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Sildenafil Mesylate (formerly UK-92480; UK92480; Revatio), the mesylate salt form of Sildenafil, is deemed as the best treatment for erectile dysfunction. It is also used as a medication to treat pulmonary arterial hypertension. Sildenafil Mesylate acts as a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) with IC50 of 5.22 nM.
| Targets |
PDE5/phosphodiesterase 5
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| ln Vitro |
When compared to serotonin stimulation alone, pretreatment with 1 μM sildenafil citrate enhances phosphorylation of ERK1/ERK2, increases the proportion of cells in S phase, and promotes cell proliferation (P<0.05). An abrupt rise in the optical density (OD value) to 0.33 occurs after pretreatment with 1 μM sildenafil citrate and serotonin stimulation. This is significantly different from serotonin stimulation alone (P<0.05). It is evident that 1 μM sildenafil increases the upregulation of serotonin-induced ERK1/ERK2 phosphorylation[2].
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| ln Vivo |
Sildenafil citrate dramatically raises ICP and ICP/BP in the canine erection model, but has no discernible effect on blood pressure when compared to the vehicle[1]. Treatment with sildenafil dramatically reduces TL+-cell counts at 10 mg/kg, but not at 0.5 mg/kg. At this stage, animals treated with PBS have cells positive for the M1-like marker COX-2+ in the ischemic core, while animals treated with 10 mg/kg of sildenafil (but not 0.5 mg/kg) have most of these cells in the penumbra. In contrast, sildenafil therapy (0.5 or 10 mg/kg dosage) significantly reduces the amount of microglia/macrophages stained by Iba-1 eight days after pMCAo[3]. By boosting the release of growth factors (FGF and VEGF), sildenafil citrate has been proven to reduce flap necrosis in preclinical animal models. It has also been demonstrated histologically to be efficacious in rat cavernous nerve architecture[4].
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| Enzyme Assay |
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]
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. 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. |
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| Cell Assay |
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. 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% |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Absorption 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 %. Route of Elimination 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). Volume of Distribution 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. Clearance 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. View More
Metabolism / Metabolites
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). |
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| Toxicity/Toxicokinetics |
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. 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). Effects During Pregnancy and Lactation View More
◉ Summary of Use during Lactation
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. 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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| Additional Infomation |
Sildenafil citrate is the citrate salt of sildenafil. It has a role as a vasodilator agent and an EC 3.1.4.35 (3',5'-cyclic-GMP phosphodiesterase) inhibitor. It contains a sildenafil.
Sildenafil Citrate is the citrate salt form of sildenafil, an orally bioavailable pyrazolopyrimidinone derivative structurally related to zaprinast, with vasodilating and potential anti-inflammatory activities. Upon oral administration, sildenafil selectively targets and inhibits cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), thereby inhibiting the PDE5-mediated degradation of cGMP found in smooth muscle and increasing cGMP availability. This results in prolonged smooth muscle relaxation in the corpus cavernosum of the penis, thereby causing vasodilation, blood engorgement and a prolonged penile erection. In the smooth muscle of the pulmonary vasculature, the increase in cGMP results in smooth muscle relaxation, vasodilation of the pulmonary vascular bed, relieving pulmonary hypertension and increasing blood flow in the lungs. In addition, sildenafil may reduce airway inflammation and mucus production. A PHOSPHODIESTERASE TYPE-5 INHIBITOR; VASODILATOR AGENT and UROLOGICAL AGENT that is used in the treatment of ERECTILE DYSFUNCTION and PRIMARY PULMONARY HYPERTENSION. Drug Indication AdultsTreatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. Paediatric populationTreatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see section 5. 1). AdultsTreatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. Paediatric populationTreatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. Drug Indication Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor that is predominantly employed for two primary indications: (1) the treatment of erectile dysfunction; and (2) treatment of pulmonary hypertension, where: a) the US FDA specifically indicates sildenafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%); b) the Canadian product monograph specifically indicates sildenafil for the treatment of primary pulmonary arterial hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) in adult patients with WHO functional class II or III who have not responded to conventional therapy. In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy; and c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. View MoreTreatment of adult patients with pulmonary arterial hypertension classified as World Health Organization (WHO) functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. Paediatric populationTreatment of paediatric patients aged one year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. Revatio solution for injection is for the treatment of adult patients with pulmonary arterial hypertension who are currently prescribed oral Revatio and who are temporarily unable to take oral therapy, but are otherwise clinically and haemodynamically stable. Revatio (oral) is indicated for treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. 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/ 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. 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). Mechanism of Action Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the 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 cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. By diminishing the effect of PDE5, sildenafil facilitates the effect of nitric oxide during sexual stimulation; cGMP levels increase, smooth muscle relaxes, and blood flows into the corpus cavernosum, producing an erection. Without sexual stimulation, sildenafil has no effect on erections. It has been extensively demonstrated that hydrogen sulfide (H2S) is implicated is several physiological and pathological conditions. In particular, it has been shown that H2S causes relaxation in human penile tissues and inhibits phosphodiesterase (PDE) activity in vessels. Beside sildenafil increases H2S generation in human bladder and tadalafil in myocardial tissues. Therefore, /the/ aim /of the study/ was to demonstrate the link between H2S and PDE-5 in mice corpus cavernosum tissues. ... The effects of sildenafil (10 uM, 0.5 hr); PDE-5 inhibitor, on H2S production as well as the H2S -induced relaxations in mice penile tissues /was investigated/. Penile tissues from CD1 mouse corpus cavernosum (MCC) were used. Functional studies were performed by myograph in Krebs solution. Western blot analysis was performed in order to evaluate CBS and CSE expression and methylene blue assay for measurement of H2S levels. In order to investigate functional significance of H2S on sildenafil-induced augmentation of endothelial relaxation in MCC the sildenafil effect was evaluated on acetylcholine (ACh), L-cysteine and NaHS-induced relaxations in presence or not of CSE enzyme inhibitor PPG (10 uM, 0.5 hr). In order to achieve this issue the H2S production in MCC tissues was also evaluated by incubating the penile tissue with sildenafil in presence or absence of the CSE inhibitor PPG (10 uM, 0.5 hr) Both CBS and CSE were expressed in MCC and the enzymes efficiently converted L-cysteine into H2S. Further /it was shown/ that sildenafil caused a significant increase in H2S production and this augmentation was reversed by CSE inhibition. /It was/ found that sildenafil induced an increase in both ACh and L-cysteine-induced relaxations and these augmentations reversed by CSE inhibitor PPG in MCC pre-contracted with phenylephrine (3.10-5M). Beside sildenafil did not significantly increase the NaHS -induced relaxations. Therefore /it was/ suggested that both gaseous transmitters NO and H2S affect sildenafil action. In particular ... results demonstrate that sildenafil effect is partially mediated by H2S pathway. Thus, H2S signaling may represent a new mechanism involved in the effect of sildenafil on erectile dysfunction. PMID:24948280 Sildenafil citrate (Viagra), a cGMP-selective phosphodiesterase (PDE) inhibitor, is widely used to treat erectile dysfunction and pulmonary arterial hypertension. In contrast to its well established action on erectile dysfunction, little is known on the action of sildenafil on cGMP/cAMP signaling and testicular steroidogenesis. This study was designed to assess the effects of prolonged sildenafil treatment on NO synthase-dependent signaling and steroidogenic function of rat Leydig cells. Male adult rats were treated with Viagra (1.25 mg/kg body wt) daily for 30 days. /Studies indicate/, serum testosterone and ex vivo testosterone production significantly increased in sildenafil-treated animals. Human chorionic gonadotropin-stimulated testosterone production and cAMP accumulation were also significantly higher in Leydig cells obtained from sildenafil-treated rats. The expression of soluble guanylyl cyclase (GUCY1) subunits (Gucy1a1, Gucy1b1) significantly increased; cAMP-specific Pde4a, cGMP-specific Pde6c, and dual Pde1c and Nos2 were inhibited and expression of Nos3, protein kinase G1 (Pkg1), and Pde5 remained unchanged. Treatment of purified Leydig cells with NO donor caused a dose-dependent increase in both testosterone and cGMP production. Testosterone and cGMP production was significantly higher in Leydig cells obtained from sildenafil-treated animals. The stimulatory effect of NO donor was significantly enhanced by saturating concentrations of hCG in both Leydig cells obtained from control and sildenafil-treated animals. Occurrence of mature steroidogenic acute regulatory protein also increased in sildenafil treated animals in accord with increased cAMP and cGMP production. In summary, inhibition of PDE activity during prolonged sildenafil treatment increased serum testosterone level and Leydig cells' steroidogenic capacity by coordinated stimulatory action on cAMP and cGMP signaling pathway. Introduction: TPN729MA is a newly developed phosphodiesterase type 5 inhibitor (PDE5i) for the treatment of erectile dysfunction, which offers potential for greater selectivity and longer duration of action than PDE5i in current clinical use. Aim: We investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes, and its efficacy in animal models. Methods: The inhibition of 11 human recombinant PDEs by TPN729MA, sildenafil, and tadalafil were determined using radioimmunoassay. The effect of TPN729MA and sildenafil on intracavernous pressure (ICP), blood pressure (BP), and ICP/BP ratio were determined in a rat model of erection induced by electric stimulation and in a dog model of erection induced by sodium nitroprusside injection. Main outcome measures: The main outcome measures were IC50 of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum ICP; BP and ICP/BP ratio. Results: The IC50 of TPN729MA, sildenafil, and tadalafil for PDE5 was 2.28, 5.22, and 2.35 nM, respectively. TPN729MA showed 248, 366, 20, and 2671-fold selectivity against PDE1, PDE4, PDE6, and PDE11, respectively. TPN729MA showed excellent selectivity against PDE2, 3, 7, 8, 9, and 10 (>10,000-fold). In the rat model of erection, TPN729MA (5.0 and 2.5 mg/kg), but not sildenafil, significantly increased the maximum ICP compared with vehicle. Significantly increased ICP/BP was observed in the TPN729MA (5.0 mg/kg) group at all time points, in the TPN729MA (2.5 mg/kg) group at 75, 90, 105, and 120 minutes time points, and in sildenafil group at 75 and 90 minutes time points compared with vehicle. In the dog model of erection, TPN729MA and sildenafil significantly increased ICP and ICP/BP but showed no significant effect on BP compared with vehicle.[1] Background: Sildenafil is one of the selective phosphodiesterase 5 inhibitors that has been proven by many investigators to suppress growth factor stimulated (e.g. platelet-derived growth factor (PDGF) or epidermal growth factor (EGF)) proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMCs) via cGMP/cGKIa pathway. Serotonin promotes cell cycle progression leading to cell mitogenesis and plays a key role in the pathogenesis of pulmonary artery hypertension. The role of sildenafil in proliferation of PASMCs induced by serotonin has not been investigated so far. In this study we explored the underlying mechanism of the effect of sildenafil on serotonin induced proliferation of porcine PASMCs. Methods: PASMCs were cells from primary cultures by the explant method from the pulmonary artery of swine and cells at passage 3 - 5 were used in this study. MTT colorimetric assay and flow cytometry analysis were used to evaluate the cell proliferation and alterations in cell cycle progression respectively. Western blotting analysis was applied to determine the expression of phosphorylated extracellular signal-regulated kinase (ERK), proliferating cell nuclear antigen (PCNA) and mitogen activated protein kinase (MAPK) phosphatase-1 (MKP-1). Results: Serotonin (10 µmol/L) induced the upregulation of phosphorylation of ERK1/ERK2 and PCNA, an increase in the percentage of cells in S phase and subsequent cell proliferation. Pretreatment with 1 µmol/L sildenafil potentiated the phosphorylation of ERK1/ERK2, an increase in the percentage of cells in S phase and cell proliferation, compared with serotonin stimulation alone (P < 0.05). Furthermore, 30-minute pretreatment with 10 µmol/L U0126, specific antagonist for ERK kinase (MEK) prevented the increase in phosphorylation of ERK1/ERK2 and abolished cell cycle progression and the proliferation of PASMCs induced by sildenafil. Conclusion: This study shows that sildenafil potentiated the proliferative effect of serotonin on PASMCs via phosphorylation of ERK1/ERK2.[2] Background: Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation. Methods: Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed. Results: Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2(+) microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals. Conclusions: Our findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery.[3] Background: Severe functional and anatomical defects can be detected after the peripheral nerve injury. Pharmacological approaches are preferred rather than surgical treatment in the treatment of nerve injuries. Aims: The aim of this study is to perform histopathological, functional and bone densitometry examinations of the effects of sildenafil on nerve regeneration in a rat model of peripheral nerve crush injury. Study design: Animal experiment. Methods: 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. Results: During the rotarod test, rats from group 3 spent the least amount of time on the rod compared to the drug treatment groups at speeds of 20 rpm, 30 rpm and 40 rpm. In addition, the duration for which each animal could stay on the rod throughout the accelerod test significantly reduced in rats from group 3 compared to rats from groups 1 and 2 in the 4-min test. For the hot-plate latency time, there were no differences among the groups in either the basal level or after sciatic nerve injury. Moreover, there was no significant difference between the groups in terms of the static sciatic index (SSI) on the 42(nd) day (p=0.147). The amplitude was better evaluated in group 1 compared to the other two groups (p<0.05). Under microscopic evaluation, we observed the greatest amount of nerve regeneration in group 1 and the lowest in group 3. However, this difference was not statistically significant. Moreover, there was no significant difference in the bone mineral density (BMD) levels among the groups. Conclusion: We believe that a daily single dose of sildenafil plays an important role in the treatment of sciatic nerve damage and bone healing and thus can be used as supportive clinical treatment.[4] |
| Molecular Formula |
C23H34N6O7S2
|
|---|---|
| Molecular Weight |
570.682062625885
|
| Exact Mass |
570.193
|
| CAS # |
1308285-21-3
|
| Related CAS # |
Sildenafil;139755-83-2
|
| PubChem CID |
135425271
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| Appearance |
Typically exists as solid at room temperature
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
11
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
38
|
| Complexity |
931
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
S(C1C=CC(=C(C2=NC3C(CCC)=NN(C)C=3C(N2)=O)C=1)OCC)(N1CCN(C)CC1)(=O)=O.S(C)(=O)(=O)O
|
| InChi Key |
WEWNUXJEVSROFW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H30N6O4S.CH4O3S/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;1-5(2,3)4/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29);1H3,(H,2,3,4)
|
| Chemical Name |
5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one;methanesulfonic acid
|
| Synonyms |
sildenafil mesylate; 1308285-21-3; Sildenafil (Mesylate); 5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one;methanesulfonic acid; sildenafilmesylate; SCHEMBL2112660;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7523 mL | 8.7615 mL | 17.5230 mL | |
| 5 mM | 0.3505 mL | 1.7523 mL | 3.5046 mL | |
| 10 mM | 0.1752 mL | 0.8761 mL | 1.7523 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05558176 | Recruiting | Drug: Sildenafil citrate | Foetal Hypoxia | Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso |
April 8, 2022 | Phase 4 |
| NCT02845388 | Completed | Drug: Sildenafil citrate Drug: estradiol valerate |
Infertility | Omar Ahmed El Sayed Saad | September 2015 | Phase 2 |
| NCT05951413 | Recruiting | Drug: Sildenafil Citrate Drug: estradiol |
IVF | Beni-Suef University | June 30, 2023 | Phase 2 Phase 3 |
| NCT03417492 | Terminated | Drug: Sildenafil Citrate | Traumatic Brain Injury Mild Traumatic Brain Injury |
University of Pennsylvania | March 1, 2018 | Phase 1 |
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