Administration Of Sildenafil Research Articles

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.

In Silico studies of novel Sildenafil self-emulsifying drug delivery system absorption improvement for pulmonary arterial hypertension.

Sildenafil is a potent selective inhibitor of phosphosdiesterase-5 previously used in erectile dysfunction and subsequently approved in 2005 for pulmonary arterial hypertension treatment. Since oral administration of sildenafil shows pharmacokinetic problems with mean absolute bioavailability of 41%, the goal of this work was to develop a novel sildenafil self-emulsifying drug delivery system (SEDDS) for oral absorption improvement and management of dosage. One pharmaceutical solution and four SEDDS containing sildenafil were successfully obtained and SEDDS formed O/W nanoemulsion with droplet size less than 300 nm. The stability studies evidenced that the SEDDS containing 3.3% w/w of sildenafil yielded the best results. The safety of 2-pyrrolidone/isobutanol in oral formulations was assessed in mice and no lethality was achieved in the placebo groups with LD50 of 490 mg/Kg for SEDDS II-3.3, suggesting it as a safe excipient for humans. Therewithal, in silico studies using PBPK models provided the pharmacokinetic profile of sildenafil SEDDS. Subsequently, in silico evaluation indicated that the sildenafil SEDDS droplet size influenced its bioavailability, enhancing absorption, assuring a good pharmacokinetic profile. These findings suggest that the formulations developed here presented the potential to enhance drug oral absorption with the possibility to control drug dosage as they are liquid pharmaceutical formulations.

Sildenafil alters biogenic amines and increases oxidative damage in brain regions of insulin-hypoglycemic rats.

The aim of the present study was to determine the effect of sildenafil on dopamine, 5-hydroxyindol acetic acid (5-HIAA) and selected biomarkers of oxidative stress in the brain of hypoglycemic rats. The animals were treated intraperitoneally as follows: group 1 (control), saline solution; group 2, insulin (10 U per rat or 50 U kg-1); group 3, insulin + single dose of sildenafil (50 U kg-1 + 50 mg kg-1); group 4, insulin + three doses of sildenafil every 24 hours (50 U kg-1 + 50 mg kg-1). In groups 2, 3 and 4, insulin was administered every 24 hours for 10 days. Blood glucose was measured after the last treatment. On the last day of the treatment, the animals´ brains were extracted to measure the levels of oxidative stress markers [H2O2, Ca2+,Mg2+-ATPase, glutathione and lipid peroxidation (TBARS)], dopamine and 5-HIAA in the cortex, striatum and cerebellum/medulla oblongata by validated methods. The results suggest that administration of insulin in combination with sildenafil induces hypoglycemia and hypotension, enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines. Administration of insulin and sildenafil promotes biometabolic responses in glucose control, namely, it induces hypoglycemia and hypotension. It also enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines.

Sildenafil as a Rescue Agent Following Intestinal Ischemia and Reperfusion Injury

BackgroundAcute mesenteric ischemia carries a significant morbidity. Measures to improve blood flow parameters to the intestine may ameliorate the disease. Sildenafil, a phosphodiesterase 5 inhibitor, increases cyclic guanosine monophosphate and has been shown to prevent the effects of ischemia when given before injury. However, its effects as a rescue agent have not been established. We therefore hypothesized that sildenafil, when given as a rescue agent for intestinal ischemia, would improve mesenteric perfusion, limit intestinal epithelial injury, and decrease intestinal leukocyte chemoattractants. MethodsEight to 12 wk-old-male C57BL/6J mice underwent laparotomy and temporary occlusion of the superior mesenteric artery for 60 min. Following ischemia, reperfusion was permitted, and before closing the abdomen, sildenafil was injected intraperitoneally in a variety of concentrations. After 24 h, reperfusion was reassessed. Animals were euthanized and intestines evaluated for histologic injury and leukocyte chemoattractants. ResultsPostischemic administration of sildenafil did not improve mesenteric perfusion following intestinal ischemia and reperfusion injury. However, sildenafil did improve histologic injury scores in dose ranges of 0.01 to 10 mg/kg. No difference was noted in histological injury with 100 mg/kg dose, and all members of the 1000 mg/kg group died within 24 h of injury. Epithelial protection was not facilitated by the leukocyte chemoattractants Regulated on Activation, Normal T Cell Expressed, and Secreted, macrophage inflammatory protein 1 alpha, monocyte chemoattractant protein, neutrophil activating protein, or granulocyte colony stimulating factor. ConclusionsAdministration of sildenafil following intestinal ischemia may limit intestinal mucosal injury but does not appear to alter mesenteric perfusion or leukocyte chemoattractant influx. TypeBasic science. Level of evidenceN/A.

Effects of iloprost and sildenafil treatment on elabela, apelin-13, nitric oxide, and total antioxidant and total oxidant status in experimental enzyme-positive acute coronary syndrome in rats

ABSTRACTDespite significant advances in medicine, mortality due to cardiovascular disease is not yet preventable. We investigated the amounts of elabela (ELA) and apelin, synthesized by cardiomyocytes, and changes of these compounds in cardiac tissue and circulation after administration of iloprost (ILO) and sildenafil (SIL) in rats with induced myocardial ischemia (MI). We also investigated a connection with circulating troponin-I, creatine kinase (CK), creatine kinase-myocardial band (CK-MB) and nitric oxide (NO), and total anti-oxidant (TAS)/total oxidant status (TOS). We established eight study groups of five rats each. Group 1, sham, was given only physiologic serum; group 2, ILO; group 3, SIL; group 4, ILO + SIL; group 5, MI; group 6, MI + ILO; group 7, MI + SIL; group 8, MI + ILO + SIL. Troponin-I, CK, CK-MB and TAS-TOS were investigated using an autoanalyzer. NO, ELA and apelin were analyzed by ELISA. Tissue apelin and ELA expressions and localizations were determined by immunohistochemistry. The MI group compared to the control (sham) group showed that ELA, apelin, troponin-I, CK, CK-MB, NO and TOS levels were elevated significantly. Concentrations of these factors increased in MI, but decreased after ILO and SIL administration. The largest decrease of TOS was identified in the ILO + SIL group. ELA and apelin may be novel indicators of MI and administration of ILO and SIL, individually or together, may be useful for treating MI.

Administration of sildenafil citrate not able to reduced hs-CRP on erectile dysfunction patient at Doctor Soetomo Hospital, Surabaya, Indonesia

Background: Phosphodiesterase type-5 (PDE5) inhibitors was the first choice for the oral treatment of erectile dysfunction because of its ability to prevent endothelial dysfunction and restored erectile function properly. However, the inflammatory parameter such as hs-CRP can be used to assess the performance of PDE5 inhibitors as well as clinical questionnaires, IIEF-5, and EHS. So that, this study aims to determine the effect of PDE5 inhibitors administration such as sildenafil citrate 50 mg per day can decrease the value of hs-CRP, as well as increased the IIEF-5 and EHS at Dr. Soetomo General Hospital.Methods: A true clinical experimental studies used pretest and posttest control group design were carried out among 20 patients during 4 weeks. In the next 2 weeks, the crossover was conducted among respondents for the washout period whereas divided into 2 groups, control (K1 and K2) and treatment (P1 and P2). Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.0 software for Windows.Results: The average age of group K1 and P2 was 51 ± 12.07 years old whereas 48.60 ± 15.40 years old in group P1 and K2. The research was conducted in Andrology Clinic of Doctor Soetomo Hospital in Surabaya during June to November 2017. The research data were not normally distributed, then analyzed by two-tail T-group tests and Wilcoxon test at significance level α=0.05. The results showed that PDE5 inhibitors did not decrease the hs-CRP significantly (p>0.05), but increased EHS (p<0.05) and increased IIEF-5 (p<0.05) significantly.Conclusion: This study concluded that the administration of sildenafil citrate per day by oral increased the EHS and IIEF-5, but not able to reduced hs-CRP in patients with erectile dysfunction significantly.

The effect of sildenafil on pleural and peritoneal effusions after the TCPC operation.

We evaluated whether the administration of sildenafil in children undergoing the TCPC operation shortened the interval from the operation to the removal of the pleural and peritoneal drains. We retrospectively reviewed the data of 122 patients who had undergone the TCPC operation between 2004 and 2014. Patients were divided into two groups on the basis of their treatments. Sildenafil was orally administered pre-operatively in the morning of the procedure or within 24hours after the TCPC operation to the sildenafil group (n=48), which was compared to a control group (n=60). Fourteen patients were excluded from the study. The primary outcome measure was the time from the operation to the removal of the drains. The study groups had similar demographics. The median [interquartile range] time for the removal of drains (sildenafil group 11 [8-19] vs control group 11 [7-16] d, P=.532) was comparable between the groups. The median [interquartile range] fluid balance on the first post-operative day was significantly higher (P=.001) in the sildenafil group compared with controls (47 [12-103] vs 7 [-6-67] mLkg-1 ). The first post-operative day fluid balance was a significant predictor for a prolonged need for drains in the multivariate analysis. Sildenafil administration, pre-operatively or within 24hours after the TCPC operation, did not reduce the required time for pleural and peritoneal drains but was associated with a significantly higher positive fluid balance.

A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of neurodegenerative cognitive impairment, defined by abnormal accumulations of amyloid-β and tau. Approaches directly targeting these proteins have not resulted in a disease modifying therapy. Neurovascular unit dysfunction is a feature of AD offering an alternative target for intervention. Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves cognitive functioning in mouse models of AD. Recent work in AD patients has demonstrated increased cerebral blood flow, as well as brain oxygen utilization after a single dose of sildenafil. Its effect on nitric oxide-cGMP signaling may have downstream effects on neuroplasticity, amyloid-β processing, and improved neurovascular unit function. Fractional amplitude of low frequency fluctuations (fALFF) assesses spontaneous neural activity via resting state fMRI BOLD signal (0.01-0.08 or 0.10 Hz). In AD, other assessments have revealed increased fALFF in hippocampi and parahippocampal gyri. Here, we examined the effects of a single dose of sildenafil on fALFF in a cohort of 10 AD patients. We found a decrease (p < 0.03, α= 0.05) in fALFF an hour after sildenafil administration in the right hippocampus. Additionally, cerebral vascular reactivity in response to carbon dioxide inhalation, a measure of neural vascular reserve previously collected on most of these participants, was not significantly correlated with this decrease, implying that change in fALFF may not have been solely due to altered vascular reactivity to CO2. We demonstrate that in patients with AD, hippocampal fALFF decreases in response to sildenafil, suggesting a normalization. These findings support further investigation into the effects of sildenafil in AD.

EFFECTS OF THE CHRONIC INHIBITION OF TYPE 5 PHOSPHODIESTERASE ON PENILE MICROVASCULAR ENDOTHELIAL REACTIVITY AND BLOOD PRESSURE IN HYPERTENSIVE PATIENTS WITH ERECTILE DYSFUNCTION

Objective: The primary aim of this study was to test penile endothelial microvascular function and blood pressure in patients with treated primary arterial hypertension, before and after a chronic oral treatment with sildenafil citrate (SIL). Design and method: This was a prospective, randomized, double blinded and crossover study, controlled against placebo (PLA), with 30 day washout between treatments. Penile endothelial-dependent microvascular reactivity of hypertensive patients (aged 57.4 ± 5.6 years, n = 50) was evaluated using cutaneous laser speckle contrast imaging (LSCI) before and after chronic administration of placebo or sildenafil (50 mg twice daily during 30 days). LSCI was coupled with the cutaneous iontophoresis of acetylcholine (ACh) using increasing anodal microcurrents (30–180 μA). The measurements of skin blood flow (arbitrary perfusion units, APU) were divided by values of mean arterial pressure to give the cutaneous vascular conductance (CVC) in APU/mmHg. Erectile function was evaluated using the Simplified International Index of Erectile Function (IIEF-5) score. 24 hour ambulatory blood pressure monitoring (ABPM) was performed using oscillometric devices (Spacelabs). Results: IIEF-5 scores significantly increased after SIL [18(16–20) and 21.5(19.75–23); P < 0.0001] but not after PLA [18(14.75–19.25) and 17.84 ± 3.88; P = 0.16]. The basal values of CVC in the penis increased significantly after SIL (P = 0.004), but not after PLA (P = 0.86). Maximum CVC values after cutaneous ACh administration increased only with SIL treatment (P = 0.001); after PLA (P = 0.63). The area under the curve of penile microvascular vasodilation induced by ACh also significantly increased after SIL (P = 0.003) but not after PLA (P = 0.98). Finally, 24 hours diastolic arterial pressure significantly decreased after SIL (83.5 ± 8.9 and 79.9 ± 8.2; P = 0.0003) but not after PLA (P = 0.27). The decrease in 24-hour systolic blood pressure was not statistically significant after SIL or PLA, but it was significant in the office measurements after treatment with sildenafil [136(130–144.3) and 131.5 (119–139.3); P = 0.02] but not with placebo [136(130.8–145) and 134.7 ± 13;P = 0.23]. Conclusions: Penile endothelium-dependent microvascular reactivity and erectile function improved after chronic treatment with sildenafil. The treatment also reduced blood pressure suggesting that, in addition to the effects on erectile function, chronic treatment with sildenafil could improve blood pressure control.

Sildenafil for Antenatal Treatment of Congenital Diaphragmatic Hernia: From Bench to Bedside.

Persistent pulmonary hypertension (PPH) is one of the main causes of mortality and morbidity in infants affected by congenital diaphragmatic hernia (CDH). Since the structural changes that lead to PPH take place already in utero, a treatment starting in the prenatal phase may prevent the occurrence of this complication. To summarize the development process of antenatal sildenafil for CDH. The pharmacokinetics and efficacy of sildenafil have been assessed in the rat and the rabbit model. The transfer of the drug through the human placenta has been measured with the ex-vivo placenta perfusion model. Results from this experiment are being incorporated in a pregnancy-physiologically based pharmacokinetic (p- PBPK) model. A phase I-IIb placental transfer and safety study is ongoing. Sildenafil administration to pregnant rats and rabbits led to therapeutic foetal drug levels without maternal and foetal toxicity, although it was associated with impaired vascular development in foetuses with nonhypoplastic lungs. Peak concentrations and 24-hour exposure were higher in pregnant rabbits compared to nonpregnant ones. In rat and rabbit foetuses with CDH, sildenafil rescued the lung vascular anomalies and partially improved parenchymal development. Sildenafil crossed the human placenta at a high rate ex-vivo, independently from the initial maternal concentration. There is preclinical evidence that maternally administered sildenafil prevents the vascular changes that lead to PPH in CDH newborns. The phase I/IIb clinical study together with the p-PBPK model will define the maternal dose needed for a therapeutic effect in the foetus. Foetal safety will be investigated both in the clinical study and in the sheep. The final step will be a multicentre, randomized, placebo-controlled trial.

The Toxic Effect Of Sildenafil Citrate On Adult Albino Rat Testis And The Possible Protective Role Of Royal Jelly (Histological And Immunohistochemical Study)

Background: Phosphodiesterase inhibitor was appearing as a magic tool in treatment of erectile dysfunction, however, it might lead to harmful effects in high dose and long term administration. The aim of the work: This study aimed to evaluate the toxic effect of sildenafil citrate on the histological structure of the testis of adult albino rats and the possible protective role of royal jelly. Materials and methods: Thirty five adult male albino rats were divided into 3 groups; the control group divided into (subgroup Ca, Cb and Cc), experimental group divided into (subgroup Ea and Eb) and treated group divided into (subgroup Ta and Tb). In the experimental group sildenafil citrate was given at a dose of 9 mg/kg in subgroup Ea and 13.5mg/kg in subgroup Eb orally daily for 30 days. In the treated group rats were treated by royal jelly at a dose of 100 mg/kg for 30 days orally after stoppage of sildenafil citrate. In the present study, the sperm count, histological and immunohistochemical studies were evaluated. Result : Daily oral administration of sildenafil citrate (9mg/kg and13.5 mg/kg ) for 30 day had reduced the sperm count and induced apparent degeneration with detached, distorted germ cell and congested blood vessels with significant decrease in Proliferating cell nuclear antigen Labeling Index (PCNA- LI). After royal jelly administration, there was an improvement in sperm count and histopathological changes induced by sildenafil citrate with a significant increase in PCNA -LI. Conclusion: Long-term daily use of Sildenafil citrate produced histological changes in the testis and reduced the spermatogenesis with a significant decrease in sperm count and these side effects can be prevented by using royal jelly.

Ultra-high field MR angiography in human migraine models: a 3.0\u2009T/7.0\u2009T comparison study

BackgroundSildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery.MethodsFive subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design.ResultsStandard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T.ConclusionsOur findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies.Trial registrationThe study is part of a parent study, which is registered at ClinicalTrials.gov (NCT03143465).

Sildenafil enhances central hemodynamic responses to exercise, but not V̇o2peak, in people with diabetes mellitus.

Exercise capacity is frequently reduced in people with diabetes mellitus (DM), and the contribution of pulmonary microvascular dysfunction remains undefined. We hypothesized that pulmonary microvascular disease, measured by a novel exercise echocardiography technique termed pulmonary transit of agitated contrast (PTAC), would be greater in subjects with DM and that the use of pulmonary vasodilator agent sildenafil would improve exercise performance by reducing right ventricular afterload. Forty subjects with DM and 20 matched controls performed cardiopulmonary exercise testing and semisupine exercise echocardiography 1 h after placebo or sildenafil ingestion in a double-blind randomized crossover design. The primary efficacy end point was exercise capacity (V̇o2peak) while secondary measures included pulmonary vascular resistance, cardiac output, and change in PTAC. DM subjects were aged 44 ± 13 yr, 73% male, with 16 ± 10 yr DM history. Sildenafil caused marginal improvements in echocardiographic measures of biventricular systolic function in DM subjects. Exercise-induced increases in pulmonary artery systolic pressure and pulmonary vascular resistance were attenuated with sildenafil, while heart rate (+2.4 ±1.2 beats/min, P = 0.04) and cardiac output (+322 ± 21 ml, P = 0.03) improved. However, the degree of PTAC did not change (P = 0.93) and V̇o2peak did not increase following sildenafil as compared with placebo (V̇o2peak: 31.8 ± 9.7 vs. 32.1 ± 9.5 ml·min-1·kg-1, P = 0.42). We conclude that sildenafil administration causes modest acute improvements in central hemodynamics but does not improve exercise capacity. This may be due to the mismatch in action of sildenafil on the pulmonary arteries rather than the distal pulmonary microvasculature and potential adverse effects on peripheral oxygen extraction. NEW & NOTEWORTHY This is one of the largest and most comprehensive studies of cardiopulmonary exercise performance in people with diabetes mellitus and to our knowledge the first to assess the effect of sildenafil using detailed echocardiographic measures during incremental exercise. Sildenafil attenuated the rise in pulmonary vascular resistance while augmenting cardiac output and intriguingly heart rate, without conferring any improvement in exercise capacity. The enhanced central hemodynamic indexes may have been offset by reduced peripheral O2 extraction.

Proconvulsant effects of sildenafil citrate on pilocarpine-induced seizures: Involvement of cholinergic, nitrergic and pro-oxidant mechanisms

Sildenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Proconvulsant effect is a serious adverse event associated with sildenafil use. Here, we investigated the possible proconvulsant effects of sildenafil in pilocarpine (PILO)-induced seizures model, which mimics some aspects of temporal lobe epilepsy. We also evaluated sildenafil’s effects on hippocampal markers related to PILO-induced seizure, for instance, acetylcholinesterase (AChE) activity, oxidative stress and nitric oxide (NO) markers, namely nitrite, inducible NO synthase (iNOS) and neuronal NOS (nNOS). The influences of muscarinic receptors blockade on sildenafil proconvulsant effects and brain nitrite levels were also evaluated. Male mice were submitted to single or repeated (7 days) sildenafil administration (2.5, 5, 10 and 20 mg/kg). Thirty minutes later, PILO was injected and mice were further evaluated for 1 h for seizure activity. Sildenafil induced a dose- and time-progressive proconvulsant effect in PILO-induced seizures. Sildenafil also potentiated the inhibitory effect of PILO in AChE activity and induced a further increase in nitrite levels and pro-oxidative markers, mainly in the hippocampus. Repeated sildenafil treatment also increased the hippocampal expression of iNOS and nNOS isoforms, while the blockade of muscarinic receptors attenuated both sildenafil-induced proconvulsant effect and brain nitrite changes. Our data firstly demonstrated the proconvulsant effect of sildenafil in PILO-model of seizures. This effect seems to be related to an increased cholinergic-nitrergic tone and pro-oxidative brain changes. Also, our findings advert to caution in using sildenafil for patients suffering from neurological conditions that reduces seizure threshold, such as epilepsy.

Renoprotective effect of local sildenafil administration in renal ischaemia–reperfusion injury: A randomised controlled canine study

ABSTRACTObjectives: To design a new canine model to assess the renoprotective effect of local sildenafil administration, as the renoprotective effect of systemic sildenafil administration in renal ischaemia–reperfusion (IR) injury in animal models has been shown but its local effects have not been established to date.Materials and methods: In all, 120 dogs were assigned to five groups: sham, oral control (OC) group (right nephrectomy + left renal ischaemia for 60 min), oral sildenafil (OS) group (oral sildenafil 1 mg/kg, 60 min before ischaemia), local control (LC) group (local renal perfusion with saline and heparin for 5 min) and local sildenafil (LS) group (perfusion with sildenafil 0.5 mg/kg). Renal functions, histopathological changes, expression of caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2), inflammatory cytokines (intracellular adhesion molecule 1, tumour necrosis factor α and interleukin 1β) and endothelial nitric oxide synthase (eNOS) in renal tissues were assessed in all groups at 1, 3, 7 and 14 days.Results: There were significant improvements in renal functions and cortical and medullary damage scores in the sildenafil-treated groups compared to their control groups (P < 0.05). Also, the LS group showed significantly better improvement of renal functions and cortical and medullary damage scores than the OS group (P < 0.05). Moreover, sildenafil significantly decreased the expression of caspase-3 and inflammatory cytokines and increased the expression of Nrf2 and eNOS in renal tissue, which were statistically significant in the LS group.Conclusion: LS has a greater renoprotective effect against renal IR injury than systemic administration via anti-inflammatory, antioxidant and anti-apoptotic pathways.Abbreviations: BUN: blood urea nitrogen; Ct: cycle threshold; eNOS: endothelial nitric oxide synthase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; H&E: haematoxylin and eosin; IL-1β: interleukin 1β; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; OC: oral control; OS: oral sildenafil; LC: local control; LS: local sildenafil

Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep.

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

Effect of Sildenafil Citrate on Uterine Artery Blood Flow in Patients with Unexplained Recurrent Miscarriages: A Randomized Clinical Trial

Background: Unexplained recurrent miscarriage can be a challenging and frustrating condition for both patients and clinicians. Sildenafil citrate is one of the currently available lines of treatment according to simplicity of use, reliability and degree of invasiveness but up to now there are no prospective randomized studies, powerful enough. Aim of this Work: To evaluate the efficacy of oral sildenafil citrate 20 mg on uterine arteries Doppler flow studies in patients with unexplained recurrent miscarriages. Patients and Methods: This prospective case control study was conducted at Sayed Galal Maternity Hospital outpatient clinics on 180 women who' were divided into 2 groups: (group 1) which included 91 patients who took sildenafil citrate 20 mg orally, 4 times per day for 21 days and (group 2) which included 89 patients who took placebo orally, 4 times per day for 21 days in the period starting from (August 2017 to June 2018). Results: The statistical comparison between group I (sildenafil citrate) and group II (placebo) before and after administration of drug regarding endometrial thickness showed non-significant difference before and significant difference after 3 weeks of administration of sildenafil citrate in group I and placebo in group II. The statistical comparison in patients in group I (sildenafil citrate) before and after 1 week, 2 weeks and 3 weeks administration of drug regarding pulsatility index, resistance index and systolic/diastolic ratio showed significant difference. Conclusion: Sildenafil citrate has an effective role in increasing the uterine arteries blood flow in patients with recurrent miscarriage.

Role of Low Dose Sildenafil in Improvement of Implantation Rate in Case of Recurrent ICSI failure

Background: Infertile couples to have healthy children are one of primary tasks of assisted reproductive technologies. In order to fulfill these tasks, reproductive medicine constantly needs to obtain information on physiology and pathophysiology of infertility and to develop efficient strategies for ovarian hyper-stimulation. Objectives: Aim of the current Work was to evaluate the efficacy of oral sildenafil citrate 25 mg on pregnancy outcome, endometrial thickness, pattern and uterine arteries Doppler blood flow in patients with 3 or more concoctive unexplained recurrent IVF/ICSI implantation failure. Patients and Methods: This prospective, randomized, double blinded study included a total of seventy patients undergoing ICSI trial attending at the University Maternity Hospital IVFICSI unit. The included subjects were randomly allocated into two groups: Group I (study group): included 35 women with recurrent ICSI implantation failure with another trial of ICSI using the standard drugs and technique with the addition of sildenafil 25 mg orally twice daily. Group II (control group): included 35 women with recurrent ICSI implantation failure with another trial of ICSI using the standard drugs and technique (control group). Results: The statistical comparison between group I (Sildenafil Citrate) and group II (control) regarding endometrial thickness showed non significant differences before and significant differences after 21days of administration of Sildenafil Citrate. The statistical comparison in patients in group I (Sildenafil Citrate) regarding Pulsatility index, Resistance index and Systolic/ diastolic ratio showed significant differences of these parameters. Conclusion: It could be concluded from this study that adding of sildenafil citrate 25 mg orally twice daily for 21 days to patients with unexplained recurrent ICSI implantation failure, increase in pregnancy rate.

Effect of Sildenafil Citrate on Uterine Artery Blood Flow in Patients with Unexplained Recurrent Miscarriages: A Randomized Clinical Trial

Background: Unexplained recurrent miscarriage can be a challenging and frustrating condition for both patients and clinicians. Sildenafil citrate is one of the currently available lines of treatment according to simplicity of use, reliability and degree of invasiveness but up to now there are no prospective randomized studies, powerful enough. Aim of this Work: To evaluate the efficacy of oral sildenafil citrate 20 mg on uterine arteries Doppler flow studies in patients with unexplained recurrent miscarriages. Patients and Methods: This prospective case control study was conducted at Sayed Galal Maternity Hospital outpatient clinics on 180 women who' were divided into 2 groups: (group 1) which included 91 patients who took sildenafil citrate 20 mg orally, 4 times per day for 21 days and (group 2) which included 89 patients who took placebo orally, 4 times per day for 21 days in the period starting from (August 2017 to June 2018). Results: The statistical comparison between group I (sildenafil citrate) and group II (placebo) before and after administration of drug regarding endometrial thickness showed non-significant difference before and significant difference after 3 weeks of administration of sildenafil citrate in group I and placebo in group II. The statistical comparison in patients in group I (sildenafil citrate) before and after 1 week, 2 weeks and 3 weeks administration of drug regarding pulsatility index, resistance index and systolic/diastolic ratio showed significant difference. Conclusion: Sildenafil citrate has an effective role in increasing the uterine arteries blood flow in patients with recurrent miscarriage.

Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress

AimsSpontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR. Materials and methodsMale rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot. Key findingsResting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O2−) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability. SignificanceSild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension.