Sildenafil Citrate

Sildenafil Citrate is a potent inhibitor of cGMP-specific phosphodiesterase including PDE5 with IC50 values of 3.6 nM.[1]
PDE5 (cGMP-specific phosphodiesterase type 5) is an enzyme from the phosphodiesterase class. The function of PDE5 is to accept cGMP and breaks it down. cGMP (cyclic guanosine monophosphate) is one of second messenger which is the production of guanylate cyclase. cGMP is a regulator of cellular apoptosis glycogenolysis, conductance , and ion channel. It can relaxe smooth muscle tissues. In blood vessels, It also can relaxe vascular smooth muscles, then lead to increased blood flow and vasodilation. The inhibitors of PDE5 can inhibit the degradation of cGMP, then leads to increase bloodflow to the penis. Sildenafil Citrate is used treatment of erectile dysfunction.
Sildenafil is a potent cGMP-specific phosphodiesterase. It is highly selective for PDE5. It inhibits the activity of PDE5 with an IC50 value of 3 nM in human corpus cavernosum (3.6nM in isolated rabbit platelets). At the same condition, It inhibits the activity of PDE1 and PDE3 activities with IC50s = 0.26 and 65 μM, respectively.[1] Sildenafil potently relaxed anococcygeus muscle strip swith maximum response of 100 ± 2% and a pEC50 value of 6.44 ± 0.03 in rat. Sildenafil also increased by approximately 55% the duration of nitrergic relaxations.[1, 2] Compared to the base salt, the citrate salt has pharmacokinetics and superior water solubility.[3]
References:
[1].    Teixeira CE, Priviero FB, Claudino MA, Baracat JS, De Nucci G, Webb RC, Antunes E: Stimulation of soluble guanylyl cyclase by BAY 41-2272 relaxes anococcygeus muscle: interaction with nitric oxide. Eur J Pharmacol 2006, 530(1-2):157-165.
[2].    Richalet JP, Gratadour P, Robach P, Pham I, Dechaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, Cornolo J: Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005, 171(3):275-281.
[3].    Jung SY, Seo YG, Kim GK, Woo JS, Yong CS, Choi HG: Comparison of the solubility and pharmacokinetics of sildenafil salts. Arch Pharm Res 2011, 34(3):451-454.

Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate.[Pubmed:28345432]

J Matern Fetal Neonatal Med. 2018 Apr;31(8):1045-1050.

OBJECTIVE: To assess efficacy and tolerability of Sildenafil Citrate on utero-placental blood flow and fetal growth in pregnancies complicated by fetal growth restriction (FGR). METHODS: From March 2015, a randomized controlled trial of 54 patients at 24 weeks or more complicated by FGR and abnormal Doppler indices were randomly allocated 1:1 into an intervention arm (receive Sildenafil Citrate, 50 mg) or a control arm (receive placebo). The primary outcomes were changes occurred in the Doppler parameters 2 h following drug administration. RESULTS: Baseline characteristics were similar between groups. Significant difference was observed in the Delta uterine and umbilical Doppler indices among sildenafil group as compared to placebo group (p < 0.001). Middle cerebral Doppler indices, however, decreased significantly after sildenafil, which could be the result of shifting more blood to improve the utero-placental perfusion. No difference regarding Delta cerebro-placental ratio among both groups (p = 0.979). Sildenafil was also associated with pregnancy prolongation (p = .0001), increased gestational age at delivery (p = .004), improved neonatal weight (p = .0001), and less admission to neonatal intensive care unit (p = .03). No adverse effects reported in both treatment arms. CONCLUSION: Sildenafil Citrate, by its vasodilator effect, can improve utero-placental blood flow in pregnancies complicated by FGR and abnormal Doppler. CLINICAL TRIAL: gov Registry: NCT02362399.

Sildenafil citrate in combination with tamsulosin versus tamsulosin monotherapy for management of male lower urinary tract symptoms due to benign prostatic hyperplasia: A randomised, double-blind, placebo-controlled trial.[Pubmed:28275519]

Arab J Urol. 2016 Dec 29;15(1):53-59.

OBJECTIVE: To assess the additive effect of Sildenafil Citrate to tamsulosin in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) in men with or without erectile dysfunction (ED). PATIENTS AND METHODS: In all, 150 men with untreated LUTS/BPH with or without ED were randomised to receive sildenafil 25 mg once daily (OD) or placebo OD (night time) combined with tamsulosin 0.4 mg OD (day time) for 6 months. Changes from pre-treatment scores in International Prostate Symptom Score (IPSS), IPSS-quality of life (QoL) score, maximum urinary flow rate (Qmax), and the five-item version of the International Index of Erectile Function questionnaire (IIEF-5) were assessed at 3 and 6 months. Safety profiles were assessed by physical examination and monitoring clinical adverse events. RESULTS: Group A comprised of men who received tamsulosin and sildenafil (75 men), whilst those in Group B received tamsulosin and placebo (75). The IPSS was significantly improved in Group A compared to Group B, at -29.3% vs -13.7% (P = 0.039) at 3 months and -37% vs -19.6% (P = 0.043) at 6 months after treatment. Qmax significantly improved in both groups compared with before treatment (P < 0.001). The IIEF-5 scores improved more in Group A than in Group B, at 58.7% vs 11.7% at 3 months and 62.4% vs 12.4% at 6 months after treatment (both P < 0.001). CONCLUSION: Sildenafil Citrate combined with tamsulosin improved LUTS, erectile function, and patient QoL more than tamsulosin monotherapy with the merit of a comparable safety profile in patients with LUTS/BPH.

Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial.[Pubmed:28277352]

Obstet Gynecol. 2017 Apr;129(4):615-620.

OBJECTIVE: To compare sildenafil plus hydration with hydration alone in improving the amniotic fluid index and neonatal outcomes in pregnancies complicated by idiopathic oligohydramnios ( amniotic fluid index less than 5 cm without underlying maternal or fetal causes and with normal fetal growth). METHODS: This was an open-label randomized trial for women carrying singleton pregnancies at 30 weeks of gestation or more with idiopathic oligohydramnios detected during routine ultrasonogram. Women received either oral Sildenafil Citrate (25 mg every 8 hours) plus intravenous infusion of 2 L isotonic solution or fluids only until delivery. The primary study outcome was the amniotic fluid volume at 6 weeks of follow-up or the final volume before delivery, whichever occurred first. Secondary outcomes were duration of pregnancy prolongation, mode of delivery, and select neonatal outcomes. The study was powered to detect a 45% difference between groups, so, at an alpha level of 0.05 and 80% power, a sample size of 167 women was required. RESULTS: From February 24, 2015, through April 2016, 196 women were screened and 184 were randomized. Follow-up was completed in 166 (90%): 82 in the sildenafil group and 84 in the hydration group. Baseline characteristics were similar between groups. The amniotic fluid volume was higher in the sildenafil group at the final assessment (11.5 compared with 5.4 cm, P=.02). The sildenafil group delivered later (38.3 compared with 36.0 weeks of gestation, P=.001), had a lower rate of cesarean delivery (28% compared with 73%), and their neonates were less likely to be admitted to the neonatal intensive care unit (11% compared with 41%, P=.001). CONCLUSION: Sildenafil Citrate increases amniotic fluid volume in pregnancies complicated by oligohydramnios. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02372487.

Effect of chronic administration of sildenafil citrate (Viagra) on the histology of the retina and optic nerve of adult male rat.[Pubmed:28237322]

Tissue Cell. 2017 Apr;49(2 Pt B):323-335.

BACKGROUND: Abnormal vision has been reported by 3% of patients treated with Sildenafil Citrate (Viagra). Although many men use Viagra for an extended period for treatment of erectile dysfunction, the implications of the long term-daily use of it on the retina and optic nerve are unclear. AIM OF THE WORK: To investigate the effect of chronic daily use of Sildenafil Citrate in a dose equivalent to men preferred therapeutic dose on the histology of the retina and optic nerve of adult male rat. MATERIAL & METHODS: Eighteen adult male Wistar rats were equally divided into three groups. Group I: control. Group II: treated with Sildenafil Citrate orally (10mg/kg/day) for 8 weeks. Group III (withdrawal): treated as group II and then left for 4 weeks without treatment. Specimens from the retina and optic nerve were processed for light and electron microscopy. RESULTS: In Sildenafil Citrate treated group, the retina and optic nerve revealed vacuolations and congested blood capillaries with apoptotic endothelial and pericytic cells, and thickened basal lamina. Caspase-3 (apoptotic marker) and CD31 (endothelial marker) expression increased. Glial cells revealed morphological changes: Muller cells lost their processes, activated microglia, astrocytic clasmatodendrosis, degenerated oligodendrocytes surrounded by disintegrated myelin sheathes of the optic nerve fibers. The retina and optic nerve of the withdrawal group revealed less vacuolations and congestion, and partial recovery of the glial cells. CONCLUSION: Chronic treatment with Sildenafil Citrate (Viagra) caused toxic effect on the structure of the retina and optic nerve of the rat. Partial recovery was observed after drug withdrawal.

Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.[Pubmed:16883306]

Nat Rev Drug Discov. 2006 Aug;5(8):689-702.

In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.

Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds.[Pubmed:10385692]

Mol Pharmacol. 1999 Jul;56(1):124-30.

The cGMP-binding cGMP-specific phosphodiesterase (PDE5) degrades cGMP and regulates the intracellular level of cGMP in many tissues, including the smooth muscle of the corpus cavernosum of the penis. Sildenafil (Viagra), a specific PDE5 inhibitor, promotes penile erection by blocking the activity of PDE5, which causes cGMP to accumulate in the corpus cavernosum. In the present study, sildenafil, like other PDE5 inhibitors, stimulates cGMP binding to the allosteric sites of PDE5 by interacting at the catalytic site of this enzyme, but the drug does not compete with cGMP for binding at the allosteric sites. Both sildenafil and zaprinast are competitive inhibitors of PDE5, and double-inhibition analysis shows that these two inhibitors added together interact with the catalytic site of PDE5 in a mutually exclusive manner. After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain of PDE5, the pattern of changes in the IC50 values for sildenafil or UK-122764 is similar to that found for zaprinast. However, among the three inhibitors, sildenafil exhibits the most similar pattern of changes in the IC50 to that found for the affinity of cGMP, implying similar interactions with the catalytic domain. This may explain in part the stronger inhibitory potency of sildenafil for wild-type PDE5 compared with the other inhibitors [sildenafil (Ki = 1 nM) > UK-122764 (Ki = 5 nM) > zaprinast (Ki = 130 nM)]. The affinity of each of these inhibitors for PDE5 is much higher than that of cGMP itself (Km = 2000 nM). It is concluded that residues such as Tyr602, His607, His643, and Asp754 may form important interactions for sildenafil in PDE5, but because these amino acids are conserved in all mammalian PDEs, the selectivity and potency of sildenafil is likely to be provided by a nonconserved residue or residues in the PDE5 catalytic domain.

Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes.[Pubmed:9598563]

J Urol. 1998 Jun;159(6):2164-71.

PURPOSE: Sildenafil, an inhibitor of cGMP-specific phosphodiesterase 5 (PDE5), is currently undergoing evaluation as an oral therapy for penile erectile dysfunction. The aims of this study were to investigate the mechanism of action of sildenafil on the neurogenic relaxation of human corpus cavernosum (HCC) in vitro and to determine the activity of sildenafil against a full range of PDE isozymes. MATERIALS AND METHODS: Strips of HCC tissue were precontracted with phenylephrine. Relaxation responses resulting from electrical field stimulation (EFS) were then determined in the presence and absence of sildenafil. The effects of sildenafil on PDE1 to 5 prepared from human tissues and PDE6 from bovine retina were determined by measuring the conversion of [3H]-cGMP or [3H]-cAMP to their respective [3H]-5'-mononucleotides. RESULTS: Sildenafil (0.001 to 1 microM) enhanced the EFS-induced, nitric oxide (NO) dependent, relaxation of HCC in a concentration-dependent manner to a maximum of 3 times the pretreatment level at 1 microM sildenafil. Compared with zaprinast, an early PDE5 inhibitor, sildenafil was approximately 240-fold more potent, inhibiting PDE5 from HCC with a geometric mean IC50 of 3.5 nM. For sildenafil, IC50 values for inhibition of PDE1 to 4 were 80 to more than 8500 times greater than that for PDE5 and the IC50 for PDE6 (33 nM) was approximately 9-fold greater. CONCLUSIONS: The data support the proposal that enhancement of penile erection by sildenafil in patients with erectile dysfunction involves potentiation of the NO-stimulated cGMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. Sildenafil is a potent inhibitor of PDE5 from HCC, with high selectivity for PDE5 relative to other PDE isozymes.