Sildenafil Vertex, 1 piece, 25 mg, film-coated tablets
Sildenafil is a powerful selective inhibitor of cGMP-specific PDE-5. Mechanism of action The physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum and increased blood flow. Sildenafil does not have a direct relaxant effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.
Sildenafil is selective against PDE-5 in vitro, its activity against PDE-5 exceeds that against other known PDE isoenzymes: PDE-6 - 10 times; PDE-1 - more than 80 times; PDE-2, PDE-4, PDE-7 - PDE-11 - more than 700 times. Sildenafil is 4000 times more selective for PDE-5 compared to PDE-3, which is of utmost importance since PDE-3 is one of the key enzymes in the regulation of myocardial contractility. A prerequisite for the effectiveness of sildenafil is sexual stimulation. Clinical data Cardiac studies. The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum reduction in SBP in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg, and DBP was 5.3 mmHg. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates. In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), resting SBP and DBP decreased by 7 and 6%, respectively, and pulmonary SBP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also led to an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries.
In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 s; 0.9–38.9 s) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.
A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n=568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.
Studies of visual impairments. In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Mansel 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.
In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n=9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Hamuri perimeter and photostress).
Efficacy The effectiveness and safety of sildenafil were assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview.
The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportions of patients who reported that therapy improved their erections were: 62% (25 mg sildenafil dose), 74% (50 mg sildenafil dose), and 82% (100 mg sildenafil dose) versus 25 % in the placebo group). Analysis of the International Index of Erectile Function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.
According to the pooled data, among patients who reported improved erections with sildenafil treatment were 59% of patients with diabetes, 43% of patients who had undergone radical prostatectomy, and 83% of patients with spinal cord injuries (versus 16, 15, and 12% in the placebo group, respectively).
Pharmacokinetics The pharmacokinetics of sildenafil in the recommended dose range is linear. Absorption After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 25 to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE-5 activity by 50%. After a single dose of sildenafil in a dose of 100 mg, the average Cmax of free sildenafil in the blood plasma of men is about 18 ng/ml (38 nM) and is achieved when sildenafil is taken orally on an empty stomach for an average of 60 minutes (from 30 to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and Tmax increases by 60 minutes, but the degree of absorption does not change significantly (AUC decreases by 11%).
The Vss distribution of sildenafil averages 105 L. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after taking the drug.
Metabolism Sildenafil is metabolized mainly in the liver under the influence of the cytochrome CYP3A4 isoenzyme (major pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE-5 in vitro is about 50% of the activity of sildenafil.
The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; T1/2 is about 4 hours.
Excretion The total clearance of sildenafil is 41 l/h, and the final T1/2 is 3–5 hours. After oral administration, as well as after intravenous administration, sildenafil is excreted in the form of metabolites, mainly by the intestines (about 80% of the oral dose) and to a lesser extent - by the kidneys (about 13% of the oral dose).
Pharmacokinetics in special groups of patients Elderly patients. In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is approximately 40% higher than in young patients (18–45 years of age). Age does not have a clinically significant effect on the incidence of side effects.
Renal dysfunction. With mild (Cl creatinine - 50-80 ml/min) and moderate (Cl creatinine - 30-49 ml/min) degree of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (Cl creatinine ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those with normal renal function in patients of the same age group .
Liver dysfunction. In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh stage C) has not been studied.
The role of sildenafil in the life of men and women
A person experiences earthquakes, epidemics, the horrors of illness and all sorts of torments of the soul, but for all times the most painful tragedy for him was, is and will be - the tragedy of the bedroom. (L.N. Tolstoy in the memoirs of his contemporaries)
Introduction
The first mention of erectile dysfunction (ED) was noted in the manuscripts of Ancient Egypt [1]. Since then, there have been continuous attempts to improve a man's sexual potential, but a revolutionary breakthrough came with the discovery by Furchgott, Ignarro and Murad of the role of nitric oxide in the functioning of the cardiovascular system. The authors received the Nobel Prize and, in the course of further research, created sildenafil, which has continued its triumphal march across the planet since 1998 [2]. Sildenafil is familiar to many as a drug for the treatment of ED, but the range of its therapeutic possibilities is wider [3]. The efficacy and safety of sildenafil were assessed in 48 randomized, double-blind, parallel-group, double-blind, parallel-group studies involving 11,364 men with ED [3]. It was shown that in all age groups, including people over 75 years of age, the effectiveness of sildenafil citrate (SC) was high, and the frequency of side effects, among which headache and hot flashes predominated, was low [4]. Taking SC leads to an improvement in erectile function in patients of different ages, regardless of the etiology, severity and duration of ED. Sildenafil affects both arterial and venous blood flow in the penis, which makes it primarily indicated for vasculogenic ED. The drug improves cavernous electrical activity, which justifies its use in the neurogenic form of the disease [5]. Another recent study confirmed that phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are generally well tolerated. The authors emphasize that there are no studies comparing various drugs in this group; all comparisons were made with placebo [6]. Confirmation of the effectiveness and safety of sildenafil was obtained in a population-based study using the example of residents of Chinese megacities [7]. Studying the effectiveness of various doses of SC in 3674 patients with ED, we came to the conclusion that the satisfaction of patients who took 100 mg of sildenafil was higher than that of those who took 50 mg of SC [8]. In general, it is recommended to approach dose selection in a personalized manner [9]. Physical exercise, diet, and normalization of plasma glucose levels are not sufficient to restore erectile function in patients with diabetes [10]. A systematic review of 17 well-designed studies confirmed the effectiveness and safety of sildenafil in diabetic patients with ED [11]. SC did not increase adverse reactions in diabetic patients taking metformin and thiazolidine [12]. In the treatment of urological diseases combined with ED (hypogonadism, benign prostatic hyperplasia), a potentiation of the effect of the combined use of basic therapy and sildenafil was noted [1, 13]. It is emphasized that daily use of sildenafil by patients with ED after prostatectomy gives a less pronounced effect than on-demand use [14], which is absolutely logical, since PDE-5 inhibitors cause an erection only in the presence of sexual stimulation. A fracture of the pelvic bones with damage to the urethra naturally leads to the development of ED. However, even in such a severe group, daily administration of sildenafil is effective in 61.5% of cases [15]. Not a single drug from the PDE-5 inhibitor group provides a 100% effect in the treatment of ED. To find out the reasons for this phenomenon, a molecular genetic study was conducted in Spain, which showed genetic polymorphism in responses to PDE-5 inhibitors. As it turned out, the effectiveness of treatment with PDE-5 inhibitors is genetically determined and cannot be changed. There was also a clear correlation between glycemic status and the effectiveness of treatment with sildenafil [16]. Recently, non-drug methods of treating patients with ED have become popular, in particular extracorporeal shock wave therapy [17]. An experimental study was conducted showing that this method, when taking sildenafil, significantly increases the effectiveness of treatment [18]. Some patients prefer oral tablets that do not require swallowing and drinking water, and these are already on the market [19]. Chronic prostatitis, both common and specific, can be complicated (accompanied) by ED [20–24]. Hypothetically, one can expect a positive effect of SC in prostatitis, since it has been shown that sildenafil affects the course of the inflammatory process, since it reduces the activity of pro-inflammatory factors. After taking sildenafil, TNF-α immediately decreases, and the level of C-reactive protein decreases [25]. However, along with the anti-inflammatory effect, sildenafil reduces the activity of ciprofloxacin in the treatment of patients with chronic prostatitis complicated by ED [26], this must be taken into account when prescribing therapy for such patients. Those who are moderate in matters of sexual problems claim that the problem of ED is exaggerated, and that a person may well be happy, for example, doing his favorite job or hobby. However, our research has shown that this is not the case: a multicenter cohort study found a positive correlation between the quality of men’s sexual function and their level of overall success [20]. In women, however, such a dependence is not observed [27], partly, apparently, because a woman’s gender role does not depend on her sexual satisfaction. We set out to
study how sexual partners of men with ED assessed their sex lives before their men began taking PDE5 inhibitors and after the course of treatment.
Material and methods
An open, single-center cohort study was conducted involving 128 men with mild to moderate ED aged 32 to 54 years (average 42.1 years). All patients had not previously taken PDE-5 inhibitors. The patients were prescribed sildenafil 50 mg “on demand” 1 hour before expected intercourse. A second visit to the doctor was scheduled after 2 weeks. therapy for possible dose adjustment. The third, final visit was scheduled after 3 months. from taking the first dose of sildenafil. The effectiveness of treatment was assessed using the International Index of Erectile Function scale; patients recorded adverse reactions in their diaries. If a strong or prolonged (more than 6 hours) undesirable effect occurred, patients came for an unscheduled appointment with a doctor. After 3 months wives (regular sexual partners) of men with effective treatment were surveyed regarding satisfaction with the quality of treatment of their husbands. The wives were asked to independently assess the couple's initial sex life and the changes that occurred after treatment using a questionnaire. The ultimate goal of the study was to analyze this assessment.
results
Of the 128 men, only one (0.78%) developed nasal congestion, impaired color vision and headache while taking sildenafil so severely that he stopped taking the drug. Another 15 (11.7%) had side effects, but the patients considered them minor and continued therapy. For 24 (18.75%) men with very good erections, but with adverse reactions, the dose was reduced to 25 mg, which did not affect the effectiveness, but improved tolerability. In 32 (25.0%) patients, on the contrary, the attending physician considered it necessary to increase the dose to 100 mg, the remaining 72 (56.25%) continued therapy with the initial dose of SC 50 mg. Taking sildenafil and, accordingly, sexual intercourse (or an attempt at it) occurred on average with a frequency of 2.7 times a week. A positive effect of sildenafil was noted by 83 (64.84%) patients. When asked to invite their wives for a conversation, two admitted that they lived in a homosexual couple, 27 men did not have a permanent girlfriend and realized their restored sexual potency in casual relationships, 11 women refused to talk, and 43 agreed to answer the questions. Initially, 38 wives (88.37%) rated the couple’s sex life as unsatisfactory, although 5 women did not consider their husband’s ED a problem, since they themselves had low sexual desire. After 3 months sildenafil therapy, 19 (44.18%) women considered family sex life good, 22 (51.16%) - excellent. At the same time, according to 2 (4.65%) women, no changes occurred, which once again proves that for a woman in sex, a good erection in a sexual partner is not enough. The assessment results are presented in Figure 1.
Thus, 41 (95.35%) women were satisfied with the result of their husband’s treatment with the drug SC and considered that the improvement in the quality of erection had a positive impact on family life.
Discussion
Drug correction of sexual deviations in women remains questionable; the psychological component of the process probably plays a leading role here [28]. Our study showed that 95.35% of women are satisfied with the results of treating their sexual partners with sildenafil, therefore, sildenafil affects the sexual function of women, albeit indirectly. There are a number of pitfalls in the use of PDE-5 inhibitors. Firstly, there are many counterfeits and low-quality generics on the market [29]. A spectral analysis of base sildenafil and SC was carried out [30]. Sildenafil crystallizes as base sildenafil, SC - with a higher crystal characteristic (Fig. 2). The presence of various impurities disrupts the quality characteristics of SC.
When treating sildenafil, the general rules for taking medications are followed. It is recommended to take medications with water rather than any other drink to avoid interactions and prevent inactivation of the drug or its biotransformation during competitive metabolism involving the cytochrome isoenzymes CYP3A4 and CYP2C9. Inhibitors of CYP3A4 and CYP2C9 isoenzymes (ketoconazole, erythromycin, cimitidine) reduce metabolism and increase the concentration of sildenafil in the blood. In this case, treatment with sildenafil begins with a dose of 25 mg, since otherwise, due to competitive metabolism, an overdose of SC is possible, which has a hepatotoxic effect [31]. The level of sildenafil in the blood plasma was compared in men who took the tablets with water diluted with lemon or orange juice. It was found that orange juice significantly increased the concentration of sildenafil in the blood (the peak concentration was 44% higher, the “cleansing period” was 30% longer). Lemon juice, to the surprise of the researchers, had no effect on the pharmacokinetics of sildenafil [32]. Since 2011, the group’s production center (Dynamico) has been represented on the Russian pharmaceutical market, which in 2014 received the “Platinum Ounce” - the highest award in the pharmaceutical industry and again won the competition award in 2015. A study conducted in Russia showed that Dynamico provides high-quality erection, has a minimum of side effects and is not addictive [33-34].
conclusions
Sildenafil plays an important, albeit indirect, role in a woman’s life - it increases her sexual satisfaction by improving erection in her sexual partner. According to the study, 95.35% of women are satisfied with the results of treating their sexual partners with sildenafil.
Sildenafil
Sildenafil is a powerful selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Mechanism of action
The physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum and increased blood flow.
Sildenafil does not have a direct relaxant effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.
Sildenafil is selective for PDE5 in vitro, its activity against PDE5 exceeds that of other known phosphodiesterase isoenzymes: PDE6 - 10 times; PDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDEZ, which is of utmost importance since PDEZ is one of the key enzymes in the regulation of myocardial contractility.
A prerequisite for the effectiveness of sildenafil is sexual stimulation.
Clinical data
Cardiac research
The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic pressure in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg. Art., and diastolic pressure - 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates.
In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic blood pressure decreased by 7% and 6%, accordingly, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries.
In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 seconds; 0.9 - 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.
A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.
Visual impairment studies
In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electro-retinogram, intraocular pressure or pupil diameter.
In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Humphrey perimeter, and photostress).
Efficiency
The efficacy and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview.
The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and was confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients who reported that therapy improved their erections was: 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose) compared with 25%. in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.
According to the pooled data, among patients who reported improved erections with sildenafil treatment, 59% of patients with diabetes, 43% of patients who had undergone radical irostatectomy and 83% of patients with spinal cord injuries (versus 16%, 15% and 12% in the placebo group, respectively) ).
Pharmacokinetics
The pharmacokinetics of sildenafil in the recommended dose range is linear.
Suction
After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of sildenafil at a dose of 100 mg, the average Cmax of free sildenafil in the blood plasma of men is about 18 ng/ml (38 nM). Cmax when taking sildenafil orally on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and TCmax increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).
Distribution
The volume of distribution of sildenafil at steady state averages 105 liters. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after dosing.
Metabolism
Sildenafil is metabolized mainly in the liver under the influence of the cytochrome isoenzyme CYP3A4 (major pathway) and the cytochrome isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; T1/2 is about 4 hours.
Removal
The total clearance of sildenafil is 41 l/hour, and the final T1/2 is 3-5 hours. After oral administration, as after intravenous administration, sildenafil is excreted in the form of metabolites, mainly by the intestines (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).
Pharmacokinetics in special groups of patients
Elderly patients
In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is approximately 40% higher than in young patients (18-45 years of age). Age does not have a clinically significant effect on the incidence of side effects.
Renal dysfunction
With mild (creatinine clearance (CL) 50-80 ml/min) and moderate (CL 30-49 ml/min) degrees of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance <30 ml/min), the clearance of sildenafil is reduced, leading to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those with normal renal function in patients of the same age group.
Liver dysfunction
In patients with liver cirrhosis (stages A and B according to the Child-Pyot classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared to those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (stage C according to the Child-Pyot classification) has not been studied.
