Administration Of Sildenafil Research Articles

The Pharmacokinetics of Sildenafil May Be Affected by Intestinal Absorption Rate in Children Admitted to the Intensive Care Unit.

This study was performed for a better understanding of the pharmacokinetics of sildenafil (SIL) and N-desmethyl sildenafil (DMS) in 13 children treated in the intensive care unit (ICU). Blood samples were taken periodically after the first oral administration of SIL (0.5 mg/kg). Plasma concentrations were analyzed by tandem LC/MS. Of the 13 patients, apparent peaks in the plasma concentration of SIL were observed in four patients, with the other nine patients showing reduced or delayed drug absorption of SIL. The maximum plasma concentrations of SIL after administration varied in range from 7.8 to 101.0 ng/mL. The parent drug-to-metabolite (SIL/DMS) ratios of the nine patients with reduced or delayed drug absorption of SIL were relatively lower than those in the four patients with rapid absorption of the drug. These observations suggested that the inter-individual variability of intestinal absorption and/or first-pass extraction of SIL was involved in the pharmacokinetic variability of the drug. Next, we evaluated the impact of changes in the gastrointestinal absorption rate on the pharmacokinetics of the drug. That is, SIL (2.5 mg/body) was administered at two different rates in the duodenum of rats. When SIL was administered for 10 min, the Cmax and bioavailability were 3.46 ± 1.65 µg/mL and 23.2 ± 11.1%, respectively. When SIL was administered for 60 min, the Cmax and bioavailability were 0.990 ± 0.352 µg/mL and 9.91 ± 3.79%, respectively. These findings suggest that the drug absorption rate was at least partly responsible for the pharmacokinetic variability of SIL in the ICU children.

Abstract 16412: The Predictors of Hemodynamic Response to Phosphodiesterase-5a Inhibition in Advanced HFrEF

Introduction: In advanced HFpEF, acute phosphodiesterase 5 (PDE5) inhibition leads to favorable change in pulmonary vascular resistance (PVR) and to an increased cardiac output (CO) of variable degree. The determinants of the response are poorely understood. Methods: 47 HFrEF patients (85% males, 57±11 years, NYHA 2.9±0.5, 55% non-ischemic, PAmean 42±8 mmHg, 43% RV dysfunction) underwent clinical exam, echocardiography, biochemical tests and right heart catheterization (RHC) before and after I.V. administration of sildenafil (20 mg). Baseline predictors of absolute and relative (%diff) change of PVR and CO were studied. Results: PDE5i led to highly significant (p<0.001) reduction of pulmonary artery (PA) mean pressure (-11±9 mmHg), PVR (-2.2±1.6 WU;-42±24%), PA wedge pressure (-5.2±7.3 mmHg), CVP (-3.2±2.3 mmHg) and to increase in cardiac output (+0.6±0.7 l/min; +18±23%). PVR decreased more than systemic resistance (PVR/SVR -27±30%diff). Predictors of high CO response (COdiff%) were: low BMI, no diabetes, low baseline CO and severity of mitral or tricuspid regurgitation (r=0.53 or =0.43, both p<0.003). The strongest predictor of high PVR%diff was plasma potassium level. HF etiology, renal function, gender, RAAS inhibitor dose, renin or aldosterone levels were unelated to pulmonary vasoreactivity. Patients who dropped PVR<3 WU after PDE5i had higher plasma K+ (4.1±0.5 vs 4.5±0.3 mmol/L, p=0.01) than those who did not, similar relation was found for K+ and PDE5i-induced change of transpulmonary gradient. Conclusions: The largest increase in CO after PDE5i is observed in HFrEF patients with severe mitral (or tricuspid) regurgitation, probably due to chamber unloading and reduction of regurgitant SV. Pulmonary vasodilator response to PDE5i may be influenced by plasma potassium level. High-normal plasma potassium levels may preserve normal pulmonary vasoreactivity in HFrEF, perhaps by influencing K-channels in pulmonary vascular smooth muscle cells.

Effect of prucalopride on sildenafil-induced inhibition of esophageal peristalsis in healthy adults.

Prucalopride, a high-affinity 5-hydroxytryptamine 4 receptor agonist, promotes esophageal peristalsis, while phosphodiesterase type 5 inhibitor sildenafil inhibits esophageal peristalsis. The present study was aimed to evaluate whether prucalopride would augment esophageal peristalsis subsequent to the application of sildenafil. Seventeen healthy adults underwent high-resolution manometry by a catheter with one injection port located in the mid-esophagus. Secondary peristalsis was assessed by rapid air injections after water swallows. Two sessions were randomly performed including acute administration of sildenafil 50mg after pretreatment with prucalopride or the placebo. The frequency of primary peristalsis subsequent to the administration of sildenafil was significantly increased by prucalopride (P=0.02). Prucalopride also significantly increased distal contractile integral of primary peristalsis subsequent to the administration of sildenafil (P=0.03). No difference in the frequency of secondary peristalsis subsequent to the administration of sildenafil for air injects of 10mL (P=0.14) or 20mL (P=0.21) was found between prucalopride and placebo. Prucalopride did not change distal contractile integral of secondary peristalsis subsequent to the administration of sildenafil for air injections of 10mL (P=0.09) or 20mL (P=0.12). Prucalopride modulates sildenafil-induced inhibition of primary peristalsis by increasing its effectiveness and peristaltic wave amplitude. Our findings suggest that activation of 5-hydroxytryptamine 4 receptors plays a role in mediating sildenafil-induced inhibition of esophageal primary peristalsis rather than secondary peristalsis.

Changes in fetoplacental Doppler indices following intrapartum maternal sildenafil citrate treatment

ObjectiveUterine contractions during labour can result in a 60 % decline in fetoplacental perfusion, predisposing the fetus to hypoxic brain injury. Sildenafil citrate (SC) has shown promise in increasing uteroplacental perfusion as well as reducing the risk of operative birth for intrapartum fetal compromise (IFC). The aim of this study was to investigate the effect of intrapartum SC administration on fetoplacental blood flow indices. MethodsThis was a subgroup analysis from an earlier Phase II double blind randomized controlled trial; assessing the effect of intrapartum SC administration (50 mg orally 8 -hly in labour) compared to placebo for the reduction of operative birth for IFC. An ultrasound scan measuring fetoplacental Doppler indices was performed prior to and 1−4 h after the administration of the first treatment dose. ResultsOf the 300 women randomized to the main study, pre-treatment ultrasound scans were performed in 261 participants who received the study medication; paired pre- and post-treatment scans were performed in 70 (26.8 %). SC resulted in an increase in the middle cerebral artery pulsatility index (PI) z-score [+0.08 (1.35) vs.−0.12 (1.15)], a decline in the umbilical artery-PI z-score [−0.07 (0.96) vs. + 0.04 (1.25)] and an increase in the cerebroplacental ratio [MCA-PI/UA-PI] (CPR) z-score [+0.10 (1.13) vs.−0.26 (1.14)] although these failed to reach statistical significance. Amongst those with a pre-treatment CPR above the 5th centile, SC significantly reduced the risk of operative birth for IFC compared to placebo [logrank p = 0.02; hazards ratio 0.48, 95 % CI 0.29−0.77, p = 0.003]. ConclusionAlthough the differences in Doppler indices pre- and post- SC treatment were non-significant, there was a clear trend towards a reduction in the UA PI, a corresponding increase in the MCA PI and a rise in post treatment CPR values suggesting potential improvement in fetoplacental Dopplers with intrapartum SC treatment. However this study was limited by the small sample size. The results of this hypothesis generating study suggest that it may be possible to stratify women that would most benefit from this intervention based upon their pre-labour CPR.

Sildenafil ameliorates Alzheimer disease via the modulation of vascular endothelial growth factor and vascular cell adhesion molecule-1 in rats.

Alzheimer disease (AD) is a chronic neurodegenerative disease with multi-pathways pathogenesis. Sildenafil is a selective phosphodiesterase-5 inhibitor with a potential benefit in the treatment of AD. This study investigated the possible mechanisms underlying the effect of sildenafil in AD with emphasis on vascular endothelial growth factor (VEGF), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four adult male rats were classified into four groups; control group: received vehicles, sildenafil-control: received sildenafil (15 mg/kg/day, p.o.), AD group received Aluminum (25 mg/kg/day, p.o.), AD-treated group: received sildenafil (15 mg/kg/day, p.o.) for 6 weeks. AD was assessed by memory performance test and confirmed by histopathological examination and immunostaining of, neurogenesis marker nestin and α-synuclein. The levels of VEGF-A, VCAM-1, oxidative stress markers and TNF-α in brain tissue were evaluated. AD rats showed histopathological evidences of AD; along with increased latency time in the memory test. There was a decrease in VEGF-A, and an increase in VCAM-1, TNF-α, and oxidative stress markers. Immunohistochemical study showed a significant increase in α-synuclein and a significant decrease in nestin expressions in brain tissues. Sildenafil administration ameliorated the histopathological changes and decreased latency time. Such effect was associated with a decrease in VCAM-1, TNF-α and oxidative stress as well as an increase in VEGF-A. Sildenafil caused a significant increase in nestin and a decrease in α-synuclein immunostaining. These findings suggested a protective effect of sildenafil via modulation of VEGF-A, and VCAM-1.

The effect of sildenafil on pulmonary haemodynamics in a canine model of chronic embolic pulmonary hypertension

The effects of different doses of orally administered sildenafil on pulmonary haemodynamics in dogs with pulmonary hypertension (PH) have not been documented in an invasive and quantitative manner. In this study, we examined the effects of oral sildenafil using a canine model of chronic embolic PH (CEPH). This CEPH model was created by repeatedly injecting microspheres through a catheter into the pulmonary artery under general anaesthesia at regular weekly intervals over several months. The CEPH dogs received 1, 2 or 4 mg/kg of sildenafil orally twice a day for seven days. Then, haemodynamic measurements including pulmonary artery pressure (PAP), systemic artery pressure (SAP), pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP) and cardiac output (CO) were obtained after seven days of sildenafil administration via right heart catheterisation and oscillometric blood pressure measurements.Sildenafil was well tolerated in this study. Sildenafil administered at doses of 2 and 4 mg/kg significantly decreased systolic PAP compared with before administration. In addition, all doses of sildenafil significantly decreased the mean and diastolic PAP. Furthermore, 4 mg/kg of sildenafil significantly decreased PAP compared with 1 mg/kg. Sildenafil also significantly decreased pulmonary vascular resistance without notable changes in SAP or systemic vascular resistance. The PAWP, RAP and CO did not increase significantly at any doses. In conclusion, the oral administration of sildenafil to CEPH models decreased PAP in a dose-dependent manner.

Spontaneous tricuspid valve chordal rupture in a dog with severe, irreversible pulmonary hypertension caused by Angiostrongylus vasorum infection

BackgroundThe adult worms of Angiostrongylus vasorum reside in the pulmonary artery of dogs and can lead to cardiac, respiratory, and central neurologic signs. Due to luminal obstruction and perivascular inflammation of the pulmonary artery branches, pulmonary hypertension can arise. Pulmonary hypertension, in turn, can lead to severe damage of the right-sided cardiac structures, leading to right ventricular remodeling and tricuspid valve regurgitation.Case presentationAn 8-year-old neutered female English Cocker Spaniel was presented to the author’s institution because of abdominal distention and exercise intolerance. Ascites caused by congestive right-sided heart failure was found to be responsible for these problems. The underlying etiology of the right-sided heart failure was a severe pulmonary hypertension caused by Angiostrongylus vasorum infection. Echocardiography revealed, in addition to a severe concentric and eccentric right ventricular hypertrophy, right atrial and pulmonary trunk dilation, severe tricuspid valve regurgitation, and a systolic flail of the anterior leaflet of the tricuspid valve, resulting from ruptured chordae tendineae. As a coincidental finding, a congenital mitral stenosis was found. Oral therapy was initiated with daily administration of fenbendazole for 2 weeks along with daily administration of oral sildenafil until the re-check examination. At the 6-week re-check the dog showed full clinical and partial echocardiographic recovery, and both the blood antigen test for Angiostrongylus vasorum and the fecal Baermann larva isolation test were negative. When the sildenafil therapy was ceased after tapering the daily dosage, the owner reported recurrence of abdominal distension. Re-starting the sildenafil therapy resulted in resolution of this problem. The dog was reported to be clinically healthy with daily sildenafil administration 7 months after the initial presentation.ConclusionsThe present case report describes a dog where angiostrongylosis led to congestive right-sided heart failure resulting from severe pulmonary hypertension. The secondary right ventricular eccentric hypertrophy together with suspected papillary muscular ischemia were the suspected cause of the ruptured major tricuspid chordae tendineae, which led to a severe tricuspid valve regurgitation. Despite eradication of the worms, the severe pulmonary hypertension persisted. Treatment with daily oral sildenafil, a pulmonary arterial vasodilator, was enough to keep the dog free of clinically apparent ascites.

The Phosphodiesterase Type 5 Inhibitor Sildenafil Improves DNA Stability and Redox Homeostasis in Systemic Sclerosis Fibroblasts Exposed to Reactive Oxygen Species.

Systemic sclerosis (SSc) is a multi-system connective tissue disease characterized by the increased deposition of extracellular matrix proteins such as collagen and fibronectin. Although the pathogenesis is not completely understood, a number of studies suggest that free radicals could be the major contributors to the disease. Indeed, different studies demonstrated how oxidative stress could contribute to the fibrotic process activation at the level of the skin and visceral organs. Emerging evidences highlight the beneficial effects of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), which protects different cell lines from the cell damage induced by reactive oxygen species (ROS). These data make sildenafil a good candidate for therapeutic treatment aimed to protect biological macromolecules against oxidative damage, thus preserving cell viability. The purpose of this study was to evaluate the sensitivity of SSc dermal fibroblasts to an oxidative insult and the ability for sildenafil to prevent/reduce the DNA damage due to ROS action. Additionally, we evaluated the capacity for sildenafil to influence redox homeostasis and cytotoxicity, as well as cell proliferation and cell cycle progression. We demonstrated that SSc fibroblasts have an increased sensitivity to a pro-oxidant environment in comparison to healthy controls. The sildenafil treatment reduced ROS-induced DNA damage, counteracted the negative effects of ROS on cell viability and proliferation, and promoted the activity of specific enzymes involved in redox homeostasis maintenance. To our knowledge, in this report, we demonstrate, for the first time, that sildenafil administration prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients. These results expand the use of PDE5i as therapeutic agents in SSc by indicating a protective role in tissue damage induced by oxidative insult.

Maternal sildenafil impairs the cardiovascular adaptations to chronic hypoxaemia in fetal sheep.

Key points Fetal growth restriction induces a haemodynamic response that aims to maintain blood flow to vital organs such as the brain, in the face of chronic hypoxaemiaMaternal sildenafil treatment impairs the hypoxaemia‐driven haemodynamic response and potentially compromises fetal development. Inadequate substrate delivery to a fetus results in hypoxaemia and fetal growth restriction (FGR). In response, fetal cardiovascular adaptations redirect cardiac output to essential organs to maintain oxygen delivery and sustain development. However, FGR infants remain at risk for cardiovascular and neurological sequelae. Sildenafil citrate (SC) has been examined as a clinical therapy for FGR, but also crosses the placenta and may exert direct effects on the fetus. We investigated the effects of maternal SC administration on maternal and fetal cardiovascular physiology in growth‐restricted fetal sheep. Fetal sheep (0.7 gestation) underwent sterile surgery to induce growth restriction by single umbilical artery ligation (SUAL) or sham surgery (control, AG). Fetal catheters and flow probes were implanted to measure carotid and femoral arterial blood flows. Ewes containing SUAL fetuses were randomized to receive either maternal administration of saline or SC (36 mg i.v. per day) beginning 4 days after surgery, and continuing for 20 days. Physiological recordings were obtained throughout the study. Antenatal SC treatment reduced body weight by 32% and oxygenation by 18% in SUAL compared to AG. SC did not alter maternal or fetal heart rate or blood pressure. Femoral blood flow and peripheral oxygen delivery were increased by 49% and 30% respectively in SUALSC compared to SUAL, indicating impaired cardiovascular adaptation to chronic hypoxaemia. Antenatal SC directly impairs the fetal haemodynamic response to chronic hypoxaemia. Consideration of the consequences upon the fetus should be paramount when administering interventions to the mother during pregnancy.

Combined Intravenous Sildenafil and l-Arginine Administration in a Porcine Animal Model: Hemodynamic Safety Profile and Effects on Coronary Blood Flow

BackgroundEndothelial dysfunction in the nitric oxide-cyclic guanosine monophosphate pathway is a potential contributor to perioperative myocardial ischemia. The nitric oxide precursor, l-arginine, and the cyclic guanosine monophosphate degradation blocker, sildenafil, have vasodilatory effects under high dosage.ObjectiveThis study examined the hemodynamic safety and effect profiles of the combined administration of l-arginine and sildenafil using an in-vivo pig model.MethodsHemodynamic safety including mean arterial pressure, central venous pressure, heart rate, coronary vascular resistance, and systemic vascular resistance, as well as effect profiles including cardiac output and left anterior descending blood flow were measured in ten female swine after administrations of l-arginine, sildenafil, as well as combined l-arginine and sildenafil. Measurements were compared using repeated-measures analysis of variance and linear mixed models.ResultsThe combination of l-arginine and sildenafil produced a significant dose-dependent increase in left anterior descending flow and cardiac output. In contrast, mean arterial pressure, heart rate, central venous pressure, coronary vascular resistance, and systemic vascular resistance did not show any significant changes. No significant change in serum osmolality was observed after administrations of l-arginine.ConclusionsThe combined intravenous administration of sildenafil and l-arginine in a porcine animal model was safe, well tolerated, and had at least additive effects on left anterior descending artery blood flow. Simultaneous application of both drugs might have dose-sparing effects leading to desired coronary effects at lower and safer sildenafil and l-arginine plasma concentrations. Hyperosmolality was only a minor factor in l-arginine hemodynamic effects.

Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project.

BackgroundA pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm,” that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability.ObjectivesNumerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease.Materials and methodsWe performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial).”ResultsThe reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications.Discussion and ConclusionIf the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.

Evaluation of the preoperative administration of sildenafil on operative and early postoperative outcome after mitral valve replacement in patients with pulmonary hypertension

Background: Mitral valve diseases are commonly associated with pulmonary hypertension. The aim of this study was to evaluate the effect of preoperative administration of sildenafil on the outcome after mitral valve replacement in patients with pulmonary hypertension.
 Methods: This prospective randomized study was carried out on 67 patients who had a mitral valve replacement and associated high systolic pulmonary artery pressure more than 50 mmHg. Patients were randomized into three groups: group A (n= 20) received preoperative sildenafil for one week, group B (n=22) received sildenafil for one month, and group C (n= 25) did not receive sildenafil. All patients had transthoracic echocardiography preoperatively, one week and one month postoperatively.
 Results: There was no difference in preoperative and operative variables among groups. Dobutamine support was required in 15 patients (60%) in group C vs. 6 patients (30%) in group A and 5 patients (22.5%) in group B (p= 0.012). Duration of mechanical ventilation was significantly longer in group C (389.2 ± 48.79 minutes) compared to group A and B (295.5 ± 17.01 and 281.4 ± 39.44 minutes, respectively, p<0.001). ICU stay was longer in group C (61.72 ± 13.69 hours) compared to groups A and B (53.55 ± 14.49 and 45.64 ± 13.43 hours, respectively, p=0001). The hospital stay was longer in group C (8.0 ± 1.80 days) compared to group A and B (6.05 ± 0.94 and 6.27 ± 1.24 days, respectively; p< 0.001). The transthoracic echocardiographic study one month after the operation showed that pulmonary artery systolic pressure significantly lower in groups A and B (28.30 ± 3.3 and 28.2 ± 4.98 mmHg, respectively) compared to group C (43.12 ± 4.99 mmHg) (p <0.001). There was no statistically significant difference between groups A and B regarding PASP after five days (p= 0.287) or one month (p= 0.939).
 Conclusion: We found that preoperative administration of oral sildenafil in patients with pulmonary hypertension undergoing mitral valve replacement may reduce pulmonary hypertension postoperatively. We could not find a difference in the administration of sildenafil for either one week or one month preoperatively.

Progressive Effects of Sildenafil on Visual Processing in Rats

Photoreceptors are light-sensitive cells in the retina converting visual stimuli into electrochemical signals. These signals are evaluated and interpreted in the visual pathway, a process referred to as visual processing. Phosphodiesterase type 5 and 6 (PDE5 and 6) are abundant enzymes in retinal vessels and notably photoreceptors where PDE6 is exclusively present. The effects of the PDE inhibitor sildenafil on the visual system, have been studied using electroretinography and a variety of clinical visual tasks. Here we evaluate effects of sildenafil administration by electrophysiological recordings of flash visual evoked potentials (VEPs) and steady-state visual evoked potentials (SSVEPs) from key regions in the rodent visual pathway. Progressive changes were investigated in female Sprague-Dawley rats at 10 timepoints from 30 min to 28 h after peroral administration of sildenafil (50 mg/kg). Sildenafil caused a significant reduction in the amplitude of VEPs in both visual cortex and superior colliculus, and a significant delay of the VEPs as demonstrated by increased latency of several VEP peaks. Also, sildenafil-treatment significantly reduced the signal-to-noise ratio of SSVEPs. The effects of sildenafil were dependent on the wavelength condition in both assays. Our results support the observation that while PDE6 is a key player in phototransduction, near full inhibition of PDE6 is not enough to abolish the complex process of visual processing. Taken together, VEPs and SSVEPs are effective in demonstrating progressive effects of drug-induced changes in visual processing in rats and as the same paradigms may be applied in humans, representing a promising tool for translational research.

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction

Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. To determine whether sildenafil reduces perinatal mortality or major morbidity. This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. ClinicalTrials.gov Identifier: NCT02277132.

Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH). Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO. CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls. The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ± 0.3% vs 2.3 ± 0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ± 0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm2 vs 3.5 ± 0.9 br/mm2, P=0.043) and lung mechanics (static elastance 61 ± 36 cmH2O /mL vs 113 ± 40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm2, P=0.001 and 31 ± 9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ± 2.9% and 41.8 ± 3.2%, vs 24.0 ± 2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ± 2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil. In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.

Evaluation of the Autonomic Nervous System in a Canine Model of Chronic Embolic Pulmonary Hypertension.

Sildenafil improves autonomic dysfunction caused by pulmonary hypertension (PH) in humans, but its effect is unknown in dogs with PH. This prospective study aimed to evaluate the autonomic nervous system function of a canine model of chronic embolic PH (CEPH) and the autonomic nervous system function of a canine model of CEPH in which sildenafil was administered. This study used five clinically healthy female beagle dogs. Evaluation parameters included hemodynamic parameters, heart rate (HR) and heart rate variability (HRV). Each evaluation parameter was compared before and after creating the CEPH model (before, BL; after, CEPHBL) and between the CEPHBL model and after the administration of sildenafil (1mg/kg, BID) in the CEPH model dogs (CEPHSil). In the CEPHBL model, the hemodynamic parameters indicated cardiac hypofunction, and HR was significantly increased and HRV was significantly decreased compared with BL. Further, in the CEPHSil model, the hemodynamic parameters suggested improvement in cardiac function, and HRV was significantly increased. From the results of the CEPH model dogs, autonomic dysfunction was shown to occur in PH dogs. In addition, the administration of 1mg/kg of sildenafil to CEPH model dogs may improve autonomic dysfunction.

Oxytocinergic system mediates the proconvulsant effects of sildenafil: The role of calcineurin

Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 μg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice.Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil.

Involvement of YAP and LATS1 in lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia

Purpose: To investigate the role of Hippo pathway in lung development in congenital diaphragmatic hernia (CDH).&#x0D; Methods: One oral dose of nitrofen was maternally administered for induction of CDH on embryonic day 9.5 (E 9.5). Sildenafil was administered intragastrically at a dose of 100 mg/kg on E 11.5. Three rat groups were used: control, CDH, and CDH + sildenafil. Cesarean section was used for fetal delivery on E 21.5. Fetuses with left diaphragmatic hernia (except in control rats) were chosen for investigations. Fetal body weight and weight of lung tissue were recorded, and lung histological evaluation, western blot and PCR were carried out after lung processing.&#x0D; Results: There was markedly higher expression of YAP in CDH rats than in control rats was unaffected by antenatal sildenafil administration (p &lt; 0.05). However, prenatal sildenafil intervention significantly increased LATS1 expression in the lung of CDH fetuses (p &lt; 0.05).&#x0D; Conclusion: These results indicate that increased pulmonary YAP expression in CDH rat model might contribute to pulmonary vascular remodeling and suppression of lung development. Thus, antenatal sildenafil administration not only mitigates abnormal vascular remodeling but also promotes lung development, most likely via increased expression of LATS1.&#x0D; Keywords: Congenital diaphragmatic hernia (CDH), Hippo pathway, Lung development, Sildenafil

USING SILDENAFIL TO TREAT A DOG WITH IDIOPATHIC MEGAESOPHAGUS

A 4-month old, male intact, mixed-breed dog was referred for sudden onset of regurgitation for two weeks. Thoracic radiographs revealed severe dilatation of esophagus with barium aspiration pneumonia. Idiopathic megaesophagus (IME) was diagnosed after serial laboratory, endoscopic and computed tomographic examinations. Symptomatic treatment including medication for pneumonia, feeding through percutaneous endoscopic gastrostomy (PEG) tube with upright feeding position was performed at first, but regurgitation persisted. Sildenafil (1[Formula: see text]mg/kg, PO, BID) was then administrated for two weeks and regurgitation remitted one day after. Sildenafil was then tapered to half dose (0.5[Formula: see text]mg/kg, PO, BID) for another two weeks. During following-up thoracic radiography on 10 days after sildenafil administration, the degree of esophagus dilation significantly reduced. The clinical sign was completely resolved without relapse for more than 300 days. Sildenafil was reported having inhibitory effect of canine gastric contraction without affecting gastric emptying time. This effect could ameliorate persisting regurgitation after using PEG feeding directly into the stomach while bypassing the esophagus.

Chronic Administration of Sildenafil Citrate (Viagra) on the Frontal Cortex of Adult Male Rats: An Ultrastructural Study

Objectives: Sildenafil citrate (Viagra) is widely used as an aphrodisiac drug and for the treatment of erectile dysfunction. The present study was planned to study the morphological changes that might occur in the frontal cortex of the adult rat in response to chronic intake of Viagra and discover whether these changes are reversible or irreversible. Material and Methods: Forty adult male rats were used where they were classified into three groups: A control group (10 rats), B experimental treated group (20 rats), and C recovery group (10 rats). The treated and recovery groups received therapeutic dose of Viagra for 30 days. The control and the treated group were sacrificed at the first day after the designated period (30 days), the recovery group was sacrificed two weeks after the end of experiment. Results: The pyramidal cell neurons are little in number; some of them are atrophic, degenerated. Their cytoplasm showed varied degree of cellular degenerative changes with vaculation of their myelinated axons. Pyramidal neurons of recovery animals showed nearly complete recovery. Conclusion: Chronic intake of Viagra produced reversible morphological changes in pyramidal neurons of the frontal cortex of adult male rats.