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Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

Vorinostat therapy is also associated with a risk of QT prolongation. Zafirlukast: (Minor) Vardenafil is metabolized by CYP3A4. Inhibitors of CYP3A4, such as zafirlukast, can reduce vardenafil clearance.

Increased systemic exposure sildenafil online pharmacy to vardenafil may result in an increase in vardenafil-induced adverse effects. Zileuton: (Minor) Vardenafil is metabolized by CYP3A4. Inhibitors of CYP3A4, such as zileuton, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.

Ziprasidone: (Major) Concomitant use of ziprasidone and vardenafil should be avoided due to the potential for additive QT prolongation.

Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.

In animal reproduction studies, no adverse developmental outcomes were observed during organogenesis at exposures for unbound vardenafil and its major metabolite at 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg.

Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. There is no information on the presence of vardenafil and its major metabolite in human milk, the effects on the breast-fed infant, or the effects on milk production. Vardenafil is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma; following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours. Mechanism of Action: Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP.

Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined.

Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum.

Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum.

Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation.

Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone.

These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD).

Dyspepsia is one of the more common adverse reactions associated with PDE inhibitor therapy. Vardenafil is extensively distributed throughout the body. Clearance is primarily via the hepatic cytochrome P450 isoenzyme CYP3A4 with minor metabolism by CYP3A5 and CYP2C.

The major metabolite, designated M1, is the result of desethylation at the piperazine moiety of vardenafil and is further metabolized. M1 has phosphodiesterase selectivity similar to that of vardenafil and an in vitro inhibitory potency for phosphodiesterase 5 (PDE5) that is 28% of that of vardenafil.

M1 also accounts for about 7% of the total pharmacological activity. Vardenafil is excreted as metabolites predominantly in the feces (approximately 91—95% of an oral dose) and to a lesser extent in the urine (about 2—6% of an oral dose).

The elimination half-life of vardenafil and M1 is about 4—5 hours with the use of the film-coated tablets.

The elimination half-life of vardenafil is 4—6 hours and the elimination half-life of MI is 3—5 hours with the use of the orally disintegrating tablets.

Oral film-coated tablets: Vardenafil is well-adsorbed from the gastrointestinal tract.

In healthy volunteers, peak plasma concentrations (Cmax) following a single 20 mg oral tablet dose are usually reached between 30 minutes and 2 hours (median 60 minutes) in the fasted state. The onset of action is within 1 hour of administration.

Orally disintegrating tablets: The orally disintegrating vardenafil tablets provide a higher systemic exposure than the film-coated tablets.

In a study of patients with erectile dysfunction, the mean AUC was increased by 21—29% and the mean Cmax was decreased by 19% in elderly patients (>=65) and 8% in younger patients (18—45 years) as compared to the 10 mg film-coated tablets.

In a study of healthy male volunteers (18—50 years), the mean Cmax was 15% higher and the mean AUC was 44% higher as compared to the 10 mg film-coated tablets. The median time to reach Cmax in a fasted stated was 1.5 h. High fat meals had no effect on vardenafil AUC or Tmax in healthy volunteers, but reduced the Cmax by 35%.

When the orally disintegrating vardenafil tablets were administered with water, the vardenafil AUC was reduced by 29% and the median Tmax was shortened by 60 minutes, while Cmax was not affected. Efficacy and safety of silodosin, vardenafil versus silodosin in

combination

Urolithiasis is considered one of the most common diseases in urological practice. Its prevalence is about 1% to 15% with 30 years old as the peak age of incidence. Medical expulsive therapy (MET) has been used as a conservative treatment for patients with ureteral stones. Nitrergic fibers have been identified to have a relaxant effect on the distal ureteral smooth musculature. The objective of our study was to evaluate the efficacy and safety of the combination of silodosin and vardenafil as a medical expulsive therapy in comparison with each drug alone. One hundred and two male patients with uncomplicated distal ureteric stone 6–10 mm were enrolled in the study. The patients were randomly divided into 3 equal groups, and each one consists of 34 patients.

Group I received silodosin 8 mg once daily, group II vardenafil 5 mg once daily and group III combination of silodosin 8 mg and vardenafil 5 mg once daily.

The treatment was given for all the patients until stone expulsion or a maximum of 4 weeks. The primary endpoint was the stone expulsion rate, and the secondary endpoints were time to stone expulsion, number of hospital visits for pain, amount of analgesic required and side effects associated with MET. Our study showed that the stone expulsion rate was higher in combination = 90.0% than silodosin = 76.7% and vardenafil groups = 60.0% ( P = 0.025), the time to stone expulsion was significantly shorter in combination = 11.23 ± 3.14 than silodosin = 12.50 ± 1.66 and vardenafil groups 14.67 ± 1.24 days ( P. Urolithiasis is considered one of the most common diseases in urological practice. The prevalence about 1% to 15% with 30 years is the peak age of incidence. Ureteral stones represent 20% of all urolithiasis, and about 70% of ureteral stones are in the distal ureter [1].

Ureteral stones lead to ureteral spasms which interfere with stone expulsion.

Therefore, trials to reduce these spasms without affecting the normal peristaltic activity have been made to aid stone expulsion.

Medical expulsive therapy (MET) especially using ?-blockers has been used as conservative treatment for patients with ureteral stones [2]. ?1 receptors are further classified into 3 subtypes of ?-1A, ?-1B and ?-1D, ?-1D > ?-1A > ?-1B in their distribution in the ureter.

?1-adrenoceptors stimulation leads to increase in the ureteric peristalsis frequency and the power of ureteric sildenafil online pharmacy contractions. Therefore, blockage of these receptors using silodosin reduces ureteral tone and decreases peristaltic force and frequency, leading to lowering of ureteral intra-luminal pressure which increases the stone passage chance [3].

Silodosin is a more selective ?-1A adrenoceptor blocker with a better stone expulsion rate than tamsulosin [4]. Nitrergic fibers have been identified to have a relaxant effect on the distal ureteral smooth musculature [5].

Recently, investigators focused on how blockade of this nitric buy sildenafil online without prescription oxide pathway can be effectively carried out in clinical practice until phosphodiesterase-5 inhibitors (PDE5Is) existed [6, 7].

reported that vardenafil is more potent in ureteral muscles relaxation than sildenafil and tadalafil [8]. Previous study had demonstrated that the combination of silodosin and tadalafil is more potent than either drug alone for the treatment of distal ureteric stones [1], but no study has been reported using vardenafil and silodosin in combination for the treatment of distal ureteric stones.