| 规格 | 价格 | 库存 | 数量 |
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| 250mg |
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| 500mg |
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| 1g |
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| 2g |
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| 5g |
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| Other Sizes |
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| 靶点 |
PDE5/phosphodiesterase 5
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| 体外研究 (In Vitro) |
与单独5-羟色胺刺激相比，1 μM西地那非预处理可增强ERK1/ERK2磷酸化，增加S期细胞比例，促进细胞增殖（P<0.05）。用 1 μM 西地那非和血清素刺激预处理后，光密度（OD 值）突然上升至 0.33。这与单独的血清素刺激显着不同（P<0.05）。很明显，1 μM 西地那非会增加血清素诱导的 ERK1/ERK2 磷酸化的上调[2]。
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| 体内研究 (In Vivo) |
西地那非可显着提高犬勃起模型中的 ICP 和 ICP/BP，但与媒介物相比对血压没有明显影响[1]。西地那非治疗在 10 mg/kg 时可显着减少 TL+ 细胞计数，但在 0.5 mg/kg 时则不会。在此阶段，用 PBS 处理的动物在缺血核心中具有 M1 样标记物 COX-2+ 呈阳性的细胞，而用 10 mg/kg 西地那非（但不是 0.5 mg/kg）处理的动物则大部分细胞处于缺血核心区。半影。相比之下，西地那非治疗（0.5 或 10 mg/kg 剂量）显着减少 pMCAo 后八天 Iba-1 染色的小胶质细胞/巨噬细胞的数量[3]。通过促进生长因子（FGF 和 VEGF）的释放，柠檬酸西地那非已被证明可以减少临床前动物模型中的皮瓣坏死。组织学也证明它对大鼠海绵体神经结构有效[4]。
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| 酶活实验 |
所有关于ERK1/ERK2激活、MKP-1、PCNA表达以及细胞增殖和细胞周期分析的实验都是在第3-5代培养三天的细胞上进行的。此后，细胞在含有0.2%FBS和1%抗生素的RPMI-1640中血清饥饿三天。然后，细胞暴露于1μmol/L的血清素或西地那非，然后暴露于血清素，如图所示。在一些实验中，如所示，细胞在西地那非之前用10μmol/L的U0126预处理30分钟，随后暴露于血清素。在对照组中，用等体积的磷酸盐缓冲盐水（PBS）代替试剂。[2]
ERK1/ERK2磷酸化状态的免疫印迹分析[2] 如上所述，用血清素或1μmol/L的西地那非处理亚融合血清饥饿细胞，然后用或不用U0126刺激血清素。如上所述，在指定时间提取蛋白质。通过蛋白质印迹检测ERK1/ERK2蛋白的磷酸化。简而言之，通过SDS-PAGE分离等量的蛋白质（15-20μg），转移到聚偏二氟乙烯膜上，用抗磷酸化ERK1/ERK2抗体探测，并用辣根过氧化物酶（HRP）偶联的二抗检测。为了测定总ERK1/ERK2的表达，在50°C下用剥离缓冲液洗涤膜30分钟，然后用PBST中的5%牛血清白蛋白封闭膜4小时。此后，用特异性ERK1/ERK2抗体重新探测膜。 MKP-1、PCNA的免疫印迹分析[2] 如上所述，亚融合血清饥饿的PASMC在不同时间段内暴露于西地那非、血清素或U0126。在培养期结束时，提取蛋白质并用12%凝胶进行SDS-PAGE分离。然后将总蛋白转移到聚偏二氟乙烯膜上，在4°C下用PCNA和MKP-1抗体（1:1000）、甘油醛磷酸脱氢酶（GAPDH）抗体（1:2000）检测过夜。洗涤后，在室温下加入适当的二抗（1:5000）一小时。这些印迹是用Super Signal增强化学发光试剂盒开发的，并在柯达AR胶片上可视化。使用图像分析软件通过密度测定对条带进行定量。将蛋白质的相对表达标准化为GAPDH。 |
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| 细胞实验 |
MTT比色法[2]
用0.1%胰蛋白酶/0.01%乙二胺四乙酸（EDTA）溶液收获约90%融合的细胞，以2x104个细胞/孔的密度接种到96孔板中，在含有10%FBS的RPMI-1640中生长三天，然后血清饥饿三天。然后将细胞与不同浓度的血清素或1μmol/L的 sildenafil/西地那非孵育不同时间，然后如所示，加入或不加入U0126的血清素。对照细胞以相同的方式处理，除了用无菌PBS代替药物。处理后，将培养基换成新鲜培养基，用5 g/L MTT孵育细胞4小时。然后用150μl 10%二甲亚砜（DMSO）溶解MTT 20分钟。使用微孔板读数器在570nm下测定96孔板中的光密度（OD）。 流式细胞术分析[2] 用0.1%胰蛋白酶/0.01%EDTA收获约90%融合的细胞，以5x104个细胞/孔的密度接种到6孔板中，在含有10%FBS的RPMI-1640中生长3天，然后血清饥饿3天。然后，如所示，将细胞与血清素或1μmol/L的 sildenafil/西地那非一起孵育24小时，然后用或不用U0126刺激血清素。用PBS冲洗细胞，用0.1%胰蛋白酶/0.01%EDTA溶液胰蛋白酶消化，并在20°C下以1000 r/min的速度离心5分钟收集细胞。将细胞颗粒在4°C的70%乙醇中固定至少24小时。用PBS洗涤固定的细胞两次，重新悬浮在含有50g/L RNase A和50mg/L碘化丙啶（PI）的PBS中。将悬浮液在37°C下孵育30分钟，通过200μm尼龙网过滤，然后通过流式细胞仪 进行分析。使用ModfitLT软件进行数据分析。S期细胞与所有G0G1+S+G2M期细胞的比率通过以下公式计算：S期分数（SPF）=S/（G0G1+S/G2M）x100% |
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| 动物实验 |
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| 药代性质 (ADME/PK) |
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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| 毒性/毒理 (Toxicokinetics/TK) |
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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| 参考文献 |
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| 其他信息 |
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] |
| 分子式 |
C23H34N6O7S2
|
|---|---|
| 分子量 |
570.682062625885
|
| 精确质量 |
570.193
|
| CAS号 |
1308285-21-3
|
| 相关CAS号 |
Sildenafil;139755-83-2
|
| PubChem CID |
135425271
|
| 外观&性状 |
Typically exists as solid at room temperature
|
| tPSA |
180
|
| 氢键供体(HBD)数目 |
2
|
| 氢键受体(HBA)数目 |
11
|
| 可旋转键数目(RBC) |
7
|
| 重原子数目 |
38
|
| 分子复杂度/Complexity |
931
|
| 定义原子立体中心数目 |
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)
|
| 化学名 |
5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one;methanesulfonic acid
|
| 别名 |
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
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| 溶解度 (体外实验) |
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
|
|---|---|
| 溶解度 (体内实验) |
注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。
注射用配方
注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)(IP/IV/IM/SC等) *生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。 注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline) 注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil) 示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。 View More
注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)] 口服配方
口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠) 口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素) 示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。 View More
口服配方 3: 溶解于 PEG400 (聚乙二醇400) 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 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 |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
| 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 |
FCPR-16
Mardepodect盐酸盐
盐酸阿那格雷
己酮可可碱
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