PDE5/phosphodiesterase 5

When 1 μM sildenafil was pretreated instead of serotonin stimulation alone, it improved phosphorylation of ERK1/ERK2, increased the percentage of cells in S phase, and promoted cell proliferation (P<0.05). The OD value increased dramatically to 0.33 after pretreatment with 1 μM sildenafil citrate and serotonin stimulation, which was significantly different from serotonin stimulation alone (P<0.05). The phosphorylation of ERK1/ERK2 elicited by serotonin was considerably increased by 1 μM sildenafil [2].

Sildenafil considerably raised ICP and ICP/BP in a canine erection model, but it had no discernible effect on blood pressure when compared to the vehicle [1]. At a dose of 10 mg/kg, sildenafil therapy dramatically decreased the number of TL+- cells. Eight days after pMCAo, sildenafil therapy (0.5 and/or 10 mg/kg dosages) dramatically decreased the amount of microglia/macrophages stained by Iba-1 [3]. According to preclinical animal models, sildenafil can lessen flap necrosis by secreting more growth factors (FGF and VEGF). It has also been demonstrated histologically to be beneficial against cavernous neural structures in rats [4].

All experiments on ERK1/ERK2 activation, MKP-1, PCNA expression, as well as cell proliferation and cell cycle analysis were performed on cells that were three days in culture at passages 3-5. Thereafter, cells were serum starved for three days in RPMI-1640 containing 0.2% FBS and 1% antibiotics. Cells were then exposed to serotonin or sildenafil at 1 μmol/L then serotonin, as indicated. In some experiments, cells were pretreated with 10 μmol/L of U0126 for 30 minutes before sildenafil and subsequently exposed to serotonin, as indicated. In control groups, an equal volume of phosphate buffered saline (PBS) was substituted for the reagents.[2]

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Immunoblotting analysis of ERK1/ERK2 phosphorylation status[2]
Subconfluent serum-starved cells were treated with serotonin or 1 μmol/L sildenafil then serotonin stimulation with or without U0126, as indicated above. Protein was extracted at the indicated time as described above. Phosphorylation of ERK1/ERK2 protein was examined by Western blotting. Briefly, equal amounts of proteins (15-20 μg) were separated by SDS-PAGE, transferred to polyvinylidene difluoride membranes, probed with anti-phospho-ERKl/ERK2 antibody, and detected with horseradish peroxidase (HRP)-conjugated secondary antibody. To determine the expression of total ERK1/ERK2, the membrane was washed with stripping buffer at 50°C for 30 minutes, followed by blocking the membrane with 5% bovine serum albumin in PBST for 4 hours. Thereafter, the membrane was re-probed with specific ERK1/ERK2 antibody.

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Immunoblotting analysis of MKP-1, PCNA[2]
Subconfluent serum starved PASMCs were exposed to sildenafil, serotonin or U0126 for different periods of time as described above. At the end of the incubation period, protein was extracted and separated by SDS-PAGE with 12% gels. Then total protein was transferred to polyvinylidene difluoride membrane, and probed with PCNA and MKP-1 antibody (1:1000), glyceraldehydes phosphate dehydrogenase (GAPDH) antibody (1:2000) at 4°C overnight. After being washed, the appropriate secondary antibodies (1:5000) were added for one hour at room temperature. The blots were developed with a Super Signal enhanced chemiluminescence kit and visualized on Kodak-AR film. The bands were quantified by densitometry using image analysis software. The relative expression of protein was normalized to GAPDH.

MTT colorimetric assay[2]
Cells at approximately 90% confluence were harvested with 0.1% trypsin/0.01% ethylene diamine tetraacetic acid (EDTA) solution and seeded into a 96-well plate at a density of 2x104 cells/well and grown in RPMI-1640 containing 10% FBS for three days, followed by serum starvation for three days. Cells were then incubated for different time with various concentration of serotonin or 1 μmol/Lsildenafil followed by serotonin with or without U0126, as indicated. Control cells were treated in the same way except sterile PBS replaced the drug. After treatment, medium was changed to fresh medium, and cells were incubated with 5 g/L of MTT for four hours. MTT was then dissolved with 150 μl of 10% dimethylsulfoxide (DMSO) for 20 minutes. The optical densities (OD) in the 96-well plates were determined using a microplate reader at 570 nm.

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Flow cytometry analysis[2]
Cells at approximately 90% confluence were harvested with 0.1% trypsin/0.01% EDTA and seeded into 6-well plates at a density of 5x104 cells/well and grown in RPMI-1640 containing 10% FBS for 3 days, followed by serum starvation for 3 days. Then cells were incubated for 24 hours with serotonin or 1 μmol/L sildenafil followed by serotonin stimulation with or without U0126, as indicated. Cells were rinsed with PBS, trypsinized with 0.1% trypsin/0.01% EDTA solution, and collected by centrifugation at 1000 r/min at 20°C for five minutes. The cell pellets were fixed in 70% ethanol at 4°C for at least 24 hours. The fixed cells were washed twice with PBS, resuspended in PBS containing 50 g/L RNase A and 50 mg/L of propidium iodide (PI). The suspension was incubated at 37°C for 30 minutes, filtered through 200 μm nylon mesh, then analyzed by flow cytometer (FACS Calibur). The ModfitLT software was used for data analysis. The ratio of cells in S phase to all cells that are in G0G1+ S + G2M was calculated by the formula: S phase fraction (SPF) =S/(G0G1+S+G2M) x100%

In the first set of experiments, animals were randomly divided into five groups and treated with either PBS or a single dose of sildenafil citrate (0.5, 2.5, 10, and 15 mg/kg), given intraperitoneally (i.p.) 5 min after pMCAo. In the second set of experiments, animals were randomly divided into three groups and treated with either PBS or a single dose of sildenafil citrate (0.5 and 10 mg/kg, i.p.) 5 min after pMCAo (see Additional file 1: Figure S1 for an outline of the experimental procedure).[3]

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cGMP measurement[3]
Competitive enzyme immunoassay was used to quantify cGMP in the forebrain, according to the manufacturer’s instructions. Whole brains at P9 were harvested 1 and 3 h after the administration of sildenafil (0.5 and/or 10 mg/kg) and immediately frozen at −80 °C until measurements were performed.

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Ultrasonographic brain imaging[3]
Thermoregulated mice (n = 6 per group) were subjected to ultrasound measurements under inhaled isoflurane anesthesia (0.8 % in air via a facemask) using an echograph equipped with a 14.5-MHz linear transducer (14L5 SP) [12]. Heart rate and time-average mean blood flow velocities (mBFVs) were measured in both intracranial carotid arteries (ICA) and the basilar trunk (BT) at baseline and 1 h after pMCAo and PBS and sildenafil (10 mg/kg) treatment.

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The study included a total of thirty adult Sprague-Dawley rats that were divided into three groups of ten rats each. In all rats, a crush injury was created by clamping the right sciatic nerve for one minute. One day before the procedure, rats in group 1 were started on a 28-day treatment consisting of a daily dose of 20 mg/kg body weight sildenafil citrate given orally via a nasogastric tube, while the rats in group 2 were started on an every-other-day dose of 10 mg/kg body weight sildenafil citrate. Rats from group 3 were not administered any drugs. Forty-two days after the nerve damage was created, functional and histopathological examination of both sciatic nerves and bone densitometric evaluation of the extremities were conducted.[4]

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20 mg/kg

Sprague-Dawley rats

Absorption, Distribution and Excretion
Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient. Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%). In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg. When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses. Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29%. Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 %.
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues.
The total body clearance documented for sildenafil is 41 L/h.
Sildenafil is rapidly and almost completely absorbed following oral administration. Bioequivalence has been established between the 20-mg tablet and the 10-mg/mL oral suspension when administered as a single oral dose of 20 mg. Although single-dose studies indicate that more than 90% of an oral sildenafil dose is absorbed from the GI tract, the drug undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver, with only about 40% of a dose reaching systemic circulation unchanged. Pharmacokinetics of the drug (as determined by peak plasma concentrations or area under the plasma concentration-time curve (AUC)) are dose proportional over the single-dose range of 1.25-200 mg. Peak plasma concentrations of sildenafil and its active N-desmethyl metabolite are achieved within 30-120 (median: 60) minutes following oral administration in fasting adults.
Sildenafil appears to be widely distributed in the body, with a reported volume of distribution at steady state averaging 105 L. It is not known whether sildenafil is distributed into milk. Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins; protein binding reportedly is independent of plasma concentration over the range of 0.01-10 ug/mL. Plasma protein binding of the drug in geriatric adults older than 65 years of age is slightly greater (97%) than that observed in individuals younger than 45 years of age (96%). Sildenafil is distributed to a limited extent in semen following oral administration, with less than 0.001% of a single dose appearing in semen 90 minutes after dosing in healthy individuals Such concentrations are unlikely to cause any effects in sexual partners exposed to the semen.
Sildenafil is eliminated mainly in the feces as metabolites. In healthy adults and those with erectile dysfunction, approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine.
In volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of Viagra (50 mg) were not altered. In volunteers with severe (CLcr=<30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.
For more Absorption, Distribution and Excretion (Complete) data for SILDENAFIL (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes. The predominant circulating metabolite results from the N-demethylation of sildenafil. This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug. Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects. This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects.
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a phosphodiesterase (PDE) selectivity profile similar to sildenafil and an in vitro potency for phosphodiesterase type 5 (PDE-5) approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.
Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or (14)C-sildenafil (Viagra). .... Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. Sildenafil was the major component detected in human plasma. Following oral doses, AUC (infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.
Sildenafil is eliminated mainly in the feces as metabolites. In healthy adults and those with erectile dysfunction, approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine. In feces, the N-dealkylated, hydroxylated, N-demethylated, and N-dealkylated/demethylated metabolites of sildenafil comprise about 22, 13, 3, and 3% of total fecal excretion. In healthy individuals, sildenafil is excreted in urine mainly as the hydroxylated metabolite, with this metabolite representing about 41% of total urinary excretion of the drug.
/Sprague Dawley rats (10/sex/dose) were administered 10, 45 or 200 mg/kg/day of sildenafil for 1 month by oral gavage./ Plasma concentrations of sildenafil were higher in females than in males, while concentrations of the metabolite, UK-103,320, were higher in males than in females. As a result, females were exposed predominantly to the unchanged drug and males to an almost equal balance of drug and metabolite. These data indicate that N-demethylation of sildenafil to UK-103,320 is an important route of sildenafil biotransformation in male rats. Concentrations of UK-95,340 were generally below the limit of determination (30 ng/mL). ... /From table/
Sildenafil appears to be completely metabolized in the liver to up to 16 metabolites, most of which represent only a small fraction of a dose; little or no unchanged drug is detectable in urine or feces following oral or IV administration. Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route), and potent inhibitors of CYP3A4 can substantially reduce sildenafil clearance. Hepatic metabolism of sildenafil is complex, generally involving the piperazine ring, N,N-de-ethylation (ring opening) or N-demethylation of the piperazine ring and aliphatic hydroxylation; the drug and its metabolites do not appear to undergo conjugation. The N-demethylated metabolite, the major circulating metabolite, has a phosphodiesterase selectivity profile similar to that of sildenafil and an in vitro potency for PDE type 5 of approximately 50% of the parent drug. The N-demethylated metabolite is further metabolized to an N-dealkylated N,N-de-ethylated) metabolite. The drug also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

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Biological Half-Life
The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours.
Plasma sildenafil concentrations appear to decline in a biphasic manner following oral administration, with a terminal elimination half-life of about 4 hours (range: 3-5 hours).
High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 hr), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 hr respectively).

Toxicity Summary
IDENTIFICATION AND USE: Sildenafil is a white to off-white crystalline powder that is formulated into film-coated tablets, oral suspension, and parenteral injection. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor. It is used both for the treatment of erectile dysfunction and for the treatment of pulmonary arterial hypertension (PAH) in adults to improve exercise ability and delay clinical worsening. HUMAN EXPOSURE AND TOXICITY: In general, overdosage of sildenafil may be expected to produce effects that are extensions of common adverse reactions. In studies of healthy individuals receiving single sildenafil doses up to 800 mg, the types of adverse events (e.g., decreased blood pressure, syncope, and prolonged erection) observed were similar to those observed at lower doses, but the incidences were increased. Serious adverse effects have also been reported at therapeutic dose levels including sudden decrease or loss of hearing, sudden loss of vision in one or both eyes, and prolonged erection lasting greater than 4 hours or priapism (a painful erection lasting greater than 6 hours). Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil for erectile dysfunction. Most, but not all, of these patients had preexisting cardiovascular risk factors. Therefore it was not possible to determine whether these events were related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors. The use of sildenafil is not recommended in children. In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Pulmonary vasodilators such as sildenafil may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Sildenafil profoundly potentiates the vasodilatory effects of organic nitrates and nitrites. The drug did not exhibit clastogenic potential in an in vitro human lymphocytes test system. ANIMAL STUDIES: Lethality after oral administration occurred at 1000 mg/kg and 500 mg/kg in rats and 1000 mg/kg in mice. Female rats were more affected than male rats. Acute sildenafil treatment stimulated testosterone production in adult male rats. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males. However, in another study male rats were gavaged with sildenafil citrate (0.06 mg/0.05 mL) and allowed to mate. Fertilization rates and numbers of embryos were evaluated after treatment. Fertilization rates (day 1) were markedly reduced (approximately 33%) in matings where the male had taken sildenafil citrate. Over days 2-4, the numbers of embryos developing in the treated group were significantly fewer than in the control group. There was also a trend for impaired cleavage rates within those embryos, although this did not reach significance. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. In another study, adult male rabbits received sildenafil at doses up to 9 mg/kg/day for 4 weeks to investigate the testicular histological alterations induced by overdoses of this drug. Abnormality in the germinal epithelium of the seminiferous tubules included spermatocytes karyopyknosis, spermatocytes degeneration, desquamation, spermatid giant cells and arrest of spermatogenesis. Additionally, increased Leydig cells cellularity, tubular degeneration, thickening of the interstitium were also observed. The encountered histological findings indicate that chronic exposure to sildenafil overdoses produces significant morphological and histological alterations in the testes which finally might lead to complete arrest of spermatogenesis. There was no evidence of carcinogenicity when sildenafil was administered orally to rats and mice for up to two years. Sildenafil did not exhibit evidence of mutagenicity in vitro in bacterial and Chinese hamster ovary cell assays. The drug also did not exhibit clastogenic potential in vivo in the mouse micronucleus test. Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a phosphodiesterase (PDE) selectivity profile similar to sildenafil and an in vitro potency for phosphodiesterase type 5 (PDE-5) approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.

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Hepatotoxicity
There have been at least 5 reports of acute liver injury attibuted to sildenafil use, but no instances of acute hepatic failure. The latency in most reports has been unclear because of the intermittent and sometimes unacknowledged use of sildenafil, but appears to be within 1 to 8 weeks. The pattern of serum enzyme elevations has ranged from hepatocellular to cholestatic, sometimes evolving from one to the other. The most convincing cases have been a mild cholestatic or "mixed" hepatitis arising within 1 to 3 months of starting sildenafil. Immunoallergic features and autoantibodies were not observed. Cases of acute onset with high serum aminotransferase levels have been reported after use of sildenafil that have some characteristics of ischemic injury. In other instances, the pattern of injury suggested anabolic steroid use. In two cases, re-exposure did not result in recurrence. Thus, the hepatotoxicity of sildenafil is not completely convincing and must be quite rare, if it occurs at all.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited data indicate that sildenafil and its active metabolite in breastmilk are poorly excreted into breastmilk. Amounts ingested by the infant are far below doses given to treat infants and would not be expected to cause any adverse effects in breastfed infants.
◉ Effects in Breastfed Infants
A 23-year-old woman with congenital heart disease and pulmonary hypertension was treated during pregnancy with sildenafil and bosentan in unspecified dosages. These drugs and warfarin were continued postpartum. Her infant was delivered at 30 weeks by cesarean section and weighed 1.41 kg at birth. She nursed the infant in the neonatal intensive care unit for 11 weeks "with good outcome" according to the authors, but the infant died at 26 weeks from a respiratory syncytial virus infection.[3]
A woman breastfeeding her 21-month-old infant was taking 20 mg of sildenafil 3 times daily and 125 mg of bosentan twice daily to treat pulmonary arterial hypertension. The drugs were begun more than 6 months postpartum. The mother did not report any possible adverse effects, serious health problems or hospitalization of the infant in the period from birth until day 651 postpartum when the infant was partially breastfed.[2]
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins. Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations.

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Interactions
Sildenafil and other phosphodiesterase (PDE) type 5 inhibitors (e.g., tadalafil, vardenafil) profoundly potentiate the vasodilatory effects (e.g., a systolic blood pressure reduction exceeding 25 mm Hg with sildenafil) of organic nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate), and potentially life-threatening hypotension and/or hemodynamic compromise can result. Nitrates and nitrites promote the formation of cyclic guanosine monophosphate (cGMP) by stimulating guanylate cyclase, and PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) act to decrease the degradation of cGMP via phosphodiesterase (PDE) type 5 by inhibiting this enzyme, resulting in increased accumulation of cGMP and more pronounced smooth muscle relaxation and vasodilation than with either PDE type 5 inhibitors or nitrates/nitrites alone. This interaction probably occurs with any organic nitrate, nitrite, or nitric oxide donor (e.g., nitroprusside) regardless of their predominant hemodynamic site of action.
PDE type 5 inhibitors /including sildenafil/ also may potentiate the hypotensive effects of inhaled nitrites (e.g., amyl or butyl nitrite, sometimes referred to as poppers), which may be misused (recreational use) during sexual activity for purported effects in enhancing the sexual experience. Because these agents are used recreationally, patients may be unaware of their pharmacologic effects and potential risks and may not report their use to clinicians. Concurrent use of PDE type 5 inhibitors with poppers, which dilate blood vessels with a rapid onset of action, could result in sudden and marked blood pressure reduction and potentially serious or even fatal effects. Interactions with organic nitrates and nitrites may be even more pronounced in patients who also are taking certain HIV protease inhibitors concomitantly. Homosexual males may be at particular risk because of the greater likelihood of recreational inhaled nitrite use and antiretroviral therapy in this population.
Combination antiretroviral therapy usually includes one or more HIV protease inhibitors that are inhibitors of CYP3A4 and/or CYP2C9, and the possibility for an interaction with sildenafil clearance resulting in an increased likelihood of sildenafil-associated adverse effects such as headache, flushing, visual changes, priapism, and possibly hypotension and syncope exists. Patients should inform their clinician if they are taking antiretroviral therapy.
Sildenafil potentiates the hypotensive effect of nitrates /including nitroglycerin/; concomitant use is contraindicated.
For more Interactions (Complete) data for SILDENAFIL (23 total), please visit the HSDB record page.

[1]. The Selectivity and Potency of the New PDE5 Inhibitor TPN729MA. J Sex Med. 2013 Nov;10(11):2790-7.

[2]. Sildenafil potentiates the proliferative effect of porcine pulmonary artery smooth muscle cells induced by serotonin in vitro. Chin Med J (Engl). 2011 Sep;124(17):2733-40.

[3]. Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. J Neuroinflammation. 2016 Apr 28;13(1):95.

[4]. The Effect of Sildenafil on Recuperation from Sciatic Nerve Injury in Rats. Balkan Med J. 2016 Mar;33(2):204-11.

Therapeutic Uses
Phosphodiesterase 5 Inhibitors; Urological Agents; Vasodilator Agents
Viagra is indicated for the treatment of erectile dysfunction. /Included in US product labeling/
Revatio is indicated for the treatment of pulmonary arterial hypertension in adults to improve exercise ability and delay clinical worsening. /Included in US product label/
The role, if any, of sildenafil in the management of sexual dysfunction in women remains to be established. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for SILDENAFIL (9 total), please visit the HSDB record page.

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Drug Warnings
Administration of Viagra with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, Viagra was shown to potentiate the hypotensive effects of nitrates.
Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of Viagra. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Viagra without sexual activity. Others were reported to have occurred hours to days after the use of Viagra and sexual activity. It is not possible to determine whether these events are related directly to Viagra, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors.
Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Viagra. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.
Angina pectoris, AV block, tachycardia, palpitation, myocardial ischemia and infarction, sudden cardiac death, chest pain, cerebral thrombosis, cerebrovascular hemorrhage (e.g., subarachnoid, intracerebral hemorrhage), transient ischemic attack, stroke (e.g., hemorrhagic or brainstem), cardiac or cardiopulmonary arrest, coronary artery disease, heart failure, electrocardiographic (ECG) abnormalities including ventricular arrhythmia (e.g., tachycardia, premature complexes) or Q-wave abnormalities (without myocardial infarction), hypertension, edema (including facial and peripheral), shock, and cardiomyopathy also have occurred in less than 2% of patients with erectile dysfunction receiving sildenafil in controlled clinical trials and in postmarketing surveillance, but have not been directly attributed to the drug. The incidence of myocardial infarction or stroke was similar in patients receiving sildenafil for the treatment of erectile dysfunction or placebo, and most cases occurred within a few hours to days after a sildenafil dose or placebo. Most patients experiencing serious adverse cardiovascular effects had preexisting cardiovascular risk factors, and many of these effects were reported to occur shortly after taking sildenafil, either with or without sexual activity. In at least one patient with hypertrophic cardiomyopathy, decreased blood pressure, marked reductions in ventricular dimensions, increased ejection fraction and subaortic gradient at rest, ventricular premature complexes, and unsustained ventricular tachycardia occurred following sildenafil administration for the treatment of erectile dysfunction.
For more Drug Warnings (Complete) data for SILDENAFIL (32 total), please visit the HSDB record page.

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Pharmacodynamics
In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg) . At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test).

C22H30N6O4S

474.5764

474.204

C, 55.68; H, 6.37; N, 17.71; O, 13.48; S, 6.76

139755-83-2

Sildenafil citrate;171599-83-0;Sildenafil-d3;1126745-90-1;Sildenafil-d8;951385-68-5;Sildenafil Mesylate;1308285-21-3;Sildenafil-d3N-1;1126745-87-6

135398744

White to off-white solid powder

189-190 °C
187-189 °C

1.5

1

8

7

33

838

0

S(C1C([H])=C([H])C(=C(C2=NC3C(C([H])([H])C([H])([H])C([H])([H])[H])=NN(C([H])([H])[H])C=3C(N2[H])=O)C=1[H])OC([H])([H])C([H])([H])[H])(N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])(=O)=O

BNRNXUUZRGQAQC-UHFFFAOYSA-N

InChI=1S/C22H30N6O4S/c1-5-7-17-19-20(27(4)25-17)22(29)24-21(23-19)16-14-15(8-9-18(16)32-6-2)33(30,31)28-12-10-26(3)11-13-28/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29)

Piperazine, 1-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methyl-

UK-92480; UK 92480-10; UK 92480; UK92480 citrate; UK-92,480-10. Trade names: Revatio.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol:30 mg/mL

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Solubility in Formulation 4: ≥ 10 mg/mL (21.07 mM) (saturation unknown) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)