New in the treatment of erectile dysfunction. PDE5 inhibitors (cGMP-specific PDE5 inhibitors)

The article will talk about PDE-5 inhibitor drugs. It is known that due to erectile dysfunction, the work of other organs and systems is not disturbed, it does not harm the health and life of a man, but such a sexual disorder is very difficult to perceive from a psycho-emotional point of view. A man has to worry about the quality of erection and potency for almost his entire adult life, even if there are no visible reasons for concern.

Currently, there are a large number of natural remedies that help prevent erectile disorders, and strong erection stimulants for complete dysfunction. The most effective are PDE-5 inhibitors, or type 5 phosphodiesterase inhibitors, which provide a man with a 100% erection, regardless of the etiology of the disorder and its severity.

What are the causes of erectile dysfunction?

If earlier the main causes of erectile dysfunction were considered to be various psychological problems, now the opinion has changed. It is now known that the violation in 80% of cases is of organic origin and appears as a complication of various somatic diseases.

The main organic causes: hypogonadism (dyshormonal conditions); angiopathy; neuropathy.

The prevalence of pathology of the heart and blood vessels is very high, more than 50% of the stronger sex with such diseases have erectile dysfunction, but not every patient uses PDE-5 inhibitors - a kind of "gold standard" in the treatment of sexual dysfunction. Why is it so? Unfortunately, up to the present time, patients are extremely wary of such drugs, despite the fact that their effectiveness has already been proven.

General therapeutic principles

Before selecting tablet type 5 phosphodiesterase inhibitors for the treatment of disorders of the reproductive system, each man must determine the mental and somatic prerequisites for such disorders. The following factors can affect erection:

• the presence in the body of concomitant systemic pathologies;
• the use of drugs of strong action;
• lifestyle (bad habits, passive pastime, overeating);
• frequent depression and stress.

Help from a specialist

If, after the elimination of such prerequisites for dysfunction, the violation does not go away, you can first use the help of a sexologist or psychotherapist. A conservative treatment method can be a correction of nutrition, playing sports, giving up addictions, losing weight, eliminating stressful situations that lead to depression. Among other things, an erection can be restored by treating the underlying disease, such as hormonal disorders, diabetes, etc.

What does the treatment involve?

Medical treatment involves:

• the use of tablets sublingually and orally;
• injections into the urethra or cavernous bodies of vasoactive drugs.

The use of alpha-1 blockers or PDE5 inhibitors shortly before intercourse may also help to achieve a stable erection.

special instructions

It should be noted that you can take such medications only after consulting a doctor. He will determine the dosage acceptable in each case, since if used irrationally, the drug may be ineffective or cause side effects.

Appropriateness of application

The use of PDE-5 inhibitors is advisable, this is proved by the following facts:

• such drugs represent an adapted first-line treatment;
• the use of such funds continues for more than 30 years;
• repeated clinical trials have proven their effectiveness;
• drugs are easy to use;
• in practice, millions of men have proven the safety of such funds.

Instructions for the use of drugs

Currently, the most popular drugs in the treatment of erectile dysfunction are phosphodiesterase type 5 inhibitors, which have valuable pharmacokinetic properties, are clinically effective and relatively harmless.

Pharmaceutical companies produce a large number of drugs that stimulate erection. PDE-5 inhibitors include the following drugs.

Sildenafil. It is also a selective PDE5 inhibitor, which was first produced in 1996. Film-coated almost white or white round tablets, biconvex, with an almost white or white core on a cross section.

The active ingredient is sildenafil nitrate, in one tablet - 28.09 mg, which corresponds to 20 mg of sildenafil. Auxiliary components: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate.

The film shell contains talc, hypromellose, titanium dioxide, polyethylene glycol 4000 (macrogol 4000).

The tablet should be taken one hour before intimate intercourse, the approximate daily dosage ranges from 50 to 100 mg. The effect of the drug persists for four hours.

The drug-inhibitor of phosphodiesterase type 5 "Vardenafil". It is an advanced and new highly selective inhibitor that has been proven to be highly effective in biological equivalents in multiple clinical studies (in the form of monohydrochloride trihydrate).

Such a drug is taken once a day thirty minutes before intimacy, its effect lasts 4-5 hours. The daily dosage is approximately 10-20 mg of vardenafil.

The drug "Tadalafil" is a selective inhibitor that has been sold since recently, but it is highly effective in restoring erectile dysfunction. "Tadalafil" is currently produced in the form of tablets, in which the active ingredient contains 2.5; 5; 20 and 40 mg. As an active active element, the drug "Tadalafil" includes a chemical substance of the same name. In the form of excipients, the preparation contains the following components: giproloza; lactose; croscarmellose sodium; microcrystalline cellulose; magnesium stearate; sodium lauryl sulfate; titanium dioxide; triacetin.

The principle of action and structure are somewhat different from Sildenafil, its selectivity is less than that of the first agent. The effectiveness of the composition of the tablets lasts 36 hours. The drug should be taken in an amount of 10-20 mg shortly before intimacy. In addition, such a remedy is allowed to be combined with alcohol and food, which is an indisputable advantage for patients.

"Udenafil". A modern reversible selective inhibitor that makes it easy for a man to achieve an erection. Tablets should be taken 30-90 minutes before possible sexual contact, and its effect will last for 12 hours. It is very important to comply with all the conditions that are specified in the instructions, since drugs of this type have contraindications and side effects.

Avanafil. The next representative of the group of PDE-5 inhibitors, which also promotes vasodilation and allows blood to flow to the intimate organs more easily, providing an erection by 100%. The tablets contain avanafil as an active ingredient. The composition of the drug also includes mannitol, hydroxypropylcellulose, calcium carbonate, iron oxide and magnesium stearate.

The medicine should not be taken if there is an allergic reaction to at least one of the components listed above. The therapeutic efficacy of the drug is 80%, the tablet must be taken 15-20 minutes before the upcoming sexual contact. The effectiveness of the drug lasts for six hours, it can be combined with alcohol and food. In this case, the average dosage is approximately 100 mg per day.

What can be achieved?

It is worth noting that most drugs of this type to stimulate erectile function allow for vascular expansion, muscle relaxation, and thanks to this, it will be much easier to achieve an erection.

Before taking the above drugs in the form of tablets that restore erectile function, each man should be consulted regarding the optimal dosage of a particular inhibitor, since an overdose can cause significant side effects.

Contraindications for taking PDE-5 inhibitors

It is known that drugs with synthetic components in any case have a well-defined list of contraindications and can cause a number of side effects. The same can be said about PDE-5 inhibitors, which are contraindicated in the following situations:

• the person has not reached the age of majority;
• hypersensitivity to components;
• parallel use of tablets containing organic nitrates;
• violations and pathologies of the functionality of the heart and blood vessels, in which increased sexual activity is unacceptable;
• taking "Doxazosin" and other drugs for erection;
• loss of vision in anterior non-arterial ischemic optic neuropathy;
• chronic kidney failure and the use of such stimulants more than twice a week;
• alabsorption, lactase deficiency or lactose intolerance;
• glucose-galactose malabsorption.

Side effects

The most typical undesirable effects of the irrational use of type 5 phosphodiesterase inhibitors are vomiting, nausea, headaches, visual disturbances (light perception and lack of concentration), dizziness, rhinitis and swelling of the nose, shortness of breath, redness of the face. If these symptoms occur, you should consult a doctor.

Interaction of "Trazodone" and inhibitors of phosphodiesterase type 5

Trazodone is a selective serotonin reuptake inhibitor, it also blocks 5-HT2A receptors and moderately inhibits serotonin reuptake.

"Trazodone" can be used both as a separate treatment course and in combination with other drugs for getting rid of erectile dysfunction, including androgens and type 5 phosphodiesterase inhibitors, that is, they are combined with each other, their interaction is effective.

Over the past 20 years, significant progress has been made in understanding the physiology of erection, the penis, which has led to the greatest advances in the pharmacological treatment of ED through the use of PDE-5 inhibitor drugs.

Sildenafil

The first among them was sildenafil citrate (Viagra), which opened a new era in the treatment of ED - the era of effective oral treatment. Viagra meets the basic requirements for ED therapy: efficiency up to 85%, reliability, ease of use, non-invasiveness, and a small number of side effects. Moreover, Viagra has led to a new qualitative leap in the attitude of patients to the treatment of ED, increased activity in the desire to treat this disease.

At the same time, a short half-life, as well as the dependence of the drug on food intake, leads to the need for a pre-planned sexual intercourse, loss of romance and spontaneity of sexual activity, limitation in time and frequency of sexual attempts. In addition, despite the high efficacy of sildenafil (58-85%), there remains a small proportion of patients (15-42%) in whom therapy with this drug is ineffective or ineffective.

All of the above dictated the need to continue the search for more advanced drugs, which led to the creation of new PDE-5 inhibitors.

In 2002-2003 two new drugs belonging to the group PDE-5 inhibitors - tadalafil (Cialis, Eli Lilly) and vardenafil (Levitra, Bayer). The features of their pharmacodynamics and selective effect on various types of PDEs were designed to neutralize those negative aspects that limited the use of sildenafil.

Tadalafil

So tadalafil has a number of unique properties. One of the main advantages of tadalafil is a long half-life (17.5 hours) and, accordingly, its prolonged action (36 hours or more). In turn, the patient is not subjected to temporary pressure, which leads to the choice of a convenient mode of sexual activity, and most importantly, the patient is freed from psychological dependence on taking the drug. In addition, the effect of tadalafil does not depend on food intake or alcohol.

Currently, 11 types of PDE isoenzymes have been described, which, in turn, are divided into 21 subtypes. PDE isoenzymes play an important role in the contraction of smooth and striated muscles, regulation of vascular tone, the function of endocrine and other organs.

Vardenafil

A new representative of PDE-5 inhibitors - drug vardenafil highly effective and most potent PDE-5 inhibitor for the treatment of ED. When comparing pharmacodynamic parameters, it turned out that vardenafil has the highest in vitro activity and selectivity of influence on PDE-5. Vardenafil also has less effect than sildenafil and tadalafil on PDE-6, an isoenzyme contained in the retina, blocking which causes color vision disorders, and on PDE-11, contained in the testicles.

Obviously, the high activity of vardenafil in relation to the PDE-5 isoenzyme determines the main pharmacological effect of this drug - relaxation of the smooth muscles of the vessels of the cavernous body, while its weak activity in relation to other isoenzymes - PDE-1 - PDE-4 and PDE-6 -PDE-11 types - will determine the low spectrum of side effects, as well as its best tolerability.

Features of various PDE-5 inhibitors

The pharmacokinetic features of various PDE-5 inhibitors are of great clinical importance. The distribution of these drugs in the body can be estimated based on several parameters shown in table. one.

Table 1.

Pharmacokinetic parameters of various PDE-5 inhibitors.

An important characteristic of any pharmacological drug is its side effects. The most common side effects of PDE-5 inhibitors include headache, facial flushing, dizziness, dyspepsia, nasal congestion, and visual disturbances (Table 2).

Table 2.

Main side effects of PDE-5 inhibitors

It should be noted that at sildenafil these side effects are more pronounced than other drugs in this group.

Adverse effects of all PDE-5 inhibitors are usually short-lived and tend to spontaneous regression, their duration is usually less than the duration of the therapeutic effect of drugs due to a lower concentration of PDE-5 in non-cavernous tissue and rapid adaptation of the body to a secondary effect. However, in extremely rare cases, in some patients, the duration of side effects may coincide with the duration of the therapeutic effect.

As is known, the mechanism of action of PDE-5 inhibitors is associated with limiting the breakdown of cyclic guanosine monophosphate (cGMP), which helps to relax the smooth muscle tissue of the cavernous bodies of the penis and develop an erection. Since the synthesis of cGMP is carried out as a result of exposure to NO secreted by endothelial cells and non-cholinergic non-adrenergic nerve endings, the use of PDE-5 inhibitors enhances the effect of NO. Thus, when studying endothelial function during the action of a PDE-5 inhibitor, one can evaluate its effect on the effects of endothelial NO released on smooth muscle cells, which plays a key role in the development and maintenance of penile erection.

PDE-5 inhibitors have demonstrated good efficacy and safety in numerous clinical trials, as evidenced by their widespread use as first-line therapy for men with ED.

Interesting are the first results of comparative studies of various PDE-5 inhibitors with an assessment of patient preferences. In the study by Sommer F. (2004), patients who had not previously received treatment with PDE-5 inhibitors were randomly assigned to one of the groups after a 4-week washout period: sildenafil 50 or 100 mg, vardenafil 10 or 20 mg, tadalafil 10 or 20 mg , placebo. After 6 weeks of therapy with one drug, patients were switched to another treatment regimen in accordance with the study protocol (cross-over design). The IIEF scale was used to assess the effectiveness. All drugs were found to improve erectile function compared to placebo, but no significant differences were found between them. At the same time, an analysis of patient preferences showed that when comparing drugs at maximum doses, 18% of the study subjects preferred sildenafil at a dose of 100 mg (group 1), 40% preferred tadalafil at a dose of 20 mg (group 2) and 43% preferred vardenafil at a dose of 20 mg. mg (group 3). Accordingly, 34% of patients preferred sildenafil 50 mg (group 4), 19% preferred tadalafil 10 mg (group 5) and 47% preferred vardenafil 10 mg (group 6).

According to an independent study conducted by H.Porst et al., which involved 150 patients with ED, including 24 (15%) previously untreated and 126 (85%) who constantly took sildenafil. All patients were recommended to consecutively take at least 6 tablets of each PDE-5 inhibitor (sildenafil, tadalafil or vardenafil). prolonged action).

In a double-blind study P. Govier et al. the preferences of previously untreated patients were assessed. Sildenafil and tadalafil were administered consecutively for 4 weeks. At the end of the study, 66% of patients chose tadalafil and 34% sildenafil for continued treatment.

In a study by Claes H. et al. 91 patients with ED who previously regularly took sildenafil citrate took part - each of them took at least 4 times tadalafil or vardenafil. The effectiveness of all three drugs was comparable; 19 patients chose to switch to new drugs (tadalafil or vardenafil), mainly because of better tolerability.

Preferences in patients not previously treated with PDE-5 inhibitors were studied by Eardley I. et al. in a double-blind study. Sildenafil and tadalafil were administered consecutively for 4 weeks. At the end of the study, 71% of patients opted for tadalafil and 29% for sildenafil for continued treatment.

The ability of PDE-5 inhibitors to influence the vascular endothelium has been shown in a number of experimental and placebo-controlled studies.

From this point of view, the most well-studied drug is 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, coronary artery disease and smokers.

In turn, Desouza C et al. conducted a double-blind, placebo-controlled cross-over study in 14" men with type 2 diabetes and ED. The effect of acute and two-week treatment with low doses of sildenafil (25 mg) on ​​endothelial function was evaluated. Compared with placebo, sildenafil was shown to improve endothelium-dependent vasodilation by 5-7%.

Later Gori T. et al. clarified the mechanism of improvement of endothelial function. They conducted a double-blind, placebo-controlled cross-over study in 10 healthy volunteers (age 25-45) receiving sildenafil 50 mg or placebo. Sildenafil (2 hours post-dose) improved endothelial function compared to placebo. In a separate protocol, this protective effect was blocked by pretreatment with the sulfonylurea glibenclamide (glyburide, 5 ml), which blocked the activity of potassium channels (n=7; before the test: 10.3±1.5%; after: 1.3±1.4%, P<0.05). Таким образом, авторы предположили,что силденафил уменьшает проявления эндотелиальной дисфункции за счет открытия калиевых каналов .

Sildenafil is also able to reverse smoking-induced short-term deterioration in endothelial function. 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 antiaggregant effect.

The favorable effect of another PDE-5 inhibitor, vardenafil, on the hemodynamics of the genital organs was noted in the work of domestic authors. Alyaev Yu.G. et al. using dopplerography, an increase in blood flow in the vessels of the genital organs (testicles, prostate gland, penis) was confirmed both after a single and course intake of vardenafil. The same authors concluded that long-term use of vardenafil leads to a decrease in the incidence of ED after transurethral resection of the prostate, and is accompanied by an improvement in hemodynamics in the vessels of the penis.

According to the results of a previous study in our clinic, data were obtained confirming the improvement in the endothelial function of the cavernous and brachial arteries after a single dose of vardenafil. The most pronounced effect of vardenafil on the cavernous and brachial arteries was found in patients with arteriogenic ED, who initially had a significant decrease in systemic endothelial function.

Of practical interest is also an experimental study on rats by Teixeira et al., who showed that sensitivity to endothelium is highest in vardenafil (250 times), sildenafil (45 times), tadalafil (21 times).

At the same time, Dishy et al. in 2001 described conflicting data on the effectiveness of the effect of oral administration of sildenafil on the endothelial function of the brachial arteries in healthy men, there were no significant differences when comparing the indicators obtained before and after taking the drug.

All the same scientists already in 2004, in studies that studied the effect of oral administration of sildenafil on the endothelial function of the brachial arteries in healthy men and smokers, did not reveal significant differences when comparing the indicators obtained before and after taking the drug.

At the same time, British scientists in the course of a pilot crossover study, which involved 16 male patients with coronary artery disease and 8 healthy men as controls, questioned the ability of sildenafil to completely change systemic vascular dysfunction. According to them, sildenafil increased endothelium-independent vasodilation in response to intrabronchial administration of sodium nitroprusside, but had no effect on endothelium-dependent vasodilation when taking acetylcholine or verapamil.

These findings cast doubt on the results of previous studies on the successful use of PDE-5 inhibitors in the correction of endothelial dysfunction.

Thus, all three PDE-5 inhibitors are highly effective and safe agents for the treatment of erectile dysfunction.

However, they have certain differences in efficacy and tolerability, which can vary quite individually in different patients. In the absence of clear medical criteria for choosing a drug, it is quite difficult to assess the influence of one or another factor on the preferences of a particular patient. Of interest are the first results of comparative studies of various PDE-5 inhibitors with an assessment of patient preferences.

Gasanov R.V. Influence of Regulatory Administration of Type 5 Phosphodiesterase Inhibitors on Erectile and Endothelial Functions in Patients with Arteriogenic Erectile Dysfunction

Creation date: 02/14/2017

Last modified date: 02/22/2017

PDE-5 inhibitors on the example of drugs such as Viagra, Levitra and Cialis

Sildenafil (Viagra) was approved for sale by the FDA in 1998. This substance made a breakthrough in the practice of treating erectile dysfunction. It has become incredibly popular due to its efficiency and ease of use. In 2003, the FDA approved two more active ingredients - Vardenafil (Levitra) and Tadalafil (Cialis). After 5 years (in January 2008), Cialis appeared on the market with a reduced dose of the active substance. This drug is intended for daily use. It allows (at least in theory) to have sex at any time without prior planning.

All three drugs work on the same principle, affecting the physiology of the penis. The active substances contained in them block the PDE-5 enzyme, which destroys the cyclic guanosine monophosphate necessary for erection. Thanks to this, the penis is filled with blood and is in a state of erection for as long as necessary for successful sexual intercourse.

It is important to understand that none of the listed drugs is an aphrodisiac. In order for them to begin to act and cause an erection, sexual stimulation is needed. The differences between them are in the speed and duration of the effect (Table 1). Cialis lasts the longest for daily use, which maintains a constant amount of the active substance in the blood. Then comes Cialis in the standard dosage, Levitra and Viagra.

Among the tablets that are not intended for daily use, it is worth noting Levitra. This medicine begins to act somewhat faster than Viagra (within half an hour). However, the FDA recommends taking both drugs about an hour before sexual activity.

There is evidence that Levitra can help men who do not respond to Viagra. Some doctors are skeptical of such claims. But there will be no harm if a man tries all three drugs in turn to evaluate their effect.

Cialis works longer than other drugs. If "Viagra" and "Levitra" remain active within 4-5 hours (sometimes up to 12 hours), then Cialis makes it possible not to worry about potency for 24-36 hours. Therefore, it is called the "medicine for the whole weekend." The goal of taking a daily low dose remedy is to always be ready for sex. There is another advantage

"Cialis" and "Levitra" before "Viagra" - they can be taken even after a dense meal with a high fat content.

Efficiency

Among the three drugs for the treatment of impotence, Viagra has been on the market for the longest time. Therefore, it is the most studied. In a large study involving 6659 men, Viagra helped 83% of men have sexual intercourse (at least 1 time). On the other hand, this drug cannot be called a panacea. Efficiency

The Journal of Urology published the results of a study conducted in 2001. This time, Viagra showed more modest results. Scientists have found that the drug contributed to the successful completion of sexual intercourse in 69% of cases. The efficiency indicators for Levitra and 36-hour Cialis were at the level of 59% and 69%, respectively. Least information about Cialis daily tablets. We are aware of data from only one study in which it was found that the effectiveness of the drug depends on the dosage (2.5 or 5 mg) and the severity of erectile dysfunction:

severe ED - efficiency ranging from 27% (2.5 mg) to 33% (5 mg);

the average degree of ED is from 56% (2.5 mg) to 61% (5 mg);

mild ED - from 73% (2.5 mg) to 82% (5 mg).

It is also worth noting that in the placebo group, the effectiveness was 57% (mild ED), 27% (moderate ED) and 9% (severe ED).

It has been established that Viagra can help men who develop erectile dysfunction as a result of spinal cord injury. The drug helps them in 83% of cases. In people with diabetes and cardiovascular disease, the efficiency was even lower - about 50%. In the case of radical prostatectomy, Viagra helps in 30% of cases.

Erectile dysfunction from an individual perspective

Erectile dysfunction lies not only in the plane of psychological and medical problems. People who do not have permanent partners also want to be sexually active. They face a number of their own questions and problems.

If you find yourself in their situation, you will be faced with the question of what to tell a new sexual partner, and what is better to remain silent. There is no single answer to this question. It all depends on how willing you are to admit your sexual problems, as well as on the method of therapy used. For example, a pill can be taken discreetly, and other ways to achieve an erection cannot be hidden.

If the treatment was successful, you can not tell your partner anything about erectile dysfunction, even if you are going to establish a permanent relationship. If problems arise from time to time, we can discuss them together. Moreover, it is better to do this not during intimacy, but in the process of a calm conversation.

Tell your partner about your condition, as well as about the causes of the disease that you know. If you are considering treatment, discuss possible therapies. Do not hide anything from your partner and try to answer all her questions. When it's time for sexual intimacy, take your time. You may find that after calmly discussing the problem together, the condition has improved.

Side effects

Side effects after taking all three drugs are about the same. The principle of action of these drugs is to relax smooth muscles and dilate blood vessels (mainly in the penis, but also throughout the body). The most common side effect is headache, which occurs in 16% of men (Fig. 1). Among other reactions of the body, redness of the face, indigestion, nasal congestion, inflammation of the urinary tract can be noted. But if you take the medicines according to the instructions, the side effects go away in a rather mild form and disappear after a few hours. In rare cases, some men experience temporary mild visual disturbances. This is mainly expressed in an excess of blue. But excessive photosensitivity and defocusing may also appear. Men with retinitis pigmentosa (a rare eye disease) should use these medicines with caution.

In 2005, data appeared on the effect of Viagra on another rare eye disease (ischemic optic neuropathy), which can lead to complete blindness. True, in 2006 only 50 such cases were registered. This is not much compared to the millions of cases where the drug has helped cure erectile dysfunction. To avoid problems, men over 50 years of age should regularly undergo examinations by an ophthalmologist and report to the doctor about any suspicious cases with a change in visual function after taking a PDE-5 inhibitor.

Another rare side effect that has been documented is sudden hearing loss. In 2007, the FDA issued a statement that this reaction is almost always irreversible. Temporary hearing loss was observed in only ⅓ of cases.

Interaction with other drugs

Within a few hours after taking a medicine containing a PDE-5 inhibitor, there is a tendency for a drop in blood pressure. Systolic (upper) pressure may drop by 8-10 mmHg. Diastolic (lower) pressure drops by 5-6

mmHg. Therefore, it is very important to avoid the simultaneous use of PDE-5 inhibitors and nitrate-containing drugs, because. the latter also lower the pressure. Combining these two types of drugs can lead to life-threatening low blood pressure (nitrates and nitrites found in food are not taken into account). Do not take drugs with PDE-5 inhibitors if long-acting nitrate-containing drugs are used:

isosorbide dinitrate (Isordil, Sorbitrate, etc.);

isosorbide mononitrate (Imdur, Ismo, etc.);

patch or paste with nitroglycerin.

Men taking so-called alpha-blockers should be wary of PDE-5 inhibitors. These are medicines that include doxazosin (Cardura), terazosin (Hytrin), or tamsulosin (Flomax). These substances are used to treat prostatic hyperplasia and high blood pressure. If you are taking alpha blockers, check with your doctor before using a PDE5 inhibitor. For example, Viagra should not be used for at least 4 hours after taking an alpha blocker.

Another widely used drug, cimetidine (Tagamet), interacts with PDE-5 inhibitors. It is used to treat severe heartburn and stomach ulcers. "Tagamet" slows down the decay of "Viagra", "Levitra" and "Cialis". This can lead to a doubling of the blood levels of Sildenafil, Vardenpfil and Tadalafil. Therefore, people taking cimetidine should start with reduced doses of PDE-5 inhibitors. There are no data on the interaction of these drugs. But the likelihood of side effects may increase.

Should I take erectile dysfunction medication daily?

Cialis is available in a version for daily use. This allows you to maintain a continuous effect. If you are considering taking a daily medication, discuss it with your doctor and answer the following questions:

How often do you have sex? If you have intercourse twice a week or more, it would be wise to keep your blood levels of the drug constant.

How important is spontaneity to you in having sex? Taking the pill daily, you will always be ready for intimacy if this form of medicine works for you (low dose of the active substance is not effective for all men). The usual "Cialis", not intended for daily intake, is valid until 36 hours. Most often, this time is enough to have spontaneous sexual intercourse.

How important is the cost of medication to you? The manufacturer claims that a monthly supply of daily Cialis costs the same as 8 tablets of the standard form of the drug. In reality, the situation may be different. Compare the prices of both versions of the drug.

Are you taking other medicines? Men who take nitrate-containing drugs are contraindicated in PDE-5 inhibitors. In any case, it is better to consult a doctor. It is possible that the drug you are taking also interacts with PDE-5 inhibitors. It can be a blood pressure lowering drug, an alpha blocker, an antifungal drug, an HIV drug.

Have you experienced side effects after taking medication for erectile dysfunction? Daily intake of tablets with a reduced amount of the active substance can help get rid of side effects. True, the effectiveness of the tool may also decrease. The most common side effects are headache, dyspepsia, back and muscle pain.

• How often do you drink alcohol? Constantly getting drunk to the point of intoxication is in any case unhealthy. You need to be especially careful when taking Cialis daily. In people who abuse alcohol, the drug can cause a dangerous drop in blood pressure. Of course, this is also true for the usual form of the drug. But the standard Cialis does not work constantly, but for 36 hours. Therefore, in this case, the problem does not cause strong concern.

At the time of writing, Cialis is the only drug available in a daily form. The initial dose is 2.5 mg Tadalafil. If it was ineffective, it can be increased to 5 mg. Taking part of a Levitra or Viagra tablet daily, divided to reduce the dose, can be an ill-advised move. At the moment there are no

data on the safety and efficacy of these drugs when taken daily.

What else to pay attention to?

PDE-5 inhibitors are quite expensive (about $15-20 per tablet). But you can find health insurance that covers these costs. True, usually insurance companies cover the cost of a maximum of four pills per month. But the high price is not the only problem that can arise as a result of taking PDE-5 inhibitors.

Some partners who have lived with each other for quite some time begin to feel quite comfortable without sex. If the treatment is successful, the relationship will have to be rebuilt. In addition, whether your partner will perceive your message to start taking medication as pressure and inducement to have more frequent sex. Will your partner be in the right mindset at the time you take the pill? The best way to answer these questions is to discuss them with a partner. This is especially important when you are in the relationship phase. Your partner must know that you are taking or intend to take potency medication.

What medicine is the bestseller?

The pioneer of the drug market for erectile dysfunction was Viagra, the production of which began in 1998. For 5 years, it has maintained leadership in the total sales of various drugs to combat impotence. During this time, Viagra managed to collect a huge number of loyal consumers and develop trust in the brand. Therefore, in 2003, when competitors appeared on the market, Viagra remained the most popular drug. Currently, it maintains leadership in terms of sales. But the increase in sales is slower than that of Cialis, which has come close to the leader.

In 2009 and 2010, there was a decrease in sales of Viagra by 2%. At the same time, Cialis sales grew by 8% (2009) and 9% (2010). Part of this success is due to an aggressive marketing campaign, thanks to which the name of the drug "Cialis" has become a household name (like "Viagra"). But two other factors had a much more important influence on the popularity of the drug. First, Cialis is the only remedy that has a daily version. Secondly, the drug has a longer period of action (24-36 hours versus 4-5 hours for Viagra and Levitra).

On fig. 2 shows the sales volumes of all three drugs worldwide. In 2010, Viagra was sold for $1934000000 and Cialis for $1699000000. Levitra is far behind the leaders. Its sales volumes are indicated in euros. In 2010, this drug was sold for 429,000,000 €.

Rice. 2. Annual sales of Viagra, Cialis and Levitra

We can say that the monopoly of "Viagra" in the market is over. Gradually, Cialis rises to the throne.

A.V. Sivkov, N.G. Keshishev, G.A. Kovchenko
Research Institute of Urology of the Ministry of Health and Social Development, Moscow

Benign prostatic hyperplasia (BPH) is one of the most common diseases in older men. Epidemiological studies conducted in our country indicate a gradual increase in the incidence of BPH from 11.3% at the age of 40-49 to 81.4% at the age of 80 years. Diagnosis and treatment of BPH is not only a serious medical but also a major social problem.

In recent decades, drug treatment has become so effective that in most patients the question of surgical treatment is postponed indefinitely. Surgical treatment is performed in no more than 30% of cases. The need to find a better treatment for lower urinary tract symptoms (LUTS) caused by BPH is also undeniable.

Epidemiological evidence indicates an association between LUTS and erectile dysfunction (ED), as well as the efficacy of phosphodiesterase type 5 (PDE-5) inhibitors in the treatment of lower urinary tract symptoms.

One of the first large-scale scientific studies involving 5894 men was carried out by Lukacs et al. . Based on the results of this study, a conclusion was made about the relationship of erectile dysfunction with LUTS caused by BPH.

According to the results of a survey in Cologne of 5,000 men aged 30 to 80 years, it was found that the combination of LUTS and ED was noted in 72.2% and only 27.7% of men had LUTS without ED.

However, the pathogenesis of the relationship between ED and LUTS has not yet been fully elucidated. Currently, there are four possible pathophysiological theories confirming this relationship: the theory of a decrease in the synthesis of nitric oxide (NO) in the endothelium of the pelvic organs, the theory of metabolic syndrome and autonomic hyperactivity (AH), the theory of an increase in Rho-kinase activity, and the theory of atherosclerosis of small pelvic vessels.

The theory of reducing the formation of no in the endothelium

The role of cyclic guanosine monophosphate (cGMP) in relaxing the smooth muscles of the cavernous bodies is well known. Rapid relaxation of the muscle fibers of the cavernous bodies is initiated by neurogenic and endothelial NO, which is involved in maintaining smooth muscle relaxation. NO diffuses into vascular smooth muscle cells and combines with guanylate cyclase (GC), resulting in an increase in the activity of this enzyme. This leads to increased production of cGMP, which in turn activates a protein kinase that phosphorylates several different proteins, leading to a decrease in intracellular Ca2+. The result of the described process is the relaxation of smooth muscle cells.

NO affects the process of urination by inhibiting neurotransmission to the urethral and vesical afferent fibers. NO has also been found to be involved in prostate smooth muscle tone, glandular secretion, and blood flow. Numerous studies indicate the presence of NO and phosphodiesterase in the lower urinary tract, including the prostate, bladder, and urethra. So Richter et al. and Bloch et al. revealed endothelial NO in the vascular zone of the prostate, neurogenic NO in the nerve fibers of the fibromuscular stroma. Burnett et al. proved the presence of neurogenic NO in the nerve fibers of the transition zone of the prostate.

Uckert et al. and Werkström et al. pointed to the presence of PDE-5 type isoforms in the smooth muscles of the urethra and blood vessels, as well as to the relaxation of these muscles when exposed to PDE-5 type.

In their research, Gillespie et al. found subepithelial neurogenic NO in the nerve fibers of the interstitial space of the bladder walls. These nerve fibers produce cGMP, which is involved in the relaxation of smooth muscle cells. Based on the results of the study, the authors put forward a hypothesis that it is possible that it is at this level that the PDE-5 type has an effect on the bladder.

T Theory of metabolic syndrome and autonomic hyperactivity (AH)

Epidemiological data indicate that LUTS may be due to the metabolic syndrome, which includes hyperglycemia, obesity, hyperlipidemia, and hypertension. These factors are also known to increase the risk of developing ED. Hypertension is an additional component of the metabolic syndrome, including dysregulation of parasympathetic and sympathetic tone.

Violation of the erection of the penis is due to the increased tone of the sympathetic system. This statement was confirmed in rats, in which increased sympathetic tone was deliberately modeled.

Studies confirm that the development of BPH and ED with overactive bladder, frequent urination in "older" rats is due to an increase in the activity of the autonomic nervous system, hyperlipidemia, and overnutrition. When observed by McVary et al. in 38 patients, hypertension was found to lead to LUTS. In their research, Hale et al. proved that the treatment of hypertension in rats contributed to the improvement of erectile function.

Increase in rho-kinase activity

The level of intercellular calcium provides smooth muscle contraction, however, the contraction of muscle fibers with the participation of Rho-kinase provides muscle contraction that is independent of the level of calcium. This explains the presence of a Ca2+-independent mechanism in the contraction of smooth muscle cells of the lower urinary tract. Rees et al. concluded that in human endothelial cells, a cascade of reactions involving Rho-kinase leads to a decrease in NO activity, which subsequently contributes to the inhibition of smooth muscle relaxation with the onset of LUTS.

Scientific studies report increased Rhokinase activity in prostate tissue in hypertensive rats. Increased activity of Rho-kinase is also noted in individuals suffering from diabetes and hypertension. Studies indicate that Rho-kinase influences a number of factors leading to increased smooth muscle cell activity that contributes to ED and BPH-induced LUTS, which is a linking mechanism between these diseases.

Theory of atherosclerosis of the pelvic vessels

LUTS and ED may be due to the presence of atherosclerotic lesions of the vessels of the genitourinary organs. The pathological effect of atherosclerotic lesions of the vessels of the genitourinary organs was studied in rabbit models, as a result of which a decrease in the elasticity of the bladder wall was revealed. Chronic ischemia, being a consequence of atherosclerosis, subsequently leads to fibrosis of the stromal component of the prostate, atrophy of the bladder neck and a decrease in the contractility of the smooth muscle apparatus of the lower urinary tract, which leads to ED and the appearance of LUTS.

Application of IFDE-5 type

The first data reporting a significant effect of type PDE5-i on LUTS was obtained by Sairam et al., who followed 112 patients. The effect of sildenafil on LUTS was assessed using the IPSS scale before treatment and 3 months after treatment. Sildenafil was taken before sexual intercourse or once at bedtime in the absence of sexual activity. After 3 months, 6% of the studied men showed a decrease in IPSS scores from 20-35 to 8-19. 60% of patients with moderate LUTS (IPSS 8-19 points) moved to the group of patients with mild LUTS (IPSS 0-7 points).

A similar study was presented by Mulhall et al., which involved 48 patients aged 64 ± 11 years with moderate LUTS (IPSS > 10) and ED. The level of IPSS and IIEF scores was measured before treatment and 3 months after daily intake of sildenafil 100 mg. As a result of treatment on the IPSS scale, there was an average decrease of 4.6 points (35%), and an increase of 1.4 points on the quality of life (QoL) scale. According to the ICEF scale, an increase of 7 points was noted.

A randomized, double-blind, placebo-controlled trial by McVary et al. evaluated the effect of 12 weeks of sildenafil in 366 men with ED (IIEF< 25) и ДГПЖ в сочетании с СНМП (IPSS >12). The drug was prescribed at a dosage of 50 mg at bedtime or 1 hour before sexual contact for 2 weeks, then 100 mg for 10 weeks. The level of erectile function was assessed according to the IIEF scale, the quality of urination according to the IPSS/QoL scale, as well as the maximum urination rate (Qmax). During treatment, there was a significant decrease in IPSS scores compared with placebo (-6.32 vs. -1.93). Patients with severe LUTS reported greater improvement than those with moderate LUTS prior to treatment (-8.6 vs -3.6). Positive changes were also observed on the QoL and IIEF scales, however, when assessing Qmax, no clinically significant changes were noted.

A double-blind, placebo-controlled study evaluated the effect of sildenafil on LUTS in men with ED. Patients aged 45 years and older were followed up for 12 weeks. IIEF and IPSS scores before treatment were< 25 и >12 points respectively. The result of treatment was assessed using the IPSS, Qol, IIEF scales; Qmax was determined according to uroflowmetry data. The 189 study patients receiving sildenafil experienced an improvement in erectile function compared with a group of 180 patients receiving placebo, with an increase in IIEF scores of 9.17 versus 1.86 for placebo. The decrease in IPSS scores in the active treatment group was 6.32, while the reduction in placebo was 1.93. According to the QoL scale, an increase in the number of points by 0.97 was noted, while in the placebo group by 0.29 points. It is important to note that for all these indicators, the changes between the groups were significant (p< 0,0001). Изменения со стороны максимальной скорости мочеиспускания не были клинически значимыми (р = 0,008) .

Porst et al. conducted a retrospective analysis of the effect of daily tadalafil on LUTS due to BPH in men with ED who were sexually active. The randomized, multicentre, double-blind, placebo-controlled, parallel-group study included 581 men. After screening, patients underwent a 4-week drug-free period, followed by a 4-week placebo-only period, and only then were patients treated once and daily with either placebo or tadalafil 2.5, 5, 10, or 20 mg for 12 weeks . The results were assessed on the IIEF scale, in terms of Qmax and the volume of residual urine Vres. The increase in scores on the IIEF scale after taking tadalafil at various dosages, relative to baseline, was 5.4 (2.5 mg), 6.8 (5 mg), 7.9 (10 mg), and 8.2 (20 mg ) points, compared with placebo, after which the increase was only 2.0 points (p< 0,001). Изменения пиковой скорости мочеиспускания и объема остаточной мочи не были клинически значимыми .

A randomized, double-blind, placebo-controlled study by McVary et al., which included 281 men with BPH and moderately or severely symptomatic LUTS, evaluated the effect of taking the drug tadalafil. Regarding the therapy, the patients were randomized into two groups. The first group included patients receiving tadalafil (5 mg for 6 weeks, then 20 mg for 6 weeks), the second group consisted of patients receiving placebo for 12 weeks. Efficacy was assessed by the change in IPSS scores at 6 and 12 weeks after the start of treatment, as well as by the change in Q. According to the results of treatment and at 6 and 12 weeks after the start of treatment, tadalafil therapy gave positive results. At 6 weeks post-treatment, there was a reduction in IPSS scores of 2.8 points compared with placebo of 1.2 points, while at 12 weeks with tadalafil, the decrease in IPSS was 3.8 points versus 1.7 with placebo. The analysis of obstructive symptoms also showed positive results, however, there were no clinically significant changes in Q compared with placebo.

Roehrborn et al. in a randomized, double-blind, placebo-controlled study, the results of treatment of 1058 patients at various dosages of tadalafil (2.5, 5, 10, 20 mg daily) were evaluated over a period of 12 weeks. Treatment outcomes were assessed by IPSS, QoL, Qmax scores. Positive dynamics was noted when taking tadalafil at a dose of 5 mg or more. The dynamics of the decrease in IPSS indicators relative to the prescribed dose of tadalafil was: 2.5 mg by 3.9 points (p = 0.015), 5 mg by 4.9 points (p< 0,001), 10 мг на 5,2 балла (p <0,001) и 20 мг на 5,2 балла (p < 0,001), против уменьшения показателей IPSS при приеме плацебо на 2,3 балла. Практически все пациенты отметили улучшение качества жизни. Увеличение Q по сравнению с плацебо отмечено не было ни в одной группе. Результатом проведенного исследования стало заключение, что увеличение дозы тадалафила выше 5 мг вызывает схожие изменения СНМП .

The aim of the study conducted by Broderick G.A. et al., was to determine the efficacy of tadalafil therapy for LUTS caused by BPH in men with or without ED. The criteria for evaluating the results of treatment were changes on the IPSS and Qol scales. Patients were divided into 2 groups: with ED (n = 716) and without ED (n = 340). After 12 weeks, the following results were obtained: in men with ED, when taking 2.5, 5, 10, 20 mg of tadalafil, there was a decrease in IPSS by 4.3, 4.8, 5.3, 5.6 points, respectively, while in men without ED, the decrease on the IPSS scale was 2.4, 3.2, 5.3, 5.1, 4.5 points. Similar results were noted on the QoL scale. When taking 2.5, 5, 10, 20 mg of tadalafil, in patients with ED, the increase in indicators on the quality of life scale was 0.6, 0.9, 0.9, 1.0, 1.1 points, respectively, while while, when taking the same doses of tadalafil in patients without ED, the increase in the QoL scale was 0.6, 0.7, 0.9, 0.8, 0.8 points. According to the results of this study, there was no significant difference between the effect of taking tadalafil in patients with ED and without ED.

Steef et al. studied the efficacy of vardenafil in the treatment of LUTS and ED. The study included 222 men with LUTS (IPSS > 12) who were randomized into 2 groups: verdenafil 10 mg or placebo twice daily. The age of the patients ranged from 45 to 64 years. The results were evaluated after 8 weeks in terms of IPSS, Qmax , Vres, QoL. After treatment, the decrease in IPSS scores was 5.9 points compared with placebo 3.6 points (p = 0.0017 and p = 0.0081, respectively). Erectile function and QoL results also showed a significant improvement. Changes in peak urinary flow and residual urine volume were not clinically significant.

Thus, according to the studies, all drugs of the iPDE-5 type group have a significant positive effect on LUTS with a decrease in IPSS scores, as well as on erectile function, which significantly improves the quality of life of this category of patients.

The result of this review is the demonstration of a positive effect of type PDE-5 ips to a greater extent on irritative symptoms, improving IPSS scores to a greater extent, and to a lesser extent, peak urinary flow. The question of the pathogenetic mechanism linking LUTS and ED remains unresolved. There is no doubt that there is a need for long-term scientific research.

Our review of scientific papers and publications allows us to draw the following conclusions.

1. The study of the effect of iPDE-5 type on ED in combination with LUTS caused by BPH is relevant for modern urology.
2. The use of iPDE-5 type can significantly improve erectile function and the quality of urination according to IIEF and IPSS / QoL scales, however, changes in Qmax and Vres during treatment with iPDE-5 type are clinically insignificant and unreliable.

Keywords: phosphodiesterase type 5 inhibitors, lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction.

keywords: phosphodiesterase-5 inhibitors, lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction.

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In patients, the relaxing effect of β2-agonists is reduced, and the bronchodilatory response to theophylline does not differ from the usual one. The severity of the bronchospasmolytic effect depends on the concentration of theophylline in the blood. At therapeutic concentrations, theophylline increases FEV1 by an average of 20% of baseline. There is a good reversibility of bronchial obstruction in the appointment of this drug. Theophylline administration to healthy individuals does not cause changes in the parameters of respiratory function (RF).

Mechanism of bronchodilatory action theophylline due in part to inhibition of phosphodiesterase ( PDE); the drug is a non-selective PDE inhibitor, i.e. all its 5 types, including adenyl (types III and IV) and guanyl (type V). Inhibition of type III PDE leads to an increase in the concentration of cAMP in myofibrils, intracellular redistribution of calcium ions with a decrease in their concentration in the cytosol and uptake by mitochondria. Inhibition of PDE type IV leads to suppression of the function of mast cells, eosinophils, T-lymphocytes. However, only at a very high concentration of theophylline in blood plasma (about 100 μg / ml) is there a significant inhibition of PDE. At therapeutic concentrations of theophylline, the total PDE activity in human lung extracts is suppressed by only 20%. But even this degree of inhibition can be functionally significant, since it leads to an increase in the response of cyclic nucleotides to such endogenous adenylate cyclase activators as adenosine and catecholamines. It should be noted that theophylline suppresses the high molecular weight fraction of adenyl PDE only at its high activity. It is this fraction that increases during an attack of bronchial asthma; outside an attack, it is significantly lower. That is, theophylline inhibits adenyl PDE mainly at the time of an asthmatic attack. As a result of a chronic inflammatory process and treatment with β2-agonists, PDE isoenzymes are more pronounced in patients with bronchial asthma than in healthy individuals. This may mean that theophylline has a greater inhibitory effect on PDE in the airways of asthmatics. However, derivatives of theophylline, for example, pentoxifylline, being extremely strong PDE inhibitors, are ineffective bronchospasmolytics. Thus, the mechanism of the bronchodilating action of theophylline cannot be explained only by its ability to inhibit PDE.
Of greater importance is probably the fact that theophylline is a non-selective A1- and A2-adenosine receptor antagonist. It is known that stimulation of A1 receptors leads to bronchoconstriction, A2 receptors to bronchodilation. In bronchial asthma, the effects of excitation of A1-adenosine receptors predominate. In patients with bronchial asthma, it was found that bronchial obstruction is associated with a decrease in the concentration of A2 receptors and, to a lesser extent, with an increase in the number of A1 receptors.
Blockade of adenosine receptors is observed at therapeutic concentrations of theophylline in blood plasma. Theophylline is an effective adenosine antagonist at concentrations 20-100 times lower than required to suppress PDE activity.
The relaxation of smooth muscles also leads to theophylline inhibition of the transport of calcium ions through the "slow" channels of cell membranes and a decrease in its release from intracellular depots.
Some studies have shown a small protective effect of theophylline on histamine, methacholine, distilled water, and exercise challenge.
However, after a long-term, for 1 year, treatment with theophylline, a significant decrease in sensitivity to methacholine was noted. When provoked by an allergen, theophylline has a rather weak protective effect in case of an immediate asthmatic reaction. Significant attenuation of the late asthmatic reaction by theophylline was shown. Theophylline suppresses bronchial hyperreactivity to histamine, measured 4.5 hours after the initial allergen challenge. In patients with bronchial asthma, the nocturnal increase in bronchial hyperreactivity due to the activation of the inflammatory process at this time of day is suppressed by a single evening dose of theophylline, which is especially noticeable when performing a provocative test in the early morning hours. Theophylline also reduces the sensitivity of the bronchi to platelet activating factor (PAF).
Theophylline also has some anti-inflammatory properties. In particular, it reduces the release of mediators from mast cells caused by adenosine, reduces the formation of free oxygen radicals by neutrophils and macrophages, inhibits the synthesis and release of cytokines (interleukin IL-1 and tumor necrosis factor alpha - TNFa) from monocytes and macrophages, prevents chemotaxis, activation and degranulation of eosinophils.
Theophylline has an immunomodulatory effect: it inhibits the proliferation of T-lymphocytes, their transport into the respiratory tract and the release of interleukin IL-2 by them, and increases the number of T-suppressors in the peripheral blood.
In patients with irreversible obstructive and restrictive changes in the bronchi, a decrease in dyspnea under the influence of theophylline can be associated with an increase in the activity of the respiratory center. Stimulation of the respiratory center by theophylline leads to an improvement in the mechanics of breathing and an increase in lung ventilation due to an increase in the contractility of the intercostal muscles and diaphragm.
In addition, theophylline enhances mucociliary transport, increasing the secretion of mucus by the bronchial glands and increasing the rate of oscillation of cilia in the proximal bronchi.
Theophylline reduces pressure in the pulmonary artery system (reduces transient hypertension of the pulmonary circulation during an asthma attack), causing expansion of the pulmonary vessels, which leads to a decrease in hypercapnia and an increase in blood oxygen saturation.
It is also known that theophylline reduces swelling of the bronchial mucosa. It has a diuretic effect, increasing renal blood flow and glomerular filtration. The drug dilates the coronary arteries, improves the systolic pumping function of the right and left ventricles and reduces the end-diastolic pressure in them.
Theophylline increases the synthesis and secretion of endogenous catecholamines by the adrenal medulla, reduces the release of histamine and other mediators of allergy due to the stabilization of mast cell membranes (ketotifen-like effect). The drug increases the level of prostaglandin E1; reduces the level of prostaglandin F2α and inhibits aPDE, resulting in a decrease in the conversion of cAMP to inactive 5 "-AMP, inhibits platelet aggregation and the release of biologically active substances from them, and has an immunomodulatory effect.
When studying the effect of theophylline therapy on glucocorticoid function of the adrenal cortex, some authors have found an indirect increase in cortisol secretion.
Under the influence of theophylline, an increase in the number of glucocorticoid receptors occurs. At the same time, the increase in their number is the greater, the smaller their initial number is. This leads to an increase in the activity of the adenylate cyclase system, which is manifested by an increase in cAMP stimulated by adenosine. With course treatment, theophylline also leads to an increase in the number of A2-adenosine receptors and, to a lesser extent, to a decrease in the number of A1-adenosine receptors. Thus, theophylline therapy corrects the violation of the ratio of subclasses of adenoid receptors in patients