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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 rapidly absorbed. In fasting patients, peak plasma drug concentrations are reached within 30–120 minutes after oral administration (median 60 minutes). Furthermore, the mean absolute bioavailability of sildenafil is approximately 41% (range 25–63%). In particular, with three daily oral doses of sildenafil, both AUC and Cmax increase with increasing dose within the recommended dose range of 25–100 mg. However, in patients with pulmonary hypertension, the average oral bioavailability of 80 mg sildenafil three times daily is 43% higher than the lower dose. Finally, if sildenafil is taken with food, a decrease in absorption is observed, with a mean delay of approximately 60 minutes in Tmax and a mean decrease in Cmax of approximately 29%. Nevertheless, the extent of absorption is not significantly affected, with a recorded decrease in AUC of only approximately 11%. Elimination Route After oral or intravenous administration, sildenafil is primarily excreted as metabolites in the feces (approximately 80% of the oral dose), with a small amount excreted in the urine (approximately 13% of the oral dose). Volume of Distribution The mean steady-state volume of distribution of sildenafil is approximately 105 liters, indicating that the drug can be distributed into tissues. Clearance The total clearance of sildenafil is 41 liters/hour. After oral administration, sildenafil is rapidly and almost completely absorbed. When a single oral dose of 20 mg is taken, the 20 mg tablet is bioequivalent to the 10 mg/mL oral suspension. Although single-dose studies have shown that more than 90% of the oral dose of sildenafil is absorbed from the gastrointestinal tract, the drug undergoes extensive metabolism in the gastrointestinal mucosa during absorption and during its first passage through the liver, with only about 40% of the dose entering the systemic circulation unchanged. Within a single-dose range of 1.25–200 mg, the pharmacokinetics of this drug (measured as peak plasma concentration or area under the plasma concentration-time curve (AUC)) are dose-dependent. In fasting adults, peak plasma concentrations are reached within 30–120 minutes after oral administration of sildenafil and its active metabolite N-desmethyl (median: 60 minutes). Sildenafil is widely distributed in the body, with a reported steady-state volume of distribution averaging 105 liters. It is currently unknown whether sildenafil is distributed into breast milk. The binding rate of sildenafil and its major circulating metabolite N-desmethyl to plasma proteins is approximately 96%; it has been reported that protein binding is independent of plasma concentration within the range of 0.01–10 μg/mL. Plasma protein binding is slightly higher in individuals over 65 years of age (97%) than in those under 45 years of age (96%). Following oral administration of sildenafil, its distribution in semen is limited. In healthy individuals, less than 0.001% of the single dose is present in semen within 90 minutes of administration. Such a low concentration is unlikely to have any effect on sexual partners exposed to semen. Sildenafil is primarily excreted in feces as metabolites. In healthy adults and patients with erectile dysfunction, approximately 80% of the oral dose is excreted in feces as metabolites, and 13% in urine. In volunteers with mild (creatinine clearance CL = 50–80 mL/min) and moderate (creatinine clearance CL = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of 50 mg Viagra were not altered. In volunteers with severe renal impairment (CLcr < 30 mL/min), sildenafil clearance was reduced, resulting in approximately double the AUC and Cmax values compared to age-matched volunteers with normal renal function. View MoreMetabolism/Metabolites Biological Half-Life The terminal half-life of sildenafil is approximately 3 to 5 hours. After oral administration, plasma sildenafil concentrations decrease in a biphasic manner, with a terminal elimination half-life of approximately 4 hours (range: 3-5 hours). High clearance in rodents is the main determinant of its shorter elimination half-life (0.4-1.3 hours), while moderate clearance in dogs and humans results in longer half-lives (6.1 hours and 3.7 hours, respectively). |
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| Toxicity/Toxicokinetics |
Toxicity Overview
Identification and Uses: Sildenafil is a white to off-white crystalline powder available in film-coated tablets, oral suspensions, and injections. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor. It is used to treat erectile dysfunction and pulmonary arterial hypertension (PAH) in adults to improve exercise capacity and delay clinical deterioration. Human Exposure and Toxicity: Generally, overdose of sildenafil may exacerbate common adverse reactions. In studies of single doses of up to 800 mg sildenafil in healthy subjects, the types of adverse events observed (e.g., decreased blood pressure, syncope, and prolonged erection) were similar to those observed at lower doses, but at an increased incidence. Serious adverse reactions have also been reported at therapeutic doses, including sudden hearing loss or impairment, sudden loss of vision in one or both eyes, and erections lasting longer than 4 hours or priapism (painful erections lasting longer than 6 hours). Post-marketing reports indicate a time-related correlation between sildenafil treatment for erectile dysfunction and serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden death, ventricular arrhythmias, cerebral hemorrhage, transient ischemic attack, hypertension, subarachnoid hemorrhage, and pulmonary hemorrhage. Most (but not all) of these patients had pre-existing cardiovascular risk factors. Therefore, it is impossible to determine whether these events are directly related to sildenafil, sexual activity, underlying cardiovascular disease, a combination of these factors, or other factors. Sildenafil is not recommended for children. In a long-term trial in children with pulmonary arterial hypertension (PAH), increased sildenafil doses were observed to lead to increased mortality. Pulmonary vasodilators (such as sildenafil) may significantly worsen cardiovascular conditions in patients with pulmonary venous occlusive disease. Sildenafil significantly enhances the vasodilatory effects of organic nitrates and nitrites. This drug did not show chromosome breakage in vitro in human lymphocyte assays. Animal studies: Death occurred in rats after oral administration of 1000 mg/kg and 500 mg/kg doses, and in mice after oral administration of 1000 mg/kg dose. Female rats were more affected than male rats. Acute sildenafil treatment stimulated testosterone production in adult male rats. No fertility impairment was observed in female rats administered up to 60 mg/kg daily for 36 consecutive days and in male rats for 102 consecutive days. However, in another study, male rats were given sildenafil citrate (0.06 mg/0.05 mL) by gavage and allowed to mate. Fertilization rate and embryo number were assessed after treatment. In mating of males given sildenafil citrate, the fertilization rate was significantly reduced on day 1 (approximately 33%). On days 2–4, the number of embryos developing in the treatment group was significantly lower than in the control group. The cleavage rate of these embryos also showed a decreasing trend, but this did not reach statistical significance. During organogenesis, rats and rabbits receiving doses up to 200 mg/kg/day showed no evidence of teratogenicity, embryotoxicity, or fetal toxicity. In another study, adult male rabbits were administered sildenafil up to 9 mg/kg/day for four consecutive weeks to investigate testicular histological changes caused by drug overdose. Abnormalities in the seminiferous tubule germinal epithelium included spermatocyte nuclear pyknosis, spermatocyte degeneration and shedding, spermatocyte giant cells, and spermatogenesis arrest. Furthermore, increased interstitial cells, tubular degeneration, and interstitial thickening were observed. These histological findings suggest that long-term overdose of sildenafil leads to significant morphological and histological changes in the testes, potentially leading to complete spermatogenesis arrest. Oral administration of sildenafil to rats and mice for up to two years showed no carcinogenicity. Sildenafil did not show mutagenicity in in vitro bacterial and Chinese hamster ovary cell assays. The drug also did not show chromosomal breakage in in vivo mouse micronucleus assays. Sildenafil is primarily cleared via hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). Its main circulating metabolite is the N-demethylated form of sildenafil, which itself is further metabolized. The phosphodiesterase (PDE) selectivity of this metabolite is similar to that of sildenafil, exhibiting approximately 50% of the in vitro inhibitory potency against phosphodiesterase type 5 (PDE-5) compared to the parent drug. The plasma concentration of this metabolite is approximately 40% of that of sildenafil, thus accounting for approximately 20% of the pharmacological action of sildenafil. Hepatotoxicity At least five cases of acute liver injury have been reported in connection with sildenafil use, but no cases of acute liver failure have been reported. Due to the intermittent and sometimes undocumented use of sildenafil, the latency period in most reports is unclear, but appears to be between 1 and 8 weeks. Elevated serum enzyme patterns range from hepatocellular to cholestatic, and sometimes evolve from one type to another. The most compelling case was mild cholestatic or “mixed” hepatitis occurring within 1 to 3 months of starting sildenafil. No immune hypersensitivity features or autoantibodies were observed. There have been reports of cases with acute onset and elevated serum transaminase levels following sildenafil use, exhibiting some characteristics of ischemic injury. In other cases, the injury pattern suggested use of anabolic steroids. In two cases, relapse did not occur upon re-exposure to sildenafil. Therefore, the hepatotoxicity of sildenafil is not entirely convincing, and even if it occurs, it must be extremely rare. Probability score: C (likely a rare cause of clinically significant liver injury). Effects during pregnancy and lactation View more◉ Overview of medication use during lactation Interactions Sildenafil and other phosphodiesterase type 5 (PDE) inhibitors (e.g., tadalafil, vardenafil) significantly enhance the vasodilatory effects of organic nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate) (e.g., sildenafil can lower systolic blood pressure by more than 25 mmHg), potentially leading to life-threatening hypotension and/or hemodynamic disturbances. Nitrates and nitrites promote the production of cyclic guanosine monophosphate (cGMP) by stimulating guanylate cyclase, while PDE 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) reduce cGMP degradation by inhibiting PDE 5, resulting in increased cGMP accumulation and producing more significant smooth muscle relaxation and vasodilation than PDE 5 inhibitors or nitrates/nitrites alone. This interaction can occur with any organic nitrate, nitrite, or nitric oxide donor (e.g., sodium nitroprusside), regardless of its primary hemodynamic site. Protein Binding Sildenafil and its primary circulating metabolite, N-demethylated metabolite, are typically observed to bind to plasma proteins at an estimated rate of approximately 96%. However, studies have determined that protein binding of sildenafil is independent of total drug concentration. |
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| Additional Infomation |
Sildenafil citrate is the citrate salt of sildenafil. It is a vasodilator and an EC 3.1.4.35 (3',5'-cyclic guanosine monophosphate phosphodiesterase) inhibitor. It contains sildenafil. Sildenafil citrate is the citrate form of sildenafil, a highly bioavailable pyrazolopyrimidinone derivative with a structure related to zaprostrobin, possessing vasodilatory and potential anti-inflammatory activity. After oral administration, sildenafil selectively targets and inhibits cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), thereby inhibiting PDE5-mediated degradation of cGMP in smooth muscle and increasing cGMP availability. This leads to prolonged relaxation of the smooth muscle of the corpus cavernosum, resulting in vasodilation, increased blood flow, and prolonged penile erection. In pulmonary vascular smooth muscle, increased cGMP leads to smooth muscle relaxation, dilation of the pulmonary vascular bed, thereby relieving pulmonary hypertension and increasing pulmonary blood flow. In addition, sildenafil may reduce airway inflammation and mucus secretion.
A phosphodiesterase type 5 inhibitor; a vasodilator and urinary tract medication used to treat erectile dysfunction and primary pulmonary hypertension. Indications Adults: For the treatment of adult patients with pulmonary hypertension in WHO functional class II and III to improve their exercise capacity. It has been shown to be effective in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue diseases. Pediatrics: For the treatment of children aged 1 to 17 years with pulmonary hypertension. It has been shown to improve exercise capacity or pulmonary hemodynamics in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see Section 5.1). Adults: For the treatment of adult patients with pulmonary hypertension in WHO functional class II and III to improve their exercise capacity. It has been shown to improve exercise capacity in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue diseases. Pediatrics: For the treatment of children aged 1 to 17 years with pulmonary hypertension. Sildenafil has been shown to improve exercise capacity or pulmonary hemodynamics in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. Drug Indications Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor primarily used for two main indications: (1) treatment of erectile dysfunction; (2) treatment of pulmonary hypertension, wherein: a) Sildenafil has been approved by the US FDA for the treatment of pulmonary hypertension (PAH) in adults (WHO Group I) to improve exercise capacity and delay clinical deterioration. When used in combination with eprostol, sildenafil has been shown to delay clinical deterioration. All studies demonstrating efficacy were short-term (12 to 16 weeks), primarily enrolling New York Heart Association (NYHA) functional class II-III patients with unknown etiology (71%) or pulmonary hypertension associated with connective tissue disease (CTD) (25%); b) The Canadian product information clearly states that sildenafil can be used to treat adult patients with primary pulmonary hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) who are unresponsive to conventional therapy. Furthermore, in adult patients with stable conditions who have received background therapy with eprostol, sildenafil has shown improved exercise capacity and delayed clinical deterioration; c) The European Medicines Agency (EMA) product information clearly states that sildenafil can be used to treat adult patients with pulmonary hypertension in WHO functional class II and III to improve their exercise capacity. Sildenafil is effective for both primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. The EMA label also indicates that sildenafil can be used to treat children aged 1 to 17 years with pulmonary hypertension. In primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease, its effectiveness in improving exercise capacity or pulmonary hemodynamics has been demonstrated. View MoreFor the treatment of adult patients with pulmonary hypertension classified as World Health Organization (WHO) functional class II and III, to improve their exercise capacity. Its effectiveness in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue diseases has been demonstrated. Pediatric population: For the treatment of pediatric patients aged 1 to 17 years with pulmonary hypertension. Its effectiveness in improving exercise capacity or pulmonary hemodynamics has been demonstrated in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. Revastatin injection is indicated for the treatment of adult patients with pulmonary hypertension who are currently taking oral mirtazapine but are temporarily unable to receive oral therapy and who are clinically and hemodynamically stable. Oral mirtazapine is indicated for the treatment of adult patients with pulmonary hypertension of WHO functional class II and III to improve their exercise capacity. Its efficacy has been demonstrated in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.Therapeutic Uses Phosphodiesterase type 5 inhibitor; urinary system medication; vasodilator Viagra is indicated for the treatment of erectile dysfunction. /US product label includes/ Revastatin (Revatio) is indicated for the treatment of adult pulmonary hypertension to improve exercise capacity and delay clinical progression. /US product label includes/ The role (if any) of sildenafil (sildenafil) in the treatment of female sexual dysfunction remains to be determined. /Not included on US product label/ Drug Warnings Viagra is contraindicated for use with any form of nitric oxide donor (such as organic nitrates or organic nitrites). Consistent with known effects on the nitric oxide/cGMP pathway, Viagra has been shown to enhance the hypotensive effects of nitrates. Post-marketing reports have shown a temporal association between Viagra use and the occurrence of serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden death, ventricular arrhythmias, cerebral hemorrhage, transient ischemic attack, hypertension, subarachnoid hemorrhage and cerebral hemorrhage, and pulmonary hemorrhage. Most (but not all) of these patients had pre-existing cardiovascular risk factors. Many of these events have been reported to occur during or shortly after sexual activity, and a few have been reported to occur shortly after taking Viagra without sexual activity. Other events have been reported to occur hours to days after taking Viagra and engaging in sexual activity. It is currently impossible to determine whether these events are directly related to Viagra, sexual activity, the patient's underlying cardiovascular disease, a combination of these factors, or other factors. Since Viagra's market launch, reports of erections lasting longer than 4 hours and priapism (painful erections lasting longer than 6 hours) have been uncommon. If an erection lasts longer than 4 hours, the patient should seek immediate medical attention. Untreated priapism can lead to penile tissue damage and permanent loss of sexual function. In controlled clinical trials and post-marketing surveillance, less than 2% of patients with erectile dysfunction treated with sildenafil also experienced the following adverse reactions: angina, atrioventricular block, tachycardia, palpitations, myocardial ischemia and infarction, sudden death, chest pain, cerebral thrombosis, cerebrovascular hemorrhage (e.g., subarachnoid hemorrhage, cerebral hemorrhage), transient ischemic attack, stroke (e.g., hemorrhagic stroke or brainstem stroke), cardiac or cardiopulmonary arrest, coronary artery disease, heart failure, ECG abnormalities (including ventricular arrhythmias (e.g., tachycardia, premature beats) or Q wave abnormalities (without myocardial infarction)), hypertension, edema (including facial and peripheral edema), shock, and cardiomyopathy. However, this has not been directly attributed to the drug. Patients receiving sildenafil for erectile dysfunction or placebo had similar rates of myocardial infarction or stroke, with most cases occurring hours to days after administration of either sildenafil or placebo. Most patients experiencing serious cardiovascular adverse reactions had pre-existing cardiovascular risk factors, and many of these adverse reactions have been reported to occur shortly after administration of sildenafil, regardless of sexual activity. At least one patient with hypertrophic cardiomyopathy experienced a decrease in blood pressure, significant reduction in ventricular size, increased resting ejection fraction and subaortic pressure gradient, premature ventricular contractions, and non-sustained ventricular tachycardia after administration of sildenafil for erectile dysfunction. Pharmacodynamics In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Sildenafil has a stronger effect on PDE5 than on other known phosphodiesterases. Of particular note is its selectivity for PDE6 (involved in the retinal phototransduction pathway) being 10 times greater than that for PDE6, its selectivity for PDE1 being 80 times greater than that for PDE6, and its selectivity for PDE2, 3, 4, 7, 8, 9, 10, and 11 being more than 700 times greater than that for PDE2, 3, 4, 7, 8, 9, 10, and 11. Furthermore, sildenafil's selectivity for PDE5 is more than 4000 times greater than its selectivity for PDE3 (a cAMP-specific phosphodiesterase subtype involved in the regulation of cardiac contractility). In eight double-blind, placebo-controlled crossover studies in patients with organic or psychogenic erectile dysfunction, the sildenafil group showed improved erectile function after sexual stimulation compared to the placebo group, as confirmed by objective measurements of erectile rigidity and duration (using RigiScan®). Most studies assessed the efficacy of sildenafil approximately 60 minutes after administration. Erectile responses assessed using RigiScan® generally increase with increasing sildenafil dose and plasma concentration. One study examined the time course of its action, showing that its effect could last up to 4 hours, but the response was diminished compared to 2 hours. Sildenafil causes a slight and transient decrease in systemic blood pressure, but in most cases, this decrease does not translate into a clinical effect. In patients with systemic hypertension, long-term administration of 80 mg three times daily resulted in a mean decrease of 9.4 mmHg in systolic blood pressure and 9.1 mmHg in diastolic blood pressure from baseline. In patients with pulmonary hypertension, long-term administration of 80 mg three times daily resulted in a smaller observed blood pressure-lowering effect (a decrease of 2 mmHg in both systolic and diastolic blood pressure). At the recommended dose of 20 mg three times daily, no decrease in systolic or diastolic blood pressure was observed. A single oral dose of up to 100 mg of sildenafil in healthy volunteers did not produce a clinically significant effect on electrocardiograms. Long-term administration of 80 mg three times daily in patients with pulmonary hypertension also did not report a clinically significant effect on electrocardiograms. In a study of 14 patients with severe coronary artery disease (CAD) (at least one coronary artery with stenosis >70%), a single oral dose of 100 mg sildenafil showed hemodynamic effects, with mean resting systolic and diastolic blood pressure decreasing by 7% and 6%, respectively, compared to baseline. Mean pulmonary artery systolic blood pressure decreased by 9%. Sildenafil had no effect on cardiac output and did not impair blood flow in the stenotic coronary arteries. Some subjects showed a slight and transient difference in color discrimination ability (blue/green) using the Farnsworth-Munsell 100 hue test 1 hour after taking 100 mg sildenafil; no significant effect was observed after 2 hours. It is speculated that this change in color discrimination ability is related to the inhibition of PDE6, which is involved in the phototransduction cascade in the retina. Sildenafil had no effect on visual acuity or contrast sensitivity. In a small, placebo-controlled study (n = 9) of patients diagnosed with early-stage age-related macular degeneration, no significant changes were observed in any visual tests (including visual acuity, Amsler grid, simulated traffic light color discrimination, Humphrey perimeter, and light stress test) after a single dose of 100 mg sildenafil. Mechanism of Action Sildenafil is an oral medication used to treat erectile dysfunction. In its natural state, i.e., under sexual stimulation, sildenafil restores impaired erectile function by increasing penile blood flow. The physiological mechanism of penile erection involves the release of nitric oxide (NO) from the corpora cavernosa during sexual stimulation. Nitric oxide subsequently activates guanylate cyclase, leading to an increase in cyclic guanosine monophosphate (cGMP) levels, which relaxes the smooth muscle of the corpora cavernosa, allowing blood flow. Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpora cavernosa, which is responsible for degrading cGMP. The site of action of sildenafil on erection is located in the periphery. Sildenafil has no direct relaxant effect on isolated human corpora cavernosa, but it significantly enhances the relaxant effect of nitric oxide on this tissue. When the NO/cGMP pathway is activated (e.g., during sexual stimulation), sildenafil increases cGMP levels in the corpora cavernosa by inhibiting PDE5. Therefore, sexual stimulation is a necessary condition for sildenafil to exert its intended pharmacological effect. In addition to the corpora cavernosa, PDE5 is also present in pulmonary vessels. Therefore, sildenafil can increase cGMP levels in pulmonary vascular smooth muscle cells, leading to vasodilation. In patients with pulmonary hypertension, this can lead to pulmonary vascular bed dilation and, to some extent, systemic vasodilation. Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpora cavernosa. Sildenafil enhances the effect of nitric oxide during sexual stimulation by attenuating the effect of PDE5; increased cGMP levels relax smooth muscle, allowing blood to flow into the corpora cavernosa, thus producing an erection. Without sexual stimulation, sildenafil has no effect on erection. Numerous studies have shown that hydrogen sulfide (H2S) is associated with various physiological and pathological conditions. In particular, studies have shown that H2S can relax human penile tissue and inhibit phosphodiesterase (PDE) activity in blood vessels. Furthermore, sildenafil can increase H2S production in the human bladder, while tadalafil can increase H2S production in myocardial tissue. Therefore, this study aimed to elucidate the relationship between H2S and PDE-5 in mouse penile corpus cavernosum tissue. This study investigated the effects of the PDE-5 inhibitor sildenafil (10 μM, 0.5 h) on H₂S production and its induced vasodilation in mouse penile tissue. The experiment used CD1 mouse corpus cavernosum (MCC) tissue. Functional studies were performed using actigraphy in Kjeldahl's solution. The expression of CBS and CSE was assessed by Western blot analysis, and H₂S levels were measured using the methylene blue assay. To investigate the functional role of H₂S in sildenafil-induced enhanced endothelial relaxation in MCCs, the effects of sildenafil on acetylcholine (ACh), L-cysteine, and NaHS-induced vasodilation were assessed with and without the CSE enzyme inhibitor PPG (10 μM, 0.5 h). To investigate this, we assessed H₂S production in MCC tissue by incubating penile tissue with sildenafil with and without the CSE inhibitor PPG (10 μM, 0.5 h). CBS and CSE are expressed in MCCs, and these enzymes efficiently convert L-cysteine to H₂S. Furthermore, the study showed that sildenafil significantly increased H₂S production, while the CSE inhibitor reversed this increase. The study found that sildenafil enhanced the ACh and L-cysteine-induced vasodilation response, while the CSE inhibitor PPG reversed this enhancement (in MCCs pre-constricted with norepinephrine (3 × 10⁻⁵ M)). Furthermore, sildenafil did not significantly enhance the NaHS-induced diastolic response. Therefore, we hypothesize that both the gaseous neurotransmitters NO and H2S affect the effects of sildenafil. Specifically… the results indicate that the effects of sildenafil are partly mediated through the H2S pathway. Therefore, H2S signaling may represent a novel mechanism by which sildenafil treats erectile dysfunction. PMID:24948280 Sildenafil citrate (Viagra) is a cGMP-selective phosphodiesterase (PDE) inhibitor widely used to treat erectile dysfunction and pulmonary hypertension. Compared to its well-established effects on erectile dysfunction, little is known about the effects of sildenafil on cGMP/cAMP signaling and testicular steroid production. This study aimed to evaluate the effects of long-term sildenafil treatment on NO synthase-dependent signaling and steroid production in rat testicular interstitial cells. Adult male rats were treated daily with Viagra (1.25 mg/kg body weight) for 30 days. Studies have shown that serum testosterone levels and in vitro testosterone production were significantly increased in animals treated with sildenafil. Human chorionic gonadotropin-stimulated testosterone production and cAMP accumulation were also significantly increased in the testicular interstitial cells of rats treated with sildenafil. Expression of soluble guanylate cyclase (GUCY1) subunits (Gucy1a1, Gucy1b1) was significantly increased; the expression of cAMP-specific Pde4a, cGMP-specific Pde6c, and dual Pde1c and Nos2 was inhibited, while the expression of Nos3, protein kinase G1 (Pkg1), and Pde5 remained unchanged. Treatment of purified testicular interstitial cells with NO donors resulted in a dose-dependent increase in testosterone and cGMP production. Testosterone and cGMP production in the testicular interstitial cells of animals treated with sildenafil were significantly higher than in the control group. In the testicular interstitial cells of both the control and sildenafil-treated groups, saturated concentrations of hCG significantly enhanced the stimulatory effect of NO donors. The expression of mature steroid synthesis acute regulatory proteins was also increased in animals treated with sildenafil, which was consistent with the increase in cAMP and cGMP production. In summary, the inhibition of PDE activity during long-term sildenafil treatment, through synergistic stimulation of the cAMP and cGMP signaling pathways, increased serum testosterone levels and the steroid-producing capacity of testicular interstitial cells. Introduction: TPN729MA is a newly developed phosphodiesterase type 5 (PDE5i) inhibitor for the treatment of erectile dysfunction. Compared with currently used clinical PDE5i, it has higher selectivity and a longer duration of action. Objective: We investigated the in vitro inhibitory efficacy and selectivity of TPN729MA against PDE isoenzymes, and its efficacy in animal models. Methods: Radioimmunoassay was used to determine the inhibitory effects of TPN729MA, sildenafil, and tadalafil on 11 human recombinant PDEs. In a rat model of electrically induced erection and a canine model of sodium nitroprusside-induced erection, the effects of TPN729MA and sildenafil on intracavernosal pressure (ICP), blood pressure (BP), and the ICP/BP ratio were measured. Main observation endpoints: The main observation endpoints included the IC50 values of TPN729MA, sildenafil, and tadalafil against PDE1-PDE11; maximum ICP; BP value; and ICP/BP ratio. Results: The IC50 values of TPN729MA, sildenafil, and tadalafil against PDE5 were 2.28 nM, 5.22 nM, and 2.35 nM, respectively. TPN729MA showed selectivity of 248-fold, 366-fold, 20-fold, and 2671-fold against PDE1, PDE4, PDE6, and PDE11, respectively. TPN729MA exhibited excellent selectivity (>10,000-fold) against PDE2, 3, 7, 8, 9, and 10. In a rat erectile model, TPN729MA (5.0 and 2.5 mg/kg) significantly increased maximum penile cavernous pressure (ICP), while sildenafil had no such effect. Compared with the solvent group, the TPN729MA (5.0 mg/kg) group showed a significant increase in ICP/BP at all time points, the TPN729MA (2.5 mg/kg) group showed a significant increase in ICP/BP at 75, 90, 105 and 120 minutes, while the sildenafil group showed a significant increase in ICP/BP at 75 and 90 minutes. In the canine erectile model, both TPN729MA and sildenafil significantly increased intracranial pressure (ICP) and the ICP/BP ratio, but had no significant effect on blood pressure (BP) compared with the solvent group. [1] Background: Sildenafil is a selective phosphodiesterase 5 inhibitor that has been shown by many researchers to inhibit the proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMCs) stimulated by growth factors (such as platelet-derived growth factor (PDGF) or epidermal growth factor (EGF)) through the cGMP/cGKIa pathway. Serotonin promotes cell cycle progression, leading to mitosis and playing a crucial role in the pathogenesis of pulmonary hypertension. The role of sildenafil in serotonin-induced PASMC proliferation has not yet been investigated. This study explored the potential mechanism of sildenafil in 5-hydroxytryptamine-induced proliferation of porcine pulmonary artery smooth muscle cells (PASMCs). Methods: Primary PASMCs were isolated using porcine pulmonary artery tissue block culture and passaged 3-5 times. Cell proliferation and cell cycle progression were assessed using the MTT assay and flow cytometry, respectively. The expression of phosphorylated extracellular signal-regulated kinase (ERK), proliferating cell nuclear antigen (PCNA), and mitogen-activated protein kinase-1 (MAPK) phosphatase-1 (MKP-1) was detected using Western blotting. Results: 5-hydroxytryptamine (10 µmol/L) induced upregulation of ERK1/ERK2 and PCNA phosphorylation levels, increased the proportion of cells in S phase, and promoted cell proliferation. Compared with 5-hydroxytryptamine stimulation alone, pretreatment with 1 µmol/L sildenafil enhanced ERK1/ERK2 phosphorylation, increased the proportion of cells in S phase, and promoted cell proliferation (P < 0.05). In addition, pretreatment with 10 µmol/L U0126 (an ERK kinase (MEK) specific antagonist) for 30 min prevented the increase in ERK1/ERK2 phosphorylation and eliminated sildenafil-induced cell cycle progression and proliferation of pulmonary artery smooth muscle cells (PASMCs). Conclusion: This study shows that sildenafil enhances the proliferative effect of 5-hydroxytryptamine on PASMCs by phosphorylation of ERK1/ERK2. [2] Background: Perinatal ischemic stroke is the most common type of cerebral infarction in newborns; however, evidence-based treatments are currently lacking. We have previously demonstrated that the PDE-5 inhibitor sildenafil citrate has a beneficial effect on the size of stroke lesions in newborn rats. This study aimed to investigate the regulatory effects of sildenafil on (1) hemodynamic changes and (2) astrocyte/microglia-mediated neuroinflammation in a neonatal mouse stroke model. Methods: On day 9 (P9), C57Bl/6 mice were induced to have ischemia by permanent middle cerebral artery occlusion (pMCAo), followed by intraperitoneal injection of either PBS or sildenafil. Blood flow velocity (BF) was measured using ultrasound imaging combined with continuous Doppler recording and laser speckle contrast imaging. Animals were sacrificed 72 hours or 8 days after pMCAo, and brain tissue was obtained. The expression of M1 and M2 microglia/macrophage markers was analyzed. Results: Although sildenafil (10 mg/kg) treatment significantly increased cGMP concentration, it did not affect early collateral circulation recruitment or reduce the mean infarct volume 72 hours after pMCAo. However, sildenafil significantly reduced the mean lesion extent 8 days after pMCAo in a dose-dependent manner, suggesting that its mechanism of action may involve the regulation of the inflammatory response. Sildenafil significantly reduced microglial density at both 72 hours and 8 days after pMCAo. Gene expression profiling analysis showed that sildenafil treatment also regulated the expression of M1 (ptgs2, CD32, and CD86) and M2 (CD206, Arg-1, and Lgals3) microglia/macrophages in the late pMCAo period. Therefore, in animals treated with sildenafil, the number of COX-2(+) microglia/macrophages in the ischemic penumbra was significantly increased at 72 hours after pMCAo, but significantly decreased after 8 days of ischemia. Conclusion: Our results suggest that the anti-inflammatory effect of sildenafil may play a protective role against damage propagation in the late stages after pMCAo in neonatal mice. We believe that sildenafil treatment may represent a potential strategy for treating/recovering from neonatal ischemic stroke. [3] Background: Severe neurological and anatomical defects can be detected after peripheral nerve injury. In the treatment of nerve injury, drug therapy is superior to surgical treatment. Objective: This study aimed to investigate the effects of sildenafil on nerve regeneration in a rat model of peripheral nerve crush injury through histopathology, functional analysis, and bone mineral density measurement. Study Design: Animal experiment. Methods: Thirty adult Sprague-Dawley rats were included in this study and randomly divided into three groups of 10 rats each. All rats were subjected to a crush injury model by clamping the right sciatic nerve for 1 minute. One day before surgery, rats in group 1 began treatment for 28 days, receiving sildenafil citrate at 20 mg/kg body weight via nasogastric tube daily; rats in group 2 received sildenafil citrate at 10 mg/kg body weight via nasogastric tube every other day; rats in group 3 did not receive any drug treatment. Forty-two days after nerve injury, functional and histopathological examinations were performed on both sciatic nerves, and bone mineral density measurements were taken on the limbs. Results: In the rotarod test, compared with the drug treatment group, the rats in group 3 had the shortest dwell time on the rotarod at 20 rpm, 30 rpm and 40 rpm. In addition, in the 4-minute accelerator bar test, the rats in group 3 had a significantly shorter dwell time on the rotarod than the rats in groups 1 and 2. In the hot plate test, there were no differences among the groups at baseline and after sciatic nerve injury. In addition, there were no significant differences in static sciatic nerve index (SSI) among the groups on day 42 (p=0.147). The amplitude assessment of group 1 was better than the other two groups (p<0.05). Microscopic observation showed that the nerve regeneration was the greatest in group 1 and the least in group 3. However, this difference was not statistically significant. In addition, there were no significant differences in bone mineral density (BMD) levels among the groups. Conclusion: We believe that once-daily administration of sildenafil plays an important role in the treatment and bone healing of sciatic nerve injury and can therefore be used as an adjunct 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
|
| 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
|
| 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)
|
| 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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