Viagra – Past, Present and Future | Hamidov S.I., Iremashvili V.V. | “Breast Cancer” №25 from 12/15/2005
In April 1998, the drug Sildenafil citrate was approved for clinical use. It was widely known under the trade name Viagra. This moment has not just become the starting point for the existence of the next drug in the pharmacological market. It turned out to be the beginning of a new era in the field of sexual medicine, marked by a real breakthrough in the fundamental and clinical spheres, as well as in the public perception of sexual pathology.
Viagra has become the first effective and safe oral medication for the treatment of erectile dysfunction (ED). The attitude of medicine to this disease has undergone dramatic changes over the past hundred years. Currently, there is no doubt that erectile dysfunction, previously considered as a consequence of psychological problems, in most cases is a manifestation of an organic lesion, often of a systemic nature . The main stages of the development of sexual medicine in the XX century are presented in table 1.
The history of the discovery of Viagra is an example of how random observation can have a huge impact on the viagra patent expiration progress of scientific progress. During the clinical trials of a new antianginal drug, Pfizer Inc. researchers noted that although the medication is not accompanied by a significant clinical improvement in the course of angina, in many patients it leads to the development of a kind of “side effect”, which consists in improving erectile function . This observation has led to the study of the possibility of using this substance in the treatment of ED.
However, we should not think that the discovery of Viagra was a simple success. It was preceded by the accumulation of knowledge about the role of nitric oxide NO in ensuring the normal functional state of the cardiovascular system, initiated by Furchgott and Zawadski . The authors, who received further the Nobel Prize for their discoveries, found that, in the presence of an intact endothelium, the effects of acetylcholine lead to a dose-dependent relaxation of an isolated segment of the arteries as a result of exposure to an endothelial relaxing factor. Further studies have shown that this factor is NO, which is synthesized from L-arginine by the enzyme NO – synthase (NОС) . Standing out from the endothelial cells, NO diffuses into the underlying smooth muscle tissue, where the enzyme guanylate cyclase is activated, as a result of which the amount of cyclic guanosine monophosphate (cGMP) sharply increases in cells, which in turn leads to a decrease in intracellular calcium ion concentration and relaxation. The destruction of cGMP, which limits the vasorelaxant effect of NO, is effected by the enzyme phosphodiesterase (PDE). Currently, 11 types of this enzyme are known, while in the destruction of cGMP in vascular smooth muscle cells the main role is played by PDE of 1,3 and 5 types . Thus, inhibition of PDE leads to increased effects of nitric oxide.
An erection of the penis is a hemodynamic phenomenon, the first stage of which is the relaxation of smooth muscle cells of the cavernous arteries and trabeculae, leading to the filling of the cavernous bodies with blood. The relaxation of the smooth muscle tissue of the latter, as in other vascular systems, is provided by the action of NO, released from the endothelium and non-cholinergic non-adrenergic nerve endings . The discovery of Viagra, a selective type 5 PDE inhibitor (PDE-5), has led to many fundamental studies that have shown that this type of enzyme dominates cavernous tissue, which ensures the selectivity of the drug . It should be noted that these studies also allowed to find out the mechanisms of action of other drugs that have been used in clinical practice for a long time, in particular, papaverine and prostaglandin E1 , and significantly expand knowledge of the mechanism of erection and its disorders leading to ED.
The emergence of Viagra has had a great influence on clinical research in the field of sexual medicine. In recent years, the terminology has been clarified and new definitions of various forms of sexual disorders have been developed. Clinical trials of Viagra became an incentive to create new diaries and generic viagra without a doctor prescription questionnaires to assess the state of the sexual function of men. Analysis of the demographic indicators of participants in large-scale clinical trials revealed risk factors for ED, which, in turn, contributed to an understanding of its pathogenesis .
The emergence of Viagra had a huge public outcry. A large number of patients with erectile dysfunction who had not previously visited a doctor received hope for a cure, and by now millions of men around the world have returned to a normal sex life thanks to taking this drug.
The clinical efficacy of Viagra has been evaluated in numerous studies conducted in the world. Carson et al. pooled data from 11 double-blind, placebo-controlled trials involving a total of almost 3,000 patients with ED . 12 weeks after starting the drug, 76% of men who received Viagra and 22% who received placebo noted an improvement in erection. The percentage of successful attempts at sexual intercourse was 66% and 26% in the first and second groups, respectively. The effectiveness of various doses of Viagra was 65% for 25 mg, 74% for 50 mg and 82% for 100 mg. The high efficiency of Viagra has been noted in different age groups. Thus, among patients younger and older than 65 years, the efficiency of Viagra was 77.6% and 69.2%, respectively. Significantly higher efficiency of Viagra compared with placebo also occurred in patients with ED of varying severity and different etiologies (Table 2).
Arterial hypertension (AH) is one of the risk factors for ED. Although Viagra has some antihypertensive effects, this drug is safe in patients with hypertension as receiving and not receiving antihypertensive drugs [11,12]. The effectiveness of Viagra in patients with ED, suffering from hypertension, is high. Among patients with hypertension of various origins, placebo and Viagra were accompanied by an improvement in erection in 18% and 70% of patients, respectively. Among men who took two or more antihypertensive drugs, these figures were 17.6% and 71% .
Another well-known risk factor for ED is smoking. The effectiveness of Viagra among smokers was not inferior to that among non-smokers (80% and 74% respectively), as well as among those who smoked earlier (74%) .
Many epidemiological studies have shown that depression is the second most common cause of the development of ED after cardiovascular risk factors [13,14]. In addition, the presence of ED aggravates depressive symptoms . Viagra treatment among patients with depression not only was highly effective in improving erectile function, but was also accompanied by a decrease in the severity of depressive manifestations [15,16].
Various neurological diseases can also cause ED. According to studies, the effectiveness of Viagra among patients with parkinsonism, multiple sclerosis and spinal cord injuries exceeds 80%, which corresponds to the data obtained in the general population of patients with ED [17-21].
Special groups of patients with erectile dysfunction, difficult to treat, are viagra without a doctor prescription patients with diabetes mellitus (DM) and undergoing radical prostatectomy (RP).
In patients with diabetes, the effectiveness of Viagra depends on the severity of the course of diabetes and the presence of its complications. So, in the study of Carson et al. among patients with diabetes without complications, an improvement in erection was noted by 8% of patients who received placebo and 69% who received Viagra. With one complication, these figures were 12% and 43%, and two – 10% and 43%, respectively . In all groups, the effectiveness of Viagra was significantly higher compared with placebo.
The effectiveness of the treatment of ED after RP is determined by a number of factors, including the procedure for performing the operation (non-nervous, one-sided and bilateral nerve-saving), the age of patients, the state of erectile function before the operation, the stage of prostate cancer, the size of the prostate, the qualifications of the surgeon, and socio-economic factors such as the level of education and income of the patient [22-28]. Thus, according to Raina et al., Viagra treatment was effective in 71.7% of patients after a bilateral nerve-saving RP, in 50% after a unilateral nerve-saving RP, and only in 15% of patients with ED after a non-nerve-saving ED .
In addition, the peculiarity of the course of erectile dysfunction in such patients is the possibility of a progressive improvement in erection for up to 4 years after surgery , and therefore the final ineffectiveness of a particular treatment can be judged only a few years after surgery. This is confirmed by the data of Hong et al., Who examined 316 patients with ED after RP, in 95% of cases wore a bilateral nerve-saving character. The effectiveness of Viagra was 26% during the first 6 months, 36% from 6 to 12 months, 50% from 12 to 18 months and 60% from 18 to 24 months after surgery .
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Elucidation of the features of the pathogenesis of ED after RP, including the role of fibrotic changes arising on the background of decreased oxygenation of cavernous tissues, became the basis for the use of pharmacologic prophylaxis of ED in patients undergoing PRP. Given the importance of nocturnal erections in providing trophism of the cavernous bodies, as well as data from previous studies of Viagra use at bedtime, which showed an improvement in the quality of nocturnal erections in patients with various forms of ED , Padma Nathan et al. studied the effectiveness of Viagra in the prevention of ED after RP . During the study, patients who underwent bilateral nerve-saving RP and did not suffer from ED before surgery, starting from the second month of the postoperative period, received Viagra at doses of 100 and 50 mg or placebo before going to bed for 36 weeks. Eight weeks after discontinuation of treatment, 27% of men who received sildenafil and only 4% who received placebo does viagra make you last longer reported about the possibility of a normal sex life . Thus, the appointment of Viagra can be an effective method for the prevention of ED in patients after RP as a result of improving the blood supply to the cavernous tissue, preventing the development of fibrous changes in it.
Despite the high efficacy of Viagra, a certain number of patients remain in whom the intake of this drug does not lead to an improvement in erection. In many cases, this is due to improper medication . Patients, especially at the beginning of treatment, should be advised to take Viagra on an empty stomach at least 30 minutes before the start of sexual activities. It is also important to explain to patients that the effect of the drug develops only against the background of adequate sexual arousal and largely depends on it. In many cases, treatment should begin with 100 mg, which will allow you to get the maximum response at the beginning of treatment and inspire patients with confidence in the success of treatment. In addition, studies have shown that in some patients, the maximum effect of Viagra is achieved by 6-8 reception, and therefore in many patients the final assessment of the effectiveness of the drug should be made after several attempts to use it.
Currently, discussions are continuing about the long-term effectiveness of Viagra and the possibility of developing tachyphylaxis. El – Galley et al. conducted a telephone survey of 82 patients 2 years after the appointment of Viagra. Among the respondents, 41 (59%) continued to take Viagra, while 37% were forced to increase the initial dose of the drug due to a decrease in efficiency. Stopped admission due to a decrease in the effectiveness of 17% of patients . The long-term efficacy of Viagra was also investigated by Montorsi et al., Interviewed 2618 patients who took the drug for 3 years . In general, 96% of respondents were satisfied with the treatment and only 1.6% stopped it due to low efficiency. Laboratory studies also did not confirm the existence of the effect of tachyphylaxis when taking Viagra [37,38]. Thus, the existing data do not confirm the presence of the effect of tachyphylaxis with long-term use of Viagra.
An important characteristic of any pharmacological drug is its side effects. The most frequent side effects of taking Viagra include headache (7% of cases), facial flushing (7%), dizziness (2%), dyspepsia (1.8%), nasal congestion (1.4%) and disorders of sight, usually in the form of blue coloring of objects (1.2%) . In most studies, the incidence of side effects and refusals of treatment as a result of their development were comparable in the groups of patients receiving Viagra and placebo. It should also be noted that the frequency of side effects decreases as the drug is taken. Thus, in the Carson study, the frequency of all side effects, except for visual impairment and dyspeptic disorders, decreased during the course of taking the drug. Headaches at the beginning of the study reported 7% of patients with ED, and after 16 weeks less than 1%, the frequency of vertigo also decreased from 7% to less than 1%, and nasal congestion from 1.4% to less than 0.5% [40 ]. An important fact is also the fact that two thirds of patients in the process of conducting this study increased the dose of Viagra. Thus, with prolonged use, the frequency of most side effects of Viagra does not when will generic viagra be available exceed that for placebo.
The attention of Viagra on the cardiovascular system deserves special attention. Zusman et al. investigated the effect of Viagra on blood pressure in patients with ED, taking and not taking antihypertensive drugs . Although the authors noted a slight decrease in pressure in all groups of patients, statistically significant differences occurred in only a small number of cases. The men participating in the how to take viagra study took diuretics, b – blockers, a – blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors. The most pronounced decrease in blood pressure occurred in patients who did not take antihypertensive drugs, as well as in those who received calcium antagonists. At the same time, pressure reduction in none of the groups was not dangerous for the patients .
Hermann et al. studied the effect of Viagra on exercise tolerance in patients with angina pectoris . The results showed that Viagra not only does not reduce the functional ability of the heart, but even has a positive effect on its blood supply, which, however, is not surprising given the previously described history of the appearance of this drug.
Long-term use of Viagra not only does not lead to an increase in mortality from myocardial infarction, which was a subject of concern in the early stages of the drug, but even, apparently, somewhat reduces the latter. Thus, according to Padma – Nathan et al., The frequency of fatal myocardial infarction is 0.26 per 100 patients taking Viagra per year, while the similar indicator for men of the same age from the general population is 0.6 .
In recent years, the possibility of using Viagra in various diseases, in addition to ED has attracted increasing interest.
In the study of Sairam et al. The effect of Viagra on the severity of urination disorders in patients with ED was evaluated. At 1 and 3 months after the start of treatment, a significant decrease in the severity of lower urinary tract symptoms was observed, which correlated with an improvement in erectile function .
Acceptance of Viagra leads to an improvement in the condition of patients with primary and secondary pulmonary hypertension. Several studies have shown a decrease in pressure in the pulmonary trunk and the reaction of the pulmonary vessels to hypoxia when using Viagra as monotherapy and in combination with iloprost, which was accompanied by an increase in exercise tolerance and the quality of life of patients [44–46].
One of the possible directions of future research of Viagra is the use of this drug in the treatment of endothelial dysfunction. The concept of endothelial dysfunction has arisen as a result of the accumulation of data that the endothelial cells lining the lumen of all vessels of the body not only form a barrier between the blood and surrounding tissues, but also have a number of regulatory functions, the implementation of which is extremely important to maintain the anatomical and functional integrity of the vessels . Among the most important functions of the endothelium are the regulation of vascular tone, the effect on the blood coagulation system, the ability to counteract the adhesion of blood cells and the proliferation of smooth muscle cells . All of these functions endothelium performs as a result of the development of various mediators, which occurs in response to chemical and mechanical effects on endothelial cells. The main among these mediators is nitric oxide NO, which has a vasodilating effect, as well as reducing the adhesion of blood cells to the vascular wall, inhibiting the proliferation of vascular smooth muscle cells and preventing the secretion of tissue factors that increase the likelihood of thrombus formation. Endothelial dysfunction is currently regarded as an early stage of atherosclerosis. The presence of endothelial dysfunction is accompanied by a significant increase in the risk of developing severe cardiovascular complications, primarily heart attacks and strokes, as well as death due to these diseases .
As mentioned above, Viagra, inhibiting the activity of PDE-5, enhances the effects of NO on vascular smooth muscle cells, which may be accompanied by an improvement in their endothelial function. This is especially important for patients with ED, since the latter is in most cases of arteriogenic origin and is accompanied not only by dysfunction of the endothelium of the cavernous arteries, but also by systemic endothelial dysfunction .
The effect of Viagra on the endothelial function of the coronary and brachial arteries has been studied in several papers. The use of Viagra in doses of 25 to 100 mg was free viagra samples accompanied by an improvement in endothelial function in patients with heart failure, diabetes mellitus, ischemic heart disease and smokers [50–53]. Also shown is the ability of the drug to eliminate the short-term deterioration of endothelial function caused by smoking . In studies of patients with heart failure, Viagra administration, in addition to correcting the endothelial dysfunction of the brachial and coronary arteries, also led to an improvement in pulmonary hemodynamics and had a moderate antiplatelet effect . The combined use of Viagra and the ACE inhibitor ramipril in this group of patients was accompanied by potentiation of the beneficial effect of both drugs on endothelial function .
Thus, Viagra became the first effective oral medication for the treatment of ED, with the advent of which a new era in the development of sexual medicine began, thanks to which in recent years it has become an independent section of modern urology. The clinical efficacy of Viagra has been evaluated in a large number of studies conducted in many countries around the world. The drug leads to an improvement in erectile function in patients of different ages, regardless of the etiology, severity and duration of the course of ED. The effectiveness of the drug is long-term viagra substitute in nature, and the vast majority of patients continue taking Viagra years after the start of treatment. Side effects of Viagra in most cases have moderate severity and their frequency decreases during the course of taking the drug. Acceptance of Viagra does not adversely affect the state of the cardiovascular system, moreover, it is accompanied by an improvement in the functional state of the vascular endothelium, disorders of which play an important role in the pathogenesis of various cardiovascular diseases. The possibility of correcting endothelial dysfunction with the use of Viagra in the future may lead to increased indications for the use of this drug.
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