibitors?

There are several supplements containing ingredients that may act as PDE5 inhibitors. These include horny goat weed and black ginger.

Scientists have not conducted clinical trials investigating the effects of horny goat weed on humans.

A small 2018 study of 13 participants found that black ginger may be effective in improving erectile function and males ages 50-70 without erectile dysfunction. However, more research is necessary with larger sample sizes to investigate the efficacy and safety of this plant.

However, the FDA warns people against taking supplements that companies market as natural remedies for erectile dysfunction. These supplements may contain undeclared prescription medication that can cause harm.

PDE5 inhibitors block PDE5, an enzyme in the walls of blood vessels. Blocking PDE5 causes blood vessels to relax, increasing blood flow to certain areas of the body.

This effect means that they can help manage conditions such as ED and pulmonary hypertension.

People taking nitrate medication should not take PDE5 inhibitors because the combination of drugs can cause a dangerous drop in blood pressure, which can be life-threatening.

Other drugs, foods, supplements, or herbal remedies may contain PDE5 inhibitors. These may not have FDA regulations and could contain unlisted ingredients or contaminants, or interact with other medications.

People should discuss any potential side effects or drug interactions of PDE5 inhibitors with their doctor before taking these medications.

List, how they work, foods, and more

We include products we think are useful for our readers. If you buy through links on this page, we may earn a small commission Here’s our process.

Medical News Today only shows you brands and products that we stand behind.

Our team thoroughly researches and evaluates the recommendations we make on our site. To establish that the product manufacturers addressed safety and efficacy standards, we:

• Evaluate ingredients and composition: Do they have the potential to cause harm?
• Fact-check all health claims: Do they align with the current body of scientific evidence?
• Assess the brand: Does it operate with integrity and adhere to industry best practices?

We do the research so you can find trusted products for your health and wellness.

Read more about our vetting process.

Was this helpful?

Phosphodiesterase 5 (PDE5) inhibitors are a type of drug that can affect blood flow and how cells communicate in the body. PDE5 inhibitors can also appear in some foods and supplements.

Share on PinterestKaempferia parviflora is a plant that naturally contains PDE5 inhibitors.

People may take PDE5 inhibitors to manage conditions such as erectile dysfunction (ED) or pulmonary hypertension.

In this article, we explain how PDE5 inhibitors work and the potential risks and side effects of taking them. We also provide a list of drugs and substances that contain them.

Please note that the writer of this article has not tried these products. All information presented is purely research-based and correct at the time of publication.

Medical News Today follows a strict product selection and vetting process. Learn more here.

Was this helpful?

PDE5 is an enzyme in the walls of blood vessels. It affects blood flow and how cells signal within the body.

PDE5 inhibitors block the PDE5 enzyme to prevent it from working. This inhibition relaxes the blood vessels and increases blood flow.

People may take PDE5 inhibitors to treat ED or pulmonary hypertension.

In people with ED, PDE5 inhibitors increase blood flow to the penis, improving erectile function.

In people with pulmonary hypertension, PDE5 inhibitors can help by:

• controlling blood flow to the arteries in the lungs
• increasing blood flow to the lungs
• lowering blood pressure

Research also suggests that PDE5 inhibitors may help treat heart disease, diabetes, and cancer.

Current research looks into whether PDE5 inhibitors are also effective in treating cognitive disorders like dementia.

Read more about the best pills for ED here.

Various PDE5 inhibitor drugs are available, and people usually take them in tablet form.

In the United States, the following prescription PDE5 inhibitors are available:

Avanafil (Stendra)

Avanafil, brand name Stendra, is a relatively new ED medication. An older study reports that this drug takes effect quicker than other ED treatments, taking effect around 15 minutes after ingestion, and does not last as long, with a maximum duration of 6 hours.

Additionally, a 2016 study states that avanafil has fewer side effects than some other ED medications, and the shorter onset time allows people to have more spontaneous sex.

Vardenafil (Levitra)

Vardenafil, brand name Levitra, achieves maximum effect around 60 minutes after ingesting. It lasts for a maximum of 12 hours inside the body.

Learn more about vardenafil here.

Tadalafil (Cialis, Adcirca)

Tadalafil, which has the brand names Cialis and Adcirca, has the slowest onset of ED medications, achieving maximal effect around 120 minutes after ingesting. However, it lasts for a maximum of 36 hours in the body.

Learn more about tadalafil here.

Sildenafil (Viagra)

Sildenafil, brand name Viagra, takes effect around 60 minutes after ingestion. It lasts for around 12 hours in the body.

Learn more about sildenafil here.

People can only receive ED medication through prescription. A healthcare professional must write a valid prescription that a pharmacy must fill.

Was this helpful?

However, several telemedicine companies offer prescription ED medications. Some companies also offer online doctor appointments to receive prescriptions if a person does not already have one.

Options include:

Hims

Hims is a telehealth company specializing in male health conditions, including erectile dysfunction.

This company offers sildenafil (Viagra), tadalafil (Cialis), and avanafil (Stendra). It also offers online appointments with healthcare professionals.

Learn more about Hims here.

Price: The cost of ED medication starts from $3 per dose.

LEARN MORE

Roman

Roman is a telehealth company also specializing in male health conditions, including treatment for ED.

It offers sildenafil (Viagra) and tadalafil (Cialis). Similar to Hims, Roman also offers online appointments with healthcare professionals.

Learn more about Roman here.

Price: The cost of ED medication starts from $2 per dose.

LEARN MORE

There are also several other substances and supplements that are PDE5 inhibitors. However, a person should not take any supplements that claim to treat ED without first seeking the advice of a healthcare professional.

The FDA warns that many ED supplements contain undeclared prescription medication that can cause harm.

Phentolamine (Regitine)

Phentolamine (Regitine) is a prescription medication for hypertension.

However, healthcare professionals may inject this medication if a person does not respond to any prescription PDE5 inhibitors.

Individuals should contact a doctor and discuss whether phentolamine is the right medication for their circumstances.

L-arginine

L-arginine is a type of amino acid available in many foods.

A 2020 study suggests that combining L-arginine with tadalafil may increase the effectiveness of the ED medication. The researchers also found that L-arginine had a smaller beneficial effect on ED when the participants only took this supplement.

Yohimbine (Yocon)

Yohimbine is a compound in a tree native to central and western Africa. Traditional medicine uses the bark to increase sexual arousal and performance.

The National Center for Complementary and Integrative Health states that there is not enough evidence to say that yohimbine is effective for erectile dysfunction. Additionally, yohimbine has an association with heart attacks and seizures and interacts negatively with antidepressants.

Due to safety concerns, several countries have banned yohimbine.

Black ginger

Black ginger, or kaempferia parviflora, may have a slight PDE5 inhibiting effect.

A small 2018 study of 14 participants found that ethanol extract from this plant may improve erection function. However, more research on larger sample sizes is necessary to determine the safety and effectiveness of this plant.

Tongkat ali

Eurycoma Longifolia, or tongkat ali, is a plant native to Indonesia and Malaysia.

There is some evidence that Tongkat ali may increase testosterone levels and arousal, which may help improve ED.

Tribulus terrestris

According to a 2013 study on rodents, this substance has a relaxing effect on arterial pressure, which may help improve ED.

There is slight evidence that this plant may help improve a person’s libido, however, there needs to be more research on this tribulus terrestris’ effect on humans.

Horny goat weed

Horny goat weed contains icariin, an extract from the Epimedium plant.

An older study on rats found that horny goat weed extract may benefit ED. However, there have been no clinical trials on humans.

The following table compares the PDE5 inhibitors in this article.

People who are taking nitrate medication should avoid taking PDE5 inhibitors. The combination of both medications can cause a severe decrease in blood pressure, which can potentially be fatal.

People may be taking nitrate medications for chest or heart issues. These drugs include:

• nitroglycerin (Nitrostat)
• isosorbide dinitrate (Dilatrate-SR, Isordil) or isosorbide mononitrate (Imdur, Monoket)
• amyl nitrate, or “poppers”

PDE5 inhibitors can also potentially be harmful to people with certain conditions. Before taking these medications, a person should make their doctor aware if they:

• have a history of heart attack, severe arrhythmia, or stroke in the last 6 months
• have hypotension or hypertension
• have a history of heart failure or angina
• are currently using alpha-blockers

Common, and usually mild, side effects of PDE5 inhibitors can include:

• headaches
• flushing
• symptoms resembling those of the common cold
• stomach upset
• muscle and back pain

Rare side effects may include:

• changes in vision, or sudden loss of vision, for which people with heart disease or diabetes are more at risk
• sudden loss of hearing
• prolonged or painful erections that will require treatment to prevent lasting damage

PPDE5 inhibitors may interact negatively with grapefruit juice and alcohol. They can potentially also interact with other medications, so people should make their doctor aware if they are taking other drugs or supplements.

Some herbs contain PDE5 inhibitors, so people may find them in certain supplements or herbal remedies.

However, herbs and supplements may contain additional unlisted ingredients, cause adverse side effects, or interact with other drugs.

The FDA warns that herbal or natural remedies for conditions such as ED may contain active ingredients that are also present in prescription drugs.

It is advisable to speak to a doctor before taking substances and supplements that contain PDE5 inhibitors or promise results equivalent to those of PDE5 inhibitor prescription drugs.

A person may wish to contact a doctor if they are finding it difficult to have and maintain an erection.

Doctors may ask questions about a person’s sexual history, such as:

• the frequency and length they have erections for
• whether any factors make it harder to have an erection, such as stress
• how often the person has sex
• whether the person is already trying treatments
• if the person has a partner, whether they would be willing to be involved with treatment

Healthcare professionals may also ask questions about certain risk factors, such as whether a person has type 2 diabetes or high blood pressure. They may also ask if the person smokes, drinks, uses drugs, or does regular activities.

These questions help doctors determine the best treatment option for each person. They may recommend prescription medication, such as sildenafil, to help people maintain their erection for longer.

Here we answer some common questions.

Can you mix caffeine and Viagra?

Currently, there are no known interactions between caffeine and Viagra or sildenafil.

However, people may wish to contact their doctor or another healthcare professional for advice if they intend to have beverages with high caffeine content alongside PDE5 inhibitors.

What everyday foods contain PDE5 inhibitors?

There are several supplements containing ingredients that may act as PDE5 inhibitors. These include horny goat weed and black ginger.

Scientists have not conducted clinical trials investigating the effects of horny goat weed on humans.

A small 2018 study of 13 participants found that black ginger may be effective in improving erectile function and males ages 50-70 without erectile dysfunction. However, more research is necessary with larger sample sizes to investigate the efficacy and safety of this plant.

However, the FDA warns people against taking supplements that companies market as natural remedies for erectile dysfunction. These supplements may contain undeclared prescription medication that can cause harm.

PDE5 inhibitors block PDE5, an enzyme in the walls of blood vessels. Blocking PDE5 causes blood vessels to relax, increasing blood flow to certain areas of the body.

This effect means that they can help manage conditions such as ED and pulmonary hypertension.

People taking nitrate medication should not take PDE5 inhibitors because the combination of drugs can cause a dangerous drop in blood pressure, which can be life-threatening.

Other drugs, foods, supplements, or herbal remedies may contain PDE5 inhibitors. These may not have FDA regulations and could contain unlisted ingredients or contaminants, or interact with other medications.

People should discuss any potential side effects or drug interactions of PDE5 inhibitors with their doctor before taking these medications.

A new approach to the treatment of patients with erectile dysfunction: continuous use of phosphodiesterase type 5 inhibitors (Literature review)

Phosphodiesterase type 5 inhibitors (PDE-5) are currently the drugs of choice in the treatment of erectile dysfunction (ED) [1,2]. These drugs are characterized by ease of use, high efficiency and good tolerance.

The mechanism of action of PDE-5 inhibitors is associated with the effect on the system of nitric oxide NO – cyclic guanosine monophosphate (Fig. 1). Inhibition of the destruction of the latter leads to a sharp increase in its concentration in cells in which the main form of phosphodiesterases is precisely PDE-5. In smooth muscle cells, this causes relaxation, which, in the case of cavernous arteries, allows increasing blood flow to the cavernous bodies and, as a result, promotes the development of an erection.
For a long time, drugs from the group of PDE-5 inhibitors were considered as symptomatic therapy taken “on demand”. However, more and more data have recently begun to appear that indicate the advisability of the continuous use of PDE5 inhibitors (Table 1) [3–5].
It should be noted that the pharmacodynamic properties of drugs in this group differ significantly (Table 2) and a significantly longer period of action of tadalafil (Cialis) made this drug the most preferable for continuous use [5]. This explains the prevalence of studies of long-term use of PDE-5 inhibitors with the use of tadalafil.
The main perceived benefits of using PDE-5 inhibitors as a permanent therapy can be roughly divided into five interrelated groups:
1. Increasing the effectiveness of treatment.
2. Achievement of greater “naturalness”, spontaneity of sexual life.
3. The possibility of “curing” erectile disorders.
4. Improvement of blood supply to the cavernous bodies.
5. Favorable effect on the cardiovascular system as a whole.
Already in the first comparative studies of the use of PDE-5 inhibitors “on demand” and their long-term use, it was shown that the effectiveness of the latter approach is at least as good as the conventional method of treatment [3-5]. Thus, McMahon et al. compared the efficacy and tolerability of daily tadalafil at a dose of 10 mg with its intake at a dose of 20 mg before each sexual intercourse in 143 patients with moderate to severe ED [6]. In both groups, there was a significant improvement in erectile function, but among those receiving the drug on an ongoing basis, it was significantly more pronounced. The high efficiency of continuous administration of tadalafil and sildenafil was also confirmed in a number of other studies [7–9].
Of considerable interest is also the possibility of using the continuous use of PDE-5 inhibitors in the treatment of patients in whom the use of these drugs “on demand” was ineffective or insufficiently effective. The relevance of this issue is determined by the fact that the proportion of such patients reaches 30–40% [10]. Data from studies show that this approach can achieve a significant improvement in erectile function in 10-20% of patients who initially did not respond to treatment with PDE-5 inhibitors [11,12].
In addition, the use of PDE-5 inhibitors on an ongoing basis can improve the state of erectile function in such difficult to treat groups of patients, such as patients with diabetes mellitus and undergoing radical prostatectomy [3]. The possibility of improving postoperative ED in the latter group of patients as a result of daily intake of sildenafil was studied by Padma Nathan et al. During the study, patients who underwent bilateral nerve-sparing retropubic radical prostatectomy and did not suffer from ED before surgery, starting from the second month of the postoperative period, received sildenafil at doses of 100 and 50 mg or placebo at bedtime for 36 weeks. At 8 weeks after discontinuation of treatment, 27% of men treated with sildenafil reported the possibility of a normal sexual life, and only 4% of those receiving placebo [13]. Similar results were also obtained by other authors [14, 15].
In recent years, a number of data have been obtained indicating that long-term continuous use of PDE-5 inhibitors in some patients with ED can cure this disease, that is, after stopping the drugs, erectile function remains normal [4]. For example, Sommer et al. showed that taking sildenafil at a dose of 50 mg at night for a year was not only accompanied by a significant improvement in erectile function during the treatment period, but also by maintaining the ability to achieve an erection 1 month after its completion in some patients [16]. In addition, after the end of treatment, the authors noted a significant increase in blood flow in the cavernous arteries according to pharmacodopplerography.
Recovery of erectile function has also been shown after treatment with another type 5 phosphodiesterase inhibitor, tadalafil. Caretta N. et al. observed 60 men with erectile dysfunction aged 60 to 70 years who received tadalafil at a dose of 20 mg every other day for 3 months [17]. Before the start of treatment, all patients underwent an ultrasound examination of the wall thickness of the carotid arteries. When re-examined 1 month after discontinuation of the drug, restoration of erectile function was noted in 25 patients (41. 7%). At the same time, it was found that the restoration of spontaneous erections took place in 65% of patients with normal carotid artery wall thickness and only in 16% of patients with atherosclerotic lesions. The authors explain this fact by the lower severity of damage to the arteries of the penis in most men with intact carotid arteries [17].
As noted earlier, the benefits of continuous use of PDE-5 inhibitors are in fact interrelated. So, it is the ability to constantly achieve an erection, which occurs with the daily intake of drugs, is the most important characteristic, not only providing greater naturalness of sexual life, but also increasing the satisfaction of patients with the latter. This, ultimately, is reflected in the effectiveness of treatment, which in the case of ED is evaluated by subjective feelings. It is assumed that this pattern is more relevant to younger patients, although this continues to be unproven [5]. At the same time, improved blood supply to the cavernous bodies, achieved primarily by increasing the duration of nocturnal erections, which perform the most important trophic function, ensures the preservation of the smooth muscle tissue of the cavernous bodies. The latter prevents the development of ED (in the case of patients who have undergone radical surgery) or allows the restoration of erectile function in some patients.
However, it should be noted that at present, the special interest of researchers involved in the study of ED and its treatment, including in the form of a permanent intake of PDE-5 inhibitors, is focused on the functional state of the endothelium. In this regard, we should dwell in more detail on the effect of PDE5 inhibitors on endothelial function.
Healthy endothelium has a number of diverse functions, however, in modern scientific literature, endothelial dysfunction is understood as an imbalance between vasodilators secreted by endothelial cells and vasoconstrictors, with the latter predominating [18]. The leading role in the development of endothelial dysfunction is played by a decrease in the synthesis and bioavailability of nitric oxide NO, which not only has a vasodilatory effect, but is also a deaggregant, inhibits the proliferation of vascular smooth muscle cells and prevents the release of tissue factors that increase the likelihood of thrombosis, which allows us to consider it as the main antiatherogenic agent. mediator. Nitric oxide is also the main mediator of erection, during the development of which its action leads to relaxation of the smooth muscle cells of the cavernous bodies, which provides a sharp increase in arterial blood flow to them. It is assumed that in the early stages of erection development, nitric oxide is released from nerve endings, and later from their endothelial cells under the action of increased pressure from the blood flow (Fig. 2). The development of endothelial dysfunction disrupts this process, preventing the achievement of a sufficient level of arterial blood flow in the cavernous bodies, which leads to the development of arteriogenic ED [18].
Endothelial dysfunction is currently considered as an early, potentially reversible stage of the atherosclerotic process. Thus, at the level of the penis, endothelial dysfunction leads to the development of ED, and, for example, in the coronary vessels, to the development of coronary heart disease. In our opinion, it is very important that the clinical manifestations of endothelial dysfunction are essentially limited to erectile dysfunction, while in other vascular beds such early pathological changes, as a rule, are asymptomatic. This determines the importance of ED as an early manifestation of systemic vascular disease.
The effect of PDE5 inhibitors on endothelial function has been studied in some detail in recent years. The reasons for the interest in this problem are obvious: with endothelial dysfunction, there is a violation of the action of NO secreted by the endothelium, and PDE-5 inhibitors increase the activity of the biochemical cascade, which is precisely nitric oxide that starts.
The most well-studied is the effect on the endothelial function of the coronary and brachial arteries of the drug sildenafil, which is associated with its longer availability for clinical use. The use of sildenafil at doses of 25 to 100 mg was accompanied by an improvement in systemic endothelial function in patients with heart failure, diabetes mellitus, coronary heart disease and smokers [19–22]. The ability of sildenafil to eliminate the short-term deterioration of endothelial function caused by smoking has also been shown [23]. In studies in patients with heart failure, sildenafil, in addition to correcting endothelial dysfunction of the brachial and coronary arteries, also led to an improvement in pulmonary hemodynamics and had a moderate antiplatelet effect [24]. Similar results were also obtained under experimental conditions [25].
To date, there is no doubt that all three available PDE5 inhibitors improve both systemic and local endothelial function after a single dose [18]. It should be noted that this improvement is much more pronounced in patients with arteriogenic ED. This, apparently, is explained by the fact that in the absence of endothelial dysfunction, the effect of endothelial NO secreted by the endothelium leads to close to the maximum possible vasorelaxation and, thus, an increase in the intracellular concentration of cyclic guanosine monophosphate in response to PDE5 inhibition is accompanied by only a small decrease in amplification. In the case of an initial decrease in the activity of endothelial NO, an increase in the intracellular level of cyclic guanosine monophosphate provides a significantly greater increase in vasorelaxation due to the activation of previously unused intracellular mechanisms [18]. At the same time, it should be noted that the effects of continuous use of PDE5 inhibitors on endothelial function are less fully understood.
The effects of long-term use of the PDE5 inhibitor tadalafil on systemic endothelial function have been studied by Rosano et al. in a study that included 32 patients with ED who had vascular risk factors [26]. Patients were divided into two groups receiving tadalafil 20 mg or placebo every other day for 4 weeks. Systemic endothelial function was assessed by ultrasound examination of post-compression changes in the diameter of the brachial artery, as well as by the levels of endothelin-1 and plasma nitrites. Taking tadalafil led to a statistically significant improvement in systemic endothelial function, which persisted two weeks after discontinuation of the drug [26].
In another study, Aversa et al. studied the effect of long-term administration of tadalafil on the endothelial function of cavernous arteries [27]. In this open cross-sectional study, 20 patients with ED received tadalafil 20 mg every other day or on demand for 4 weeks. The results of the work showed that after 4 weeks of continuous use of tadalafil, there was a significant improvement in the endothelial function of the cavernous arteries, as well as a significant increase in the number of morning erections. Both indicators significantly exceeded those after taking the drug “on demand”. Interestingly, the improvement in endothelial function after taking tadalafil on a permanent basis was maintained even 2 weeks after stopping treatment [27].
The results of these studies have led a number of authors to suggest that PDE-5 inhibitors are not only not dangerous for the cardiovascular system drugs, but can be considered as potentially useful for her means. The clinical feasibility of continuous use of PDE5 inhibitors has already been proven in the case of pulmonary and systemic hypertension [28]. If it is confirmed that the restoration of normal endothelial function is accompanied by an improvement in the state of the cardiovascular system and a decrease in the incidence of complications, then new prospects will open for long-term continuous use of PDE-5 inhibitors.
Thus, a sufficient amount of data has now been obtained indicating that long-term continuous use of PDE-5 inhibitors has a number of advantages over their use on demand. These benefits relate to both improving the effectiveness of the treatment of ED itself, and potentially beneficial effects on the cardiovascular system. Although the clinical benefits of continuous use of PDE-5 inhibitors in relation to cardiovascular disease have not yet been fully confirmed, data from studies suggest that the improvement in the functional state of the endothelium, noted against the background of such treatment, may be accompanied by a decrease in the number of cardiovascular complications. Pharmacokinetic parameters determine a significantly greater convenience for use as a permanent treatment of the PDE-5 inhibitor tadalafil (Cialis). Continuous use of this drug for several months allows some patients to achieve restoration of erectile function, and also improves the state of both local and systemic endothelial function, and this improvement persists after the end of treatment.

Review prepared
PhD V.V. Iremashvili (RSMU)

Literature
1 Hellstrom W.J. Current safety and tolerability issues in men with erectile receiving dysfunction PDE5 inhibitors. Int J Clin Pract. 2007; 61(9): 1547–1554.
2. Montorsi F, Salonia A, Deho F, et al. Pharmacological management of erectile dysfunction. BJU Int 2003; 91:446–454.
3. Bella AJ, Deyoung LX, Al–Numi M, Brock GB. Daily administration of phosphodiesterase type 5 inhibitors for urological and nonurological indications. EUR Urol. 2007; 52:990–1005.
4. Montorsi F, Briganti A, Salonia A, et al. Can Phosphodiesterase Type 5 Inhibitors Cure Erectile Dysfunction? EUR Urol. 2006; 49:979–986.
5. McMahon C.G. Treatment of erectile dysfunction with chronic dosing of tadalafil. Eur Urol 2006; 50:215–217.
6. McMahon C.G. Comparison, efficacy, and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2005; 2:415–425.
7. Porst H, Giuliano F, Glina S, et al. Evaluation of the efficacy and safety of once–a–day dosing of tadalafil 5mg and 10 mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double–blind, placebo controlled trial. Eur Urol 2006; 50:351–359.
8 Mirone V, Costa P, Damber JE, et al. An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. Eur Urol 2005; 47:846–854.
9. Buvat J, Faria G, Wetterauer U, et al. Tadalafil 5mg and 10 mg taken once a day for the treatment of erectile dysfunction improves patient sexual satisfaction. J Sex Med 2007;4(Suppl 1): 91 (abstract no. 84).
10. Mazo EB, Gamidov SI, Iremashvili VV. Does the clinical efficacy of vardenafil correlate with its effect on the endothelial function of cavernous arteries? A pilot study. BJU Int. 2006; 98:1054–1058.
11. McMahon C.G. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to ondemand tadalafil. J Sex Med 2004; 1:292–300.
12. Hatzimouratidis K, Moysidis K, Bekos A, et al. Treatment strategy for ‘‘non–responders’’ to tadalafil and vardenafil: a real–life study. Eur Urol 2006; 50:126–133.
13. Padma–Nathan E, McCullough AR, Giuliano F et al. Postoperative nightly administration of sildenafil citrate significantly improves the return of normal spontaneous erectile function after bilateral nerve–sparing radical prostatectomy. J Urol 2003; 4(Suppl): 375
14 Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical prostatectomy. J Urol 2004; 171:771–774.
15. Casperson JM, Steidle CP, Pollifrone DL. Penile rehabilitation in a community setting. J Sex Med 2007; 4(Suppl1): 85–86.
16. Sommer F, Schulze W. Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors. World J Urol 2005; 23:385–392.
17. Caretta N, Palego P, Ferlin A, et al. Resumption of spontaneous erections in selected patients affected by erectile dysfunction and various degrees of carotid wall alteration: role of tadalafil. Eur Urol 2005; 48:326–332.
18. Iremashvili V.V. The value of the study of endothelial function in patients with erectile dysfunction. Dis. … cand. honey. Sciences. – M., 2006. – 188 p.
19. Desouza C, Parulkar A, Lumpkin D, et al. Acute and progressive effects of sildenafil on brachial artery flow–mediated dilatation in type 2 diabetes. Diabetes Care 2002; 25:1336–1339.
20. Katz SD, Balidemaj K, Homma S, et al. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow–mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol 2000; 36:845–851.
21. Kimura M, Higashi Y, Hara K, et al. PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers. Hypertension 2003; 41:1106–1110.
22. Park JW, Mrowietz C, Chung N, Jung F. Sildenafil improves cutaneous microcirculation in patients with coronary artery disease: a monocentric, prospective, double-blind, placebo-controlled, randomized cross-over study. Clin Hemorheol Microcirc 2004; 31:173–183.
23. Vlachopoulos C, Rokkas K, Ioakeimidis N, et al. Prevalence of asymptomatic coronary artery disease in men with vasculogenic erectile dysfunction: a prospective angiographic study. Eur Urol 2005; 48:996–1002.
24. Halcox JP, Nour KR, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol 2002; 40:1232–1240.
25 Ahn GJ, Yu JY, Choi SM, et al. Chronic administration of phosphodiesterase 5 inhibitor improves erectile and endothelial function in a rat model of diabetes. Int J Androl 2005; 28:260–266.
26 Rosano GM, Aversa A, Vitale C et al. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 2005; 47:214–220.
27. Aversa A, Greco E, Bruzziches R, et al. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res 2007; 19:200–207.
28. Gamidov S.I., Iremashvili V.V. The effect of type 5 phosphodiesterase inhibitors on the cardiovascular system. Diseases of the heart and blood vessels. 2006; #2: 55–58.

Phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction: state of the art | Krivoborodov G.G., Tur E.I., Efremov N.S.

Erection is a complex mechanism consisting of the interaction of reflex and hormonal processes. Erectile dysfunction (ED) is a persistent inability to achieve and maintain an erection sufficient to achieve a sense of satisfaction from sexual intercourse. According to one of the most authoritative studies (Massachusetts), the overall prevalence of ED in the United States among men aged 40 to 70 was 52%. ED is common throughout the world.

The etiology and pathogenesis of ED includes several components. There are 3 most common causes of ED: vasculogenic, neurogenic and hormonal. At the same time, vasculogenic disorders are more common due to cardiovascular diseases, diabetes mellitus (DM), hyperlipidemia, smoking and, as a result, iatrogenic damage to the vessels of the penis [1]. Since ED includes the same risk factors as vascular atherosclerosis, it may be an important marker of serious cardiovascular disease [2]. For this reason, patients being treated for ED should be screened for cardiovascular disease and, if necessary, receive cardiotropic therapy first.
The phenomenon of exacerbation of cardiovascular diseases associated with sexual activity is well studied [3]. Patients with ED who are at risk for cardiovascular disease can be divided into low, medium and high risk categories. This classification can be widely used in clinical practice to restore sexual activity in this category of patients.
Despite many effective treatments for ED, in most cases it cannot be completely cured. The exceptions are psychogenic ED, post-traumatic arteriogenic ED in young people, and ED caused by hormonal causes. Thus, in young patients with pelvic or perineal trauma, surgical penile revascularization has a long-term positive effect in 60–70% of cases [4].
Physiology of erectile function
Understanding the mechanism of erection is the key to choosing a treatment method. During sexual stimulation of the penis, a nerve impulse occurs in the erection center of the spinal cord, which is located at the S2–S4 level [5]. From there, along the efferent nerve fibers that are part of the pelvic nerve, it reaches the pelvic plexus. Later, along postganglionic non-adrenergic, non-cholinergic (NANC – nonadrenergic noncholinergic) nerve fibers, which are part of the cavernous nerves, the nerve impulse reaches the cavernous bodies of the penis [5]. As a result, nitric oxide is released in the terminals of the NANC fibers. The latter is also produced by cavernous body endothelial cells in response to the production of acetylcholine in parasympathetic endothelial nerve fibers. It has been established that nitric oxide of the nervous tissue initiates the process of erection through endothelial nitric oxide, which leads to increased production of the latter and, as a result, to maintaining a maximum erection [6]. An additional amount of nitric oxide is produced due to the tension that has arisen in the cavernous bodies after increased blood supply [5, 7].
At the molecular level, nitric oxide is produced by the enzyme NO-synthetase, which, interacting with L-arginine, releases nitric oxide. NO synthetase is found in nerve endings and endothelial cells. Nitric oxide penetrates through the membranes of smooth muscle cells of the cavernous sinuses and activates guanylate cyclase dissolved in the cytoplasm. The latter catalyzes the formation of cyclic guanosine monophosphate (cGMP) from intracellular guanosine triphosphate. cGMP activates protein kinase, promoting hyperpolarization of smooth muscle cell membranes, and increased consumption of calcium ions occurs in the membranes of the endoplasmic reticulum [5, 7]. Hyperpolarization of cell membranes leads to the closure of calcium channels, and calcium ions are concentrated inside the endoplasmic reticulum of smooth muscle cells, which leads to relaxation of the latter.
At the same time, other neurotransmitters, such as vasoactive intestinal peptide, prostaglandin E, interact with various smooth muscle receptors and increase the level of cyclic adenosine monophosphate (cAMP), which also leads to the accumulation of potassium ions in cells and their relaxation [5, 8]. Such relaxation of the smooth muscle cells of the arteries and arterioles entails an active blood filling of the cavernous sinuses in the systolic and diastolic phases. The cavernous sinuses remain dilated as long as blood flow continues [8]. Compression of the venous plexus, located between the albuginea and the cavernous sinuses, prevents the outflow of blood from the penis [9]. The tunica albuginea adapts to the stretching of the cavernous bodies, thereby additionally occluding the emissary veins between the internal circular and longitudinal veins [10].
The participation of androgens in the maintenance of erectile function consists in the regulation of the production and interaction of neurogenic and endothelial NO synthetases in the tissue of cavernous bodies [11]. Thus, it has been established that in elderly men, due to a decrease in testosterone levels, it is difficult to develop or maintain an erection [12]. The enzyme cGMP-specific phosphodiesterase (type 5) stops the conversion of cGMP from guanosine triphosphate, as well as the hyperpolarization of cell membranes, thereby inhibiting the relaxation of smooth muscle cells, causing detumescence [13]. Additional pressure also leads to contraction of the ischiocavernosus muscles due to somatic nerve stimulation. At this time, intracavernous pressure leads to an increase in systemic arterial pressure [10].
The parasympathetic mechanism for maintaining an erection is replaced by the activation of sympathetic nerve fibers. The sympathetic nerve center is localized at the level of Th5-L2, and its activation contributes to maintaining the penis in a “passive” state. This occurs due to the release of norepinephrine from nerve terminals, which interacts with α-adrenergic receptors of cavernous smooth muscle cells [5].
Norepinephrine, endothelin-1 and prostaglandin F2α activate smooth muscle cell receptors by increasing the levels of inositol triphosphate (ITP) and diaglycerol. The accumulation of these substances inside the cell contributes to the opening of the calcium channels of the endoplasmic reticulum and the accumulation of calcium inside the cell. Calcium ions interact with the calmodulin protein and activate myosin light chains, leading to contraction of smooth muscle cells and cessation of erection [5, 14, 15].
Medical treatment
Phosphodiesterase type 5 inhibitors (PDE-5) affect the relaxation of smooth muscle cells through competitive interaction with the PDE-5 enzyme. This enzyme is responsible for the breakdown of cGMP into 5′-GMP. PDE-5 inhibitors contribute to the accumulation of cGMP inside the smooth muscle cavernous cells, as well as in the cells of the smooth muscle layer of the arteries of the penis [7, 13, 16]. Relaxation of smooth muscle cells increases arterial blood flow, resulting in an erection. It is known that PDE-5 is one of 11 discovered PDEs in the human body [7]. PDE-5 maintains the physiological concentration of cGMP in the cavernous bodies of the penis. This explains the fact why PDE-5 is selective only in relation to erectile function and has no systemic effect [17].
The action of drugs – PDE-5 inhibitors is based on the interaction of nitric oxide with NO-synthetases of nerve endings and endothelium of the cavernous bodies. This is why these drugs are not as effective in patients with vascular disease when there is endothelial dysfunction or nitric oxide bioavailability is reduced, for example, as a result of damage to the nerve pathways or after radical prostatectomy [7, 13, 16].
According to the EAU guidelines, the choice of one of the approved PDE-5 inhibitors is largely a matter of patient preference. The doctor’s task is to provide complete information to the patient regarding PDE-5 inhibitors. The efficacy against ED and the safety of PDE-5 inhibitors have been proven to date. In the course of post-marketing studies, it was found that there is no relationship between an increase in the number of cardiovascular diseases and the use of PDE-5 inhibitors [18]. Although it is obvious that contraindications to taking PDE-5 inhibitors are unstable angina pectoris, recent myocardial infarction, persistent arrhythmias and malignant arterial hypertension. PDE-5 inhibitors are completely incompatible with the use of nitric oxide donators, given the risk of developing severe hypotension and vascular collapse.
One of the PDE-5 inhibitors is sildenafil. It is safe to say that sildenafil is the most studied drug treatment for ED. To date, there are 27 clinical studies on the efficacy and safety of this drug. In this article, we present separate, but authoritative from the point of view of evidence-based medicine, publications on the use of sildenafil in different categories of patients with ED.
Thus, already in 2002, a major meta-analysis of numerous data published by that time in the world literature was carried out [19]. The authors analyzed 27 clinical trials that included 6659 patients with ED. Studies comparing sildenafil and placebo confirm the significant effectiveness of the drug compared with placebo in improving erectile function. With regard to studies comparing different doses of sildenafil, it has been found that higher doses of the drug are slightly more effective. Significantly, sildenafil was not associated with the development of any serious cardiovascular disease or death.
An important category of patients with ED are patients after radical prostatectomy. Thus, according to Mulhall (2009), the prevalence of the disease among such patients ranges from 14 to 90%. These figures are certainly influenced by many factors, such as the age of the patient, the quality of erectile function before surgery, what kind of operation was performed (unilateral or bilateral nerve-sparing radical prostatectomy), and, of course, the experience of the surgeon. It is known that patients in most cases need to restore erectile function after radical surgery on the pelvic organs. The simplest way is to prescribe PDE-5 inhibitors. The mechanism of action of drugs in this case depends entirely on the presence of cGMP in the smooth muscle cells of arteries and cavernous bodies, as well as on the ability of endothelial cells to produce nitric oxide. The main link in the pathogenesis in this case is neuropraxia (damage to the cavernous nerve), so the ability to produce nitric oxide can be significantly reduced or completely lost.
In 2008 Bannowsy et al. published results of low-dose sildenafil in men undergoing radical nerve-sparing prostatectomy. 23 patients took 25 mg of sildenafil at night, and the control group received no medical treatment. In the group treated with sildenafil, the IIEP index decreased compared to preoperative from 20.8 to 3.6 (after 6 weeks of taking the drug) and then rose to 14.1 (after 52 weeks of taking the drug). In patients of the control group, the same index decreased from 21.2 to 2.4 (after 6 weeks), and then rose to 9,3 (after 52 weeks). Thus, the authors found a significant improvement in erectile function in patients who took sildenafil after radical prostatectomy, as well as a significant reduction in rehabilitation time in the postoperative period as a result of drug treatment [20].
In the same 2008, Padma-Nathan et al. published data from the first large-scale placebo-controlled study of the use of sildenafil in patients after radical nerve-sparing prostatectomy. The study included 76 men after 4 weeks. after surgical treatment. The participants were divided into 3 groups: group 1 received sildenafil at a dose of 50 mg, group 2 also received sildenafil, but at a dosage of 100 mg, and group 3 received placebo. The drug was taken daily at night for 36 weeks. Spontaneous nocturnal erections were noted in 4% of the placebo group and 27% of patients treated with sildenafil (p≤0.01). The researchers concluded that daily intake of sildenafil after surgical treatment contributes to the restoration of normal spontaneous erections [21].
There is also evidence that long-term use of PDE-5 inhibitors, in particular sildenafil, affects the restoration of endothelial function [22]. The study included 20 patients with type 2 diabetes without ED. Both groups initially received 100 mg of sildenafil for 3 days. Then the 1st group took 25 mg of sildenafil 3 times a day for 4 weeks. The 2nd group took 25 mg of sildenafil 3 times a day for 4 days, then switched to placebo. After 1 week after the start of the study, the penile blood flow FMD (flow mediated dilatation) was assessed. In all patients, it improved by more than 50% (by 62% in the 1st group and by 64% in the 2nd). In patients of the 1st group, further improvement in FMD was noted after 2, 3, and 4 weeks. (78, 86 and 94% respectively). In patients receiving placebo, no such changes were observed: 45, 18 and 6%, respectively. Also, in patients who took sildenafil for a long time, a decrease in endothelin 1 (a powerful vasoconstrictor factor) and a significant increase in nitrogen donors were found. The authors concluded that long-term use of sildenafil in patients with diabetes contributes to the restoration of endothelial function.
Currently, several drugs are known in the world – PDE-5 inhibitors, which have a number of features and differences. That is why a retrospective study published in 2005 in the United States is very important, on a comparative analysis of 3 drugs: sildenafil, vardenafil and tadalafil [23]. The study included 146,619patients who took these drugs between 1996 and 2004. The following parameters were analyzed: the need to continue taking the same drug with which treatment was started; changing the drug to another PDE-5 inhibitor; the possibility and convenience of dose titration. As a result, it was found that 52% of patients taking sildenafil considered it necessary to continue taking the same drug, in contrast to vardenafil and tadalafil (30 and 29%, respectively) (p<0.001). Fewer patients in the sildenafil group (6.4%) had a desire to switch to another drug compared to the tadalafil group (9.0%) and vardenafil (10.4%) (p<0.001). Given the fact that patients with ED are largely a heterogeneous population, the possibility of titrating the dose up or down to improve treatment outcomes is highly relevant. Certainly, these figures lead to a promising conclusion that sildenafil may best meet the needs of patients in the treatment of ED. For a more accurate and meaningful assessment, new randomized placebo-controlled trials in this direction are required.
In 2013, Tornetis was launched on the Russian market. This medication is a generic sildenafil. This drug has the same pharmacodynamic and pharmacokinetic parameters as the original sildenafil (Fig. 1). For this reason, there is no doubt that its efficacy and safety should be that of the well-known sildenafil. The ease of use of the drug is the possibility of multiple dose titration (25, 50, 75 and 100 mg). Tornetis is produced in the form of tablets of 100 mg. For ease of use, the tablet has special notches that allow you to divide it into 4 equal parts of 25 mg each, and choose a dose of 50 and 75 mg. Thus, the manufacturer, using such a simple original tablet design, solves the problem of dose titration. The patient receives Tornetis at a dose of 100 mg and has a chance to use all possible doses of sildenafil, namely 25, 50, 75 and 100 mg. From an economic point of view, due to the original possibility of dividing the tablets, Tornetis also has clear advantages.
Thus, drug therapy with PDE-5 inhibitors remains the main treatment for ED and provides proven high efficacy. The advent of Tornetis (sildenafil) with a new and simple dose selection solution simplifies our ability to effectively treat patients with ED.

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Literature
1. Feldman H. A., Goldstein I., Hatzichristou D.G., Krane R.J., McKinlay J.B. Impotence and its medical correlates: results of the Massacusetts Male Aging Study // About Urol. 1994 Vol. 151. R. 54-61.
2. Montorsi F., Briganti A., Salonia A. et al. Erectile dysfunction prevalence, time of oneset and association with risk factors in 300 consecutive patients with accute chest pain and angiographically documented coronary artery disease // Eur Urol. 2003 Vol. 44. R. 360-365.
3. Jackson J., Rosen R.C., Kloner R.A., Kostis J.B. The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine // J Sex Med. 2006 Vol. 3. R. 28–36.
4. Rao D.S., Donatucci C.F. Vasculogenic impotence. Arterial and venous surgery // Urol Clin North Am. 2001 Vol. 3. R. 28–36.
5. Steers W.D. Neural pathways and sentral sites involved in penile erection: neuroanatomy and clinical implications // Neurosci Biobehav Rev. 2000 Vol. 24. R. 507-516.
6. Hurt K.J., Musicki B. , Palese M.A. et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection // Proc Natl Acad Sci USA. 2002 Vol. 99. R. 4061-4066.
7. Burnett A.L., Ricker D.D., Chamness S.L. et al. Localization of nitric oxide synthase in the reproductive organs of the male rate // Biol Reprod. 1995 Vol. 52. R. 1–7.
8. Lue T.F. Erectile dysfunction // N Engl About Med. 2003 Vol. 342. R. 1802-1813.
9. Fournier Jr. G.R., Juenemann K.P., Lue T.F., Tanagho E.A. Mechanism of venous occlusion during canine penile erection: an anathomic demonstration // About Urol. 1987 Vol. 137. R. 163-167.
10. Wespes E., Schulman C.C. Study of human penile venous system and hypothesis on its behavior during erection // Urology. 1990 Vol. 36. R. 68–72.
11. Martin R., Escrig A., Abreu P., Mass M. Androgen-dependent nitric oxide release in rat penis correlated with levels of constitutive nitric oxide synthase isoenzymes // Biol Reprod. 1999 Vol. 61. R. 1012-1016.
12. Pinsky M.R., Hellstrom W.J. Hypogonadism, ADAM and hormone replacement // Ther Adv Urol. 2010 Vol. 2. R. 99–104.
13. Carson C.C., Lue T.F. Phosphodiesterase type 5 inhibitors for erectile dysfunction // Br O Urol Int. 2005 Vol. 96. R. 257-280.
14. Dean R.C., Lue T.F. Physiology of penile erection and pathophysiology of erectile dysfunction // Urol Clin North Am. 2005 Vol. 32. R. 379-395.
15. Andersson K.-E., Nehra A., Lue T., Burnett A., Goldstein I., Morales A. Erectile physiological and pathophysiological pathways involved in erectile dysfunction // O Urol. 2003 Vol. 170. R. 6–14.
16. Bivalacqua T.J., Champion H.C., Hellstrom W.J.G., Kadowitz P.J. Pharmacotherapy for erectile dysfunction // Trends Pharmacol Sci. 2000 Vol. 21. R. 484-489.
17. Gopal V.K., Francis S.H., Corbin J.D. Allosteric sites of phosphodiesterase-5 (PDE5). A potential role of cGMP signaling in corpus cavernosum // Eur O Biochem. 2001 Vol. 268. R. 3304-3312.
18. Patterson D.