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Brand Viagra

30/1/2008

Pharmacological Effects
The suppression of acts Glucosamine 5, which is the enemy of erection.

Viagra - a reliable drug for the treatment of violations of erection. It has no effect by itself,
but it helps if there is a natural desire and attraction to commit a sexual act.
The drug is a potent and selective inhibitor of cGMP-specific Glucosamine type 5 (FDE5).
Physiological mechanism of erection penis involves the release of nitric oxide (NO) in the cavernous television with sexual stimulation. Nitric oxide guanilattsiklazu activates the enzyme, which leads to higher standards
Cyclical guanozinmonofosfata (cGMP), relax smooth muscles and cavernous body
enhance blood flow in sexual member.
Viagra has no direct impact on the relaxation of isolated cavernous human body,
but actively reinforces the relaxing effect of NO on this fabric through inhibition FDE5,
which is responsible for the collapse of the cartilage in the cavernous body.
When sexual initiation, the local release of NO under the influence leads sildenafila
FDE5 to oppression and raising kids in the cavernous body, resulting in
relaxation of smooth muscles and enhancing blood flow in the cavernous body.
The use of Viagra in the recommended doses ineffective in the absence of sexual stimulation.
Studies in vitro have shown high selective effect on sildenafila FDE5.
Activity sildenafila against FDE5 surpasses its activity against other known
Glucosamine isoforms (10 times - FDE6, more than 80 times - FDE1, more than 700 times - FDE2,
FDE3 and FDE4, FDE7 - FDE11). Thus managed to avoid adverse side effects.
Regarding FDE5 Viagra approximately 4000 times more active than for
FDE3 - cAMP-specific Glucosamine involved in the regulation of cardiac cuts,
that the risks of doing negative impact on the drug's heartfelt work virtually zero.
On the other hand because of low selectivity with respect to some patients FDE6
through 1 hour after taking Viagra in a dose of 100 mg detected a slight violation of discrimination and obratime
colors (blue / green) using the test Farnsworth-Munsell 100;
after 2 h after administration of the drug, these changes disappeared.
Violations of the established mechanism of colour vision is considered FDE6 oppression,
which is involved in the transmission of light in the retina.
Studies in vitro have shown that the impact on sildenafila FDE6 only 10 times concedes his activity
FDE5 against.
Viagra has no effect on visual acuity, contrast sensitivity, elektroretinogrammy,
intraocular pressure, or diameter of the pupil.
Sildenafil in a dose of 100 mg not influence locomotor activity or sperm morphology with his one-time admission healthy volunteers.
These clinical studies
A one-time admission patients in a dose of up to 100 mg not cause clinically significant changes in ECG
in healthy volunteers.
The maximum decrease in systolic blood pressure in the recumbent position in the application of the drug inside
in a dose of 100 mg averaged 8.4 mm Hg The corresponding decrease in diastolic blood pressure
in the situation of lying was 5.5 mm Hg
A more pronounced, but similarly transient effect on blood pressure was observed in patients
simultaneously receiving nitrates.
The studies the impact of a single admission sildenafila in a dose of 100 mg on hemodynamics
among 14 patients with severe coronary artery disease
(stenosis> 70% of at least one coronary artery) averages
reducing systolic and diastolic blood pressure were 7% and 6% on
the normal level. Systolic pressure in the pulmonary artery reducing by an average of 9%.
Viagra has no effect on Cardiac Output and not talk uhudshala blood through stenozirovannye
coronary artery, leading to an improvement in the result (13% approximately) reserve
adenosine-induced coronary blood flow (as in the stenosed, and
intact in the arteries).
The effectiveness and safety of sildenafila studied in 21 randomized, double-blind,
placebo-controlled study duration of up to six months. Viagra was used
more than 3000 patients with violations erection of various etiology (organic,
psychogenic, mixed) at the age of 19 to 87 years.
Effectiveness was determined on the basis of an overall evaluation, diaries, recording erection,
International evaluation index erectile function (IIEF, a questionnaire designed to assess sexual function) and the survey partners.
Sildenafila Effectiveness, which was evaluated by the ability of the drug to ensure the preservation of offensive and erection sufficient for sexual intercourse, has been demonstrated in all 21 studies and persisted during long-term treatment (1 year). When using Viagra in the share of fixed-dose patients reported improvement in erectile function, accounted for 62% (25 mg), 74% (50 mg) and 82% (100 mg), and while taking a placebo - 25%. In addition to improving erectile function IIEF analysis showed that treatment with Viagra improves to orgasm, sexual satisfaction and overall satisfaction.
In all studies proportion diabetics, reported improvement in the treatment
Viagra amounted to 59% of patients underwent radical prostatektomiyu - 43% of patients
spinal cord injury - 83% (against 16%, 15% and 12% of patients receiving placebo,
respectively).

Pharmacokinetics

Pharmacokinetics sildenafila depends on the dose, with ingestion of the recommended dose range.
Elimination is carried out mainly through drug metabolism in the liver (mainly izofermentom R450 cytochrome 3A4) with the formation of the active metabolite, sildenafilu similar properties.
Suction
After receiving the drug inside sildenafil is rapidly absorbed. Absolute bioavailability an average of 41% (25-63%). After receiving the drug on an empty stomach inside Cmax achieved during 30-120 min (average 60 minutes).
When you receive Viagra in combination with dietary fat absorption velocity decreases, T max is increased by 60 minutes, and Cmax decreased by an average of 29%.
Allocation
Vd sildenafila in the equilibrium state is an average of 105 litres, which indicates that the distribution of tissue.
Sildenafil and its main circulating metabolite N-desmetilovy approximately 96% associated with plasma proteins.
Tying with proteins is not dependent on the total concentration sildenafila.
In healthy volunteers who received Viagra (100 mg once on), less than 0.0002% (an average of 188 ng) doses of semen found in 90 min after administration.
Metabolism
Sildenafil is metabolized mainly by the action of CYP 3A4 (the main path) and CYP 2C9 (neglavny way) isozymes liver microsomal. Sildenafil is a weak inhibitor of cytochrome P450 isozymes - 1A2, 2C9, 2C19, 2D6, 2E1 and 3 A4 (IK50 <150 μ mol). In applying sildenafila in the recommended doses, it is unlikely that sildenafil can affect the clearance of these substrates isozymes.
The main circulating metabolite, which is formed by the N-desmetilirovaniya sildenafila, undergoing further metabolism.
By selective actions on FDE comparable to sildenafilom metabolite, and its activity against FDE5 in vitro is about 50% sildenafila activity itself.
Metabolite concentration in plasma is approximately 40% of such sildenafila.
N-desmetilmetabolit undergoing further metabolism; its terminal T1 / 2 equals about 4 pm
Derivation
The total body clearance of Viagra is 41 l / h, and T1 / 2 in the terminal phase - 3-5 pm After the reception, or inside / in the introduction of sildenafil in the form of metabolites derived mainly from the feces (approximately 80 % dose imposed by the interior) and to a lesser extent with urine (approximately 13% imposed by the interior dose).
The pharmacokinetics in special clinical cases
At sildenafila increase in the level in the blood plasma (AUC) affect the following factors: age over 65 years (an increase of 40% AUC), the inadequacy of liver damage (such as liver cirrhosis, 84%), severe renal insufficiency ( CC <30 mL / min, 100%), the accompanying reception drugs - inhibitors of cytochrome P450 3A4 (for example, eritromitsina, sakvinavira 182%, 210%).
In healthy elderly (65 years and older) volunteers clearance sildenafila reduced, but the concentration of the active substance free in plasma about 40% higher than concentrations in healthy young (18-45 years old) volunteers.
U volunteers with mild (CC 50-80 ml / min) and moderate (CC 30-49 mL / min) renal failure pharmacokinetic parameters after taking sildenafila once inside (50 mg) is not changed.
U volunteers with severe renal insufficiency (CC <= 30 ml / min) clearance sildenafila declined, leading to approximately twofold increase AUC (100%) and Cmax (88%) compared with those of the volunteers, selected by age, which did not have violations of kidney function.
A volunteer with light and medium liver cirrhosis (Child-Pugh A and B) clearance sildenafila declined, resulting in higher AUC (84%) and Cmax (47%) compared with those from normal volunteers with liver function, matched by age.

Indications

-- violations erection of a failure to achieve or sustain penis erection sufficient for the commission of sexual intercourse.
The drug Viagra is effective only with sexual stimulation.

The regime dosing

The drug is taken inside.
For most patients the recommended dose is 50 mg, if necessary, take the drug for about 1 hour before sexual activity. Given the efficiency and portability of the dose may be increased to 100 mg or 25 mg reduced to.
Maximum recommended multiplicity of application - 1 time per day.
In the application of the drug in patients older than 65 years, patients with violations of the functions of the liver, patients with severe renal insufficiency, as well as in patients receiving both drugs - inhibitors of cytochrome P450 3A4 (such as erythromycin, saquinavir) , there is increased in the plasma of Sildenafil, which could help increase the effectiveness of the drug as well as the possibility of the emergence of side-effects. It can be expected that even more powerful inhibitors of cytochrome P450 3 A4, such as ketoconazole or itraconazole, may lead to increased sildenafila in blood plasma. It should discuss the appropriateness of the appointment of the drug in a dose of 25 mg / d from similar groups of patients.
The drug is not intended for the use in patients under the age of 18.

Side-Effects

Side effects encountered more than 5% of patients taking sildenafil as needed, given in the table.

The number of side effects reported case of side-effect (%)
Viagra (n = 734) Placebo (n = 725)
Headache * 16% 4%
Tidal * 10% 1%
Dyspepsia * 7% 2%

* - side effect reported in clinical studies.
In clinical studies II / Phase III selection doses in patients receiving sildenafil as needed, there were between 1% and 5% the following clinically significant side effects, as well as the phenomenon whose connection with the taking was possible:
So part of the body as a whole: asthenia, pain, pain in the abdomen, back pain, infection, grippopodobny syndrome.
So part of the cardiovascular system: vazodilatatsiya (side effect reported in clinical studies).
So part of the digestive system: diarrhea, nausea.
From the musculoskeletal system: pain in the joints, pain in the muscles.
So part of the central nervous system and peripheral nervous system: dizziness (side effect reported in clinical studies), increased muscle tone, insomnia.
So part of the respiratory system: nose nose, pharyngitis, rhinitis (side effect reported in clinical studies), sinusitis, respiratory infections, respiratory function violation.
Dermatologic reaction: rash.
From the senses: vision changes (mild and transient, mainly changing the color of objects, as well as a heightened perception of light and the fog of view - a side effect reported in clinical studies), conjunctivitis.
From the urinary system: urinary tract infection.
So part of the sexual system: violation of the functions of the prostate.
When using the drug Viagra in doses greater than recommended, side effects were similar to those outlined above, but usually meet more often.
Here are undesirable phenomena recorded in the post-application.
So part of the cardiovascular system: arterial hypotension, syncope, tachycardia, palpitation.
So part of the digestive system: vomiting (a side effect reported in clinical studies).
So part of the sexual system: a prolonged erection and / or priapism.
From the senses: the pain in the eyes, redness of the eyes.
Others: allergic reactions.
Side effects were generally transient and light or moderately expressed.
In studies with fixed dose frequency of side effects increased with increasing dose.
The nature of side effects in studies that looked dose, since such studies to better reflect the recommended application of the scheme, was comparable to that in studies with fixed doses.
Contraindications

-- heightened sensitivity to the drug's components.
The drug Viagra is not indicated for use in patients receiving continuously or intermittently donatory nitrogen oxide, organic nitrates or nitrates in any form, as sildenafil enhances hypotensive effect of nitrates taken continuously or in cases of emergency.

Pregnancy and Lactation

The product is not intended to apply to women.
Adequate and strictly controlled tests in pregnancy and during lactation in women has been carried out.
The results of experimental studies
In reproductive studies in rats and rabbits sildenafila oral application does not have teratogenic action will not affect the reproductive function and did not cause violations of the blade / postnatal development.

Cautions

For diagnostic erection violations, determine their causes and possible choices adequate treatment is necessary to build a complete medical history and a thorough physical examination.
Sexual activity is at some risk of heart disease, in this regard before any therapy over violations of erection doctor may deem necessary to survey the cardiovascular system.
In clinical studies Viagra has vazodilatiruyuschee systemic action that leads to a transient lowering of blood pressure. This effect is of little value or no results in any of the consequences for most patients. However, prior to the appointment sildenafila doctor should carefully weigh the risk of unwanted expressions vazodilatiruyuschego action in patients with certain concomitant diseases, especially against the backdrop of sexual activity. Increased susceptibility to vazodilatatoram there is obstruction in patients with left ventricular output tract (such as aortic stenosis, gipertroficheskaya cardiomyopathy), as well as rarely found multiple different systems atrophy, expressed grave violation of the autonomous control of blood pressure.
Drugs intended for the treatment of erection, should be used with caution in patients with anatomical deformation penis (eg angulyatsiya, cavernous fibrosis patient or disease), and in patients with diseases that predispose to the development priapizma (such as sickle cell anemia, multiple myeloma or leukemia).
Drugs intended for the treatment of erection should not appoint men for whom sexual activity is not desirable.
Safety and effectiveness in the application of Viagra in combination with other procedures aimed at treating erection violations are not investigated, so use of such combinations is not recommended.
Research human platelets in vitro showed that Viagra increases antiagregantny effect of sodium nitroprusside (nitric oxide donor).
Details on the safety of Sildenafil in patients with diseases combined krovotochivostyu or exacerbation of ulcer disease, it is not, so such patients should use the drug with caution.
A small number of patients with hereditary pigmentary retinitis are hereditary retinal fosfodiesteraz violations. Details on the safety of sildenafila in patients with retinitis pigment is not, in this regard from sildenafil such patients should be applied with caution.
The use in pediatrics
Sildenafil is not intended to apply in children and adolescents under the age of 18.
The results of experimental studies
There was no evidence of carcinogenicity of the drug found in the 24 - a monthly study in rats at doses of 42 times greater than the maximum recommended dose for humans (MRD), calculated per kg body weight (and 5 times greater than MRD calculated mg / m2 body surface), and 18-21 - a monthly study in mice at doses greater than 5 times MRD calculated in mg / kg body weight (and approximately 2 times greater than in the MRD mg/m2 body surface).
Bacterial and in vivo mutagenicity tests for the study were negative.

Overdose

The studies in healthy volunteers, with a one-time admission of the drug in doses up to 800 mg undesirable phenomena were comparable with those in the employment sildenafila in lower doses, but met more frequently.
Treatment: if necessary hold symptomatic therapy. Dialysis is not sildenafila accelerates clearance, as well as actively associated with the latest plasma proteins and is not displayed with urine.

Drug Interactions

Farmakokinetichesky population analysis of the results of a clinical study showed decline sildenafila clearance while applying CYP 3A4 inhibitors (such as ketoconazole, erythromycin, diazepam).
Cimetidine (800 mg), a nonspecific inhibitor of CYP 3A4, while admission to sildenafilom sildenafila aroused increasing concentration in plasma by 56% in healthy volunteers.
A one-time admission sildenafila in a dose of 100 mg at the same time as eritromitsinom, a specific inhibitor of CYP 3A4 (in the employment eritromitsina 2 times per day to 500 mg for 5 days), against the backdrop of a permanent eritromitsina level in the blood, helped increase the AUC sildenafila by 182%. Also, while applying sildenafila (once in a dose of 100 mg) and sakvinavira, an inhibitor of the HIV protease, and the inhibitor of CYP 3A4 (in the employment sakvinavira 3 times per day in a dose of 1200 mg) against the backdrop of a permanent sakvinavira level in the blood, sildenafila maximum concentration in the blood increased 140%, and AUC increased to 210%. Viagra has no effect on the pharmacokinetic parameters sakvinavira. It can be expected that more powerful inhibitors of cytochrome P450 3A4, such as ketoconazole or itraconazole will result in an increase sildenafila level in the blood plasma.
The combined application sildenafila (once in a dose of 100 mg) and ritonavira, an HIV protease inhibitor and potent inhibitor of cytochrome enough R450 (with the admission of ritonavira 500 mg 2 times / day) against the backdrop of a permanent ritonavira level in the blood, Cmax increased by 300 sildenafila % (4 - multiply), and AUC at 1000% (11 - multiply). After 24 h sildenafila level in the blood plasma was approximately 200 ng / ml (comparative concentration in one single application sildenafila after 24 h was 5 ng / ml). This is consistent with the action of ritonavira to a range of drugs that are substrates cytochrome R450.
Viagra has no effect on the pharmacokinetic parameters ritonavira.
A one-time admission antatsida (magnesium hydroxide / aluminium hydroxide) is not affected by sildenafila bioavailability.
The results of pharmacokinetic studies of patients who participated in clinical trials sildenafila showed that the CYP 2 inhibitors S9 (such as tolbutamid, warfarin), CYP 2D6 (such as a reverse takeover selective serotonin inhibitors, tricyclic antidepressants), thiazides and tiazidopodobnye Diuretics, loop and kaliysberegayuschie Diuretics , APF inhibitors and calcium antagonists, are not affected at sildenafila pharmacokinetic parameters.
In healthy male volunteers azithromycin (500 mg / day for 3 days) did not influence AUC, Cmax, Tmax, and removing a constant speed T1 / 2 sildenafila or his main circulating metabolite.
Sildenafil aggravated hypotensive effect of nitrates in the core sample, and with long-term use the latest (sildenafila use in combination with nitrates or nitric oxide donatorami protivopokazano).
No signs of significant interaction with sildenafila tolbutamidom (250 mg) or varfarinom (40 mg), which are metabolised CYP 2 S9 not identified.
Sildenafil in a dose of 100 mg not influence pharmacokinetic parameters of the HIV protease inhibitors, with their constant level in the blood, such as saquinavir and ritonavir that are CYP 3A4 substrate.
Sildenafil (50 mg) did not cause further increases bleeding time in the admission of acetylsalicylic acid (150 mg).
Viagra (50 mg) did not enhance hypotensive effect of ethanol in healthy volunteers with the maximum level of ethanol in the blood by an average 80 mg / ml.
In patients with hypertension signs interaction sildenafila (100 mg) with amlodipinom not disclosed. The average additional reduction of blood pressure in lying position was: systolic - an 8 mm Hg, diastolic - by 7 mmHg
Analysis of the lack of security demonstrated differences nature of side effects in patients receiving Viagra in combination with antihypertensives means and without them.

Terms and Conditions of storage

The product should be stored at room temperature (15 ° to 30 ° C). Cautions - 5 years.
Terms of the leave pharmacies
The drug is released with a prescription.

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