Using Thermography to Assess the Affects of Sildenafil Cream, 3.6%

Sildenafil for Treatment of Urinary Incontinence in Patients With Spinal Cord Injuries

Spinal cord injury (SCI) is a devastating condition affecting 291,000 women and men in the US alone. Urinary incontinence (UI) is a common problem in these patients, affecting 52% of the population, with episodes of incontinence occurring daily in 20-27% of affected persons. UI after spinal cord injury (SCI) is a major cause of distress and morbidity amongst patients with SCI, and is associated with decreased quality of life in general, physical, and emotional domains. UI has the undesirable side effects of perineal irritation and infection, increased odor, disrupted sleep, embarrassment, need to change clothes/bedding, and sexual dysfunction, as well as significant financial burden. Persons living with a SCI have ranked urinary problems as the most important health problem after injury. Addressing this significant problem and providing relief has the potential to significantly improve the lives of patients with SCI. Typical treatment options are geared toward the type of UI in each patient. For stress UI, the goal of treatment is to provide support to the pelvic floor and urethra. Pessaries (devices placed inside the vagina in women) or surgery (e.g. suburethral sling) to elevate the urethra and/or bladder neck to increase the resistance to leak through the urethra are commonly used. Urethral bulking agents or pelvic muscle floor therapy are also employed to strengthen the closure pressure of the urethra in patients with stress UI. No pharmacologic agents are currently available to treat stress UI. For urge UI, medications or electrical stimulation aimed at relaxation of the detrusor muscle, including anticholinergics, are used. For overflow or obstructive UI, treatments are aimed at shrinking or removing the obstruction, such as medications to shrink the prostate, prostatectomy or mass removal. For neurogenic UI, surgery for diversion or implant placement may be utilized. Sildenafil (Viagra) has been well studied and used extensively in males to treat erectile dysfunction. Phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, are potent vasodilators that enhance tissue perfusion, relax smooth muscle of the vasculature and bladder, and stimulate skeletal muscle protein synthesis. It has been reported to improve lower urinary tract symptoms, including urge UI and benign prostatic hyperplasia (BPH) in men. In our team's recent study using sildenafil for treatment of UI in women, the investigators found improvement in quality of life and a decrease in the number of incontinence episodes in women taking sildenafil. Higher sildenafil plasma levels were associated with greater improvement in symptoms. While the types of UI in women are somewhat different than in men, studies have shown improvements in UI in both sexes. Thus, the investigators propose to conduct a two month randomized, placebo-controlled crossover trial of sildenafil in male and female adult SCI patients with UI to assess the therapeutic potential of sildenafil to reduce the symptoms of urinary leakage. Aims: Aim 1: To determine whether sildenafil will decrease episodes of leakage of UI in adult women and men with SCI. Aim 2: To determine the effects of sildenafil on the subjective measures of UI, including quality of life. Experimental Protocol: Investigators will study patients with spinal cord injuries (aged 18-70) with current urine leakage of more than 3 times/week (n=24). Subjects will undergo a double blinded randomized cross over treatment of sildenafil (20mg TID) and placebo. Each treatment period will last 4 weeks with a 2 week washout between treatment periods. Before and after each treatment period, subjects will undergo testing which will consist of measurements of urine post void residual volume (PVR), adverse event assessment, and questionnaires of quality of life and urinary health.

Oral Sildenafil for Exercise Capacity, Dyspnea and Cardiopulmonary Function in COPD

COPD is a condition characterized by airway obstruction and is currently the 4th leading cause of death in Canada. Patients with COPD experience significant exertional dyspnea, which has been shown to reduce quality of life and physical activity, and increase risk of mortality. Much work has examined the mechanisms for dyspnea in moderate and severe COPD, but the mechanisms for dyspnea in patients with mild COPD, in whom symptoms are often disproportionate to the degree of airway obstruction, are not well understood. Mild COPD patients show an exaggerated ventilatory response to exercise, determined by the ventilatory response to carbon dioxide production (V̇E/V̇CO2), which is a key contributor to dyspnea and is predictive of mortality. Recent work suggests that the increased V̇E/V̇CO2 during exercise in mild COPD is secondary to increased deadspace (i.e. ventilation with no perfusion) and/or ventilation/perfusion (V̇ A/Q) inequality (i.e. poor matching of ventilation to perfusion). Researchers have proposed that the increased deadspace or V̇A/Q inequality is secondary to pulmonary vascular dysfunction and hypoperfusion of the pulmonary capillaries. Recently we have shown that iNO reduces dyspnea, and V̇E/V̇CO2, and improves exercise capacity in mild COPD, suggesting that pulmonary vascular dysfunction is an important contributor to exercise intolerance in mild COPD. Importantly, this work demonstrated that pulmonary NO mediated vasodilation pathways are intact, and are a viable target for improving exercise tolerance in mild COPD. Therefore, we hypothesize that sildenafil, which potentiates intrinsic NO mediated vasodilation mechanisms, will improve exercise tolerance in mild COPD. Compared to disease free controls, mild COPD patients have a blunted diffusion capacity and pulmonary capillary blood volume response to exercise. In the supine position, which minimizes flow heterogeneity through removal of the coronal gravity-induced pressure gradient, diffusion capacity and pulmonary capillary blood volume responses to exercise were not corrected. The implication of this finding is that even mild COPD, there is a degree of permanent vascular destruction, in addition to reversible pulmonary vascular dysfunction. It is presently unknown when or if in the COPD severity continuum there is a transition from treatable pulmonary vascular dysfunction to irreversible pulmonary vascular destruction. Sildenafil was previously tested in moderate to severe COPD with mixed success. Blanco et al. tested the effect of sildenafil (20 or 40 mg dose) on hemodynamics and gas exchange in a sample of patients with moderate to severe COPD. Eighty-five percent of the sample had pulmonary hypertension defined as mean pulmonary artery pressure >20 mmHg. Sildenafil significantly reduced pulmonary artery pressure at rest and during exercise (-6 and -11 mmHg respectively), and improved VA/Q inequality. Rietema et al. found no benefit of sildenafil (3x50mg daily for 3 months) on stroke volume (supine, rest/exercise) or exercise capacity in moderate to severe COPD. In a randomized, placebo controlled trial, sildenafil (3x20 mg daily, 3 months) did not improve pulmonary rehabilitation outcomes including cycle endurance time, 6 minute walk distance, or quality of life. It is not known why the promising reduction in pulmonary artery pressure and improved V̇A/Q matching did not translate to increased stroke volume or exercise capacity with chronic sildenafil dosing. Results may partially be explained by supine body positioning during measurement of stroke volume, and the generally late disease state of COPD patients. Pulmonary vascular dysfunction observed early in disease progression may transition to irrevocable vascular/pulmonary structural changes, for which iNO or sildenafil have limited utility. Accordingly, a secondary objective of the present study is to gain understanding of pathological vascular progression in COPD to identify the therapeutic window for pulmonary vascular intervention. We hypothesize that sildenafil will have greater cardiopulmonary benefit (increased diffusion capacity at rest and during exercise, greater decrease in pulmonary artery pressure) in early, mild COPD as compared to moderate-severe COPD, indicative of vascular dysfunction in mild COPD transitioning to vascular destruction in later disease states. Trial Objectives 1. To examine the effect of acute oral sildenafil on maximal oxygen consumption (peak V̇O2) during exercise in the continuum of COPD 2. To examine whether acute oral sildenafil improves exertional dyspnea in COPD. 3. To examine the cardio-pulmonary effects and mechanisms of oral sildenafil. Trial Design Primary Study Endpoints/Secondary Endpoints Primary study endpoints for the proposed study are: 1. Exercise capacity as determined by maximal oxygen consumption (peak V̇O2). Secondary study endpoints for the proposed study are: 2. Dyspnea during exercise (modified Borg scale, 1-10) 3. Pulmonary function during exercise (V̇ E/V̇CO2, pulmonary capillary blood volume, diffusion capacity) 4. Cardiac output as determined by impedance cardiography. 5. Pulmonary artery pressure (estimated from rest/stress echocardiography). Study Design Randomized, double-blinded, placebo controlled cross-over design Treatment: Sildenafil (oral), 25 mg; Placebo: Medical grade placebo pill Seven sessions will be completed within an 8-week period in the following order: Visit 1) Participant enrollment and familiarization, medical history, COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scale, standard pulmonary function test (PFT, including bronchodilator control) and a staged to maximal cardiopulmonary exercise test (CPET) with electrocardiography (ECG), pulse oximetry, and intermittent blood pressure and rating of perceived exertion (RPE, leg fatigue and dyspnea, modified Borg scale). A small blood sample will be collected via finger prick to measure hemoglobin (to correct DLCO). An additional venous blood sample will be collected for analysis of blood biomarkers to characterize participants including serum analysis of interleukin 6, c-reactive protein and tumor necrosis factor alpha. Visits 2 and 3) Participants will be administered oral placebo/sildenafil (randomly ordered), wait for 30 minutes and then begin testing. Participants will undergo a staged to maximal CPET (gas exchange analysis, heart rate, cardiac output measured by impedance cardiography, blood pressure, RPE, arterial oxygen saturation). Visits 4 and 5) Participants will be administered oral placebo/sildenafil (randomly ordered), wait for 30 minutes and then begin testing. Testing will start with measurement of resting diffusion capacity, pulmonary capillary blood volume (Vc), and membrane diffusion capacity (Dm) using the multiple fractional inspired oxygen (FIO2)-DLCO technique. Participants will then cycle at 40 W and 50% of peak work rate as determined from Visit 1, measurements will be repeated during steady-state exercise. Heart rate, oxygen saturation, and carboxyhemoglobin will be monitored throughout. A small blood sample will be collected via finger prick following each stage (rest, 40W, 50% of peak work rate) to measure hemoglobin to correct DLCO values. Visit 6) Participants will undergo non-randomized control and then sildenafil rest and handgrip stress echocardiography. Echocardiography will be used to estimate cardiac volumes, function and pulmonary artery systolic pressure at rest and during handgrip stress. Isometric handgrip stress echocardiography was previously used in healthy and clinical populations to evoke marked cardiac stress without hyperpnoea- a major factor compromising image quality, particularly in COPD due to dynamic hyperinflation. Visit 7) Participants will undergo chest computed tomography to characterize lung structure and emphysema. Visit 1 is anticipated to take ~2 hours. Visits 2 and 3 are anticipated to take ~1.5 hours. Visits 4 and 5 are anticipated to take 2 hours. Visit 6 is anticipated to take 2 hours. Visit 7 is anticipated to take 1 hour. The anticipated total study duration is ~12 hours. Data Analysis A mixed-effects model will be used to evaluate the change in V̇O2peak with sildenafil. A two-way repeated measures ANOVA will be used to test for a difference in VO2peak response in mild COPD compared to COPD free controls. Two-way repeated measures ANOVA will be used to evaluate changes in dyspnea, cardiac output, ventilation, ventilatory efficiency (V̇E/V̇CO2), diffusion capacity and capillary blood volume during exercise. Variance in V̇O2peak changes will be explored using Pearson's regression and moderation analysis of echo-derived cardiac factors and pulmonary function/gas exchange. A three-way repeated measures ANOVA will be used to test for differences in pulmonary capillary blood volume response to sildenafil between mild and moderate COPD.

Mono vs. Dual Therapy for Pediatric Pulmonary Arterial Hypertension

A Phase III, randomized, open label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in pediatric subjects with WHO Functional Classes II or III and precapillary pulmonary hypertension of Group 1 (PAH caused by idiopathic, heritable, drugs or toxins, congenital heart disease, or connective tissue disease) or Group 3 (PAH caused by lung disease or hypoxemia) according to the WHO (Nice) classification system. Precapillary pulmonary hypertension will be defined by standard criteria as mean pulmonary artery pressure over 25 mmHg and/or pulmonary vascular resistance index (PVRI) > 3, as well as pulmonary capillary wedge pressure (or left ventricular end diastolic pressure) ≤ 15 mmHg as determined by cardiac catheterization. For infants less than one year of age for whom cardiac catheterization is not considered as part of the clinical team's recommended approach, enrollment will be possible without catheterization if the following four criteria (i-iv) are met: i. Two separate echocardiograms clearly demonstrate pulmonary hypertension by at least three of the following metrics 1. Elevated MPA pressure (early diastolic PR peak gradient >20 mmHg) 2. Right ventricular hypertrophy (qualitative as mild to severe) 3. Right atrial enlargement (scales for age will be provided) 4. Elevated right ventricular systolic pressure (>35mmHg) on at least two at least two reliable spectral Doppler envelopes during the echocardiogram and in the setting of normal for age documented systolic blood pressure at least two reliable spectral Doppler envelopes during the echocardiogram 5. Flattening or (R to L) bowing of the interventricular septum (qualitative or by elevated eccentricity index) 6. Diminished RV function (RV fractional area change <35%) and/or TAPSE below published normal range for age and weight; ii. There is no clinical or imaging evidence of left heart dysfunction; iii. Pulmonary venous stenosis and atresia are ruled out by CT angiography or MRI unless all four pulmonary veins are unequivocally normal on the two separate echocardiograms; iv. There is no evidence of hemodynamically significant left-to-right shunting across an unrestricted systemic to pulmonary shunt. Study subjects will be followed with current standard of care assessments and diagnostics, including longitudinal clinical evaluations, determinations of functional class (FC), serial NT-pro-Brain Natriuretic Peptide (NT-proBNP) levels, and echocardiography. Data from these studies will be analyzed in central core facilities that will be used by all participating study sites. Clinical endpoints are the focus of this study. However, additional data collection is planned for exploratory aims to examine the potential role for future application of novel metrics of outcomes in children with PAH (e.g., pediatric QOL and actigraphy), as described below. The investigators also plan to collect blood, swab and urine samples to determine whether inherent genomic variations or novel proteomic biomarkers will associate with clinical responsiveness to interventions within the cohort. Bio-specimens will be obtained to further test the hypothesis that therapeutic responders will have a different genomic or proteomic profile as compared to subjects who do not respond well to therapy. Bio-specimens will include the following: 1. Blood for DNA, peripheral blood mononuclear cells, plasma, and serum; and 2. Paired Box Gene (PAXgene) tubes for RNA and miRNA studies; and 3. Urine for biomarker analysis. Because sildenafil and bosentan have different mechanisms of action targeting different intracellular pathways, combination therapy is a rational treatment strategy for pediatric patients with PAH. Past work in adult PAH suggests that combination therapy with longer duration agents with the same mechanisms of action may cause greater and more sustained improvement in clinical course in comparison with monotherapy. Whether children with PAH respond and tolerate combination therapy better than monotherapy has not been studied. In addition, despite a growing experience with sequential therapy, additional medications are added only after clinical deterioration or failure to sustain responsiveness. Pharmacokinetics will be assessed during this study in order to determine whether drug levels or compliance with therapy affect outcomes in this cohort. In addition, pharmacokinetics data and related clinical responses from mono- and dual therapy participants will be compared. Interactions between these agents are well known, whereby bosentan decreases sildenafil levels. As a result, sildenafil levels during mono- and combination therapy will be further defined by the planned pharmacokinetics in the current protocol. In addition to strengthening this current study design, such data will form a basis for optimizing the use of these agents and potential strategies for dose adjustments in the broader scope of clinical care in the future.

PEnile ReHABilitation After Nerve Sparing Robot-assisted Radical Prostatectomy for Prostate Cancer 2.0 (PEHAB-II)

Rationale Postoperative erectile dysfunction (ED) is a widely observed side effect of prostate cancer surgery for clinically localized prostate cancer and it has a substantial impact on the quality of life. While nerve-sparing radical prostatectomy (nsRP) has improved the outcomes of erectile function, ED rates remain high even after well-performed nsRP. It is important to note that ED after nsRP is not primarily caused by complete transection (neurotmesis) but rather by neuronal crushing and/or overstretching (neuropraxia) of the neurovascular bundle running alongside the prostate towards the erectile tissue of the penis. It is suggested that the post-operative care is insufficient to consolidate the effects of nsRP because penile rehabilitation is necessary to activate neural recovery as well as to retain the vasculogenic functions of the penile corpora cavernosa. However, the best penile rehabilitation strategy to reduce post-operative ED remains unclear due to a lack of well-designed randomized studies. Objective This study aims to assess the effect of two different rehabilitation strategies on the recovery rate of ED after nsRP in patients who undergo nsRP. Main trial endpoint: The primary endpoint is an adequate, unassisted erection at 24 months after surgery. In this, an adequate unassisted erection is defined as an erection sufficient for successful sexual intercourse without the use of medication or devices. Measured by International Index of Erectile Function - Erectile function domain (IIEF-EF) >/=22 after a one-month drug washout or Expanded Prostate Cancer Index Composite (EPIC) -erection score (sum off Q8b, 9 and 10) >=83 for patients who did not participate in penetrative sex. Secondary trial endpoints: Secondary endpoints include erectile function (assisted, unassisted, time to recovery, penile length), health en sexual quality of life (other sexual functions, climacturia, feelings of masculinity, health related quality of life and differences between hetero versus gay/bisexual patients during follow-up), Adherence and side-effects and comparing two sexual function questionnaires. Trial design This study is a multicentre, randomized, controlled clinical trial. Trial population: Patients between the ages of 18- 70 diagnosed with non-metastatic, localized prostate cancer (PCa) who underwent nsRP as primary treatment. A total of 192 patients will be included. Interventions: Patients will be randomized 1:1: to arm 1: High intensive therapy using a daily dose of 75-100 mg Sildenafil for 12 month, combined with vacuum device (VED) therapy for 10 minutes a day, five times a week; or to arm 2: Less intensive therapy using 75/100mg Sildenafil on demand (before sexual activity). After these 12 months in therapy, the treatment intensity can be adjusted for the next 12 month until the full neuropraxia recovery time (24 month) has been reached. The treatment option that can be used to intensify the therapy is intracavernosal injection therapy (ICI), in which erections can be obtained quickly by injecting papaverine/phentolamine (Androskat) in the penis. This auxiliary therapy can be an option for those that do not want to wait any longer for the recovery of their spontaneous erections and thus that want to use ICI to obtain erections in the meantime. It is important to note that ICI is not a part of the rehabilitation program and thus is not mandatory. Patients will finish participating in the trial after 24 months follow-up. One month before end of follow-up (23 months) a drug washout will take place. Endpoints will be assessed after 24 months using validated questionnaires as well and composed validated questions. Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: In this study, patients will be evaluated at baseline and every three months thereafter through telephonic appointments, online surveys, and outpatient clinic visits. These outpatient clinic visits will take 20 minutes on average. Patients will fill out HRQoL questionnaires and questionnaires on sexual functioning online. In order to answer these questions correctly, patients will be advised to participate in sexual activity at least once a month. Answering the questionnaires will take approximately 20 minutes. In addition, patients will be asked to provide blood samples once at baseline, to determine testosterone levels, HbA1c, liver enzymes, and lipid profiles. Patients may experience side effects from sildenafil (such as dyspepsia, dizziness, and headache) or the VED (i.e. cold feeling, pain, hematoma, or oedema). These effects are temporary and subside within 25 hours. Participating patients in both arms benefit from free sildenafil and VED, along with the extra attention and guidance provided for sexual recovery, sexual health and erectile function compared to patients that do not participate in the study.

A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)

Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 3000 US live births, similar to the incidence seen within the Utah Birth Defects cohort. An early developmental diaphragmatic defect leads to herniation of abdominal contents into the thoracic cavity. Such visceral herniation compromises lung growth and alters pulmonary vascular development. This is reflected postnatally as respiratory failure, pulmonary hypertension (PH) and overall cardiopulmonary dysfunction, particularly post-repair. Survival among all liveborn infants is approximately 70% and has not changed in the past 20 years. A major contributor to morbidity and mortality of this neonatal cohort is persistent PH. CDH-related PH is related to 1) arteriolar remodeling with increased vascular smooth muscularization leading to smaller diameters of the distal arterioles; 2) a hypodense vascular bed related to compromised lung growth; and 3) endothelial dysfunction resulting in increased vasoreactivity. Given this multifactorial nature of CDH-related PH, post-natal treatment is often challenging. Moreover, there is an increased risk of PH crises with post-operative inflammatory cascades and fluid shifts. Currently, optimal management of post-repair PH remains poorly investigated. An important pulmonary vasodilatory cascade includes the nitric oxide pathway, which acts via increases in cyclic guanosine monophosphate (cGMP). Sildenafil citrate is a highly selective phosphodiesterase-5 inhibitor that increases cGMP levels, leading to smooth muscle relaxation and an anti-proliferative effect within the pulmonary vasculature. It is used off-label for many neonatal PH disorders, including PH associated with bronchopulmonary dysplasia and idiopathic persistent PH. A multi-center trial evaluating the use of sildenafil in premature infants with bronchopulmonary dysplasia (NCT04447989) is currently underway. Pharmacokinetics of sildenafil in infants have previously been studied with a dosing range of 1mg/kg every 6-8 hours. In addition, sildenafil administration in the neonatal cohort appears safe and well-tolerated. Off-label use of sildenafil to treat CDH-related PH is increasing, despite limited evidence of efficacy in neonates with CDH. Use is based on the hypothesis that administering sildenafil post-hernia repair at a time when physiological changes are rapidly shifting may assist with pulmonary vascular relaxation to alleviate PH. Improvement in PH may ultimately benefit post-operative cardiorespiratory stability. Left ventricular eccentricity index (LVEI) is a non-invasive echocardiographic measure of such PH. LVEI is an objective measure that reflects the more subjective measure of left ventricular septal flattening. Its use decreases inter-observer variability and is a reliable assessment of neonatal PH. Elevated values of LVEI ≥ 1.4 are associated with right ventricular suprasystemic pressures. Normative values of LVEI in neonates without PH are ≤1. Most neonates with CDH born within the Mountain West referral basin are managed at a quaternary care center, Primary Children's Hospital (PCH). PCH neonatal intensive care unit (NICU) averages 19 infants of CDH per year (range 12-24). Preliminary data shows that between 2007 and 2020, 60-85% of neonates with CDH managed at PCH manifest post-operative PH with LVEI values averaging between 1.4 to 2 on the post-repair echocardiogram. Of these neonates with PH, approximately 25% have been treated with off-label sildenafil. However, neither the PCH clinical care group nor others have developed/published a standardized approach for either initiating or discontinuing sildenafil therapy in this group of patients. Equipoise exists within the PCH clinical care group as the effectiveness of sildenafil use in neonates with CDH has not been well studied. Thus, the aim of this study is to assess the safety and effectiveness of sildenafil therapy for PH in neonates with CDH within the Utah cohort. Given the relatively short-term outcome and small sample size for this trial, this data can be used to support a larger multicenter randomized trial targeting long-term cardiopulmonary outcomes of infants with CDH and post-repair PH.

Delayed Dose Collagenase Clostridium Histolyticum (CCH) Protocol for Men With Peyronie's Disease

The current study would prospectively follow 40 men through the following treatment protocol: - Men would receive 4 series of CCH injections according to the protocol below, which represents a modified version of our most recently published technique.13 - Medication administered on back-to-back days - Total of 0.9 mg administered with each series, diluted to 0.8 mL - Mild in-office modeling performed on treatment day 2 of each series - Wraps performed ranging from 2-4 full-time and 2-4 part-time days to minimize bruising - Sildenafil 25 mg nightly beginning treatment day 2 until 6 weeks after final injection of the final series. - Restorex initiated beginning on post-injection day 3 or as soon as tolerated - 30 min daily, continuing until 6 weeks after final injection of the final series. - Note that men may stop sooner if they are satisfied before completing the 4 series. - If the patient is not satisfied with outcomes by the end of the 4th series, they would be permitted to enter the 'salvage' phase of the treatment protocol. - This would be performed 9-12 months after the 4th series of injections. - The technique would be similar to the one noted above with the exception of more aggressive in-office modeling as described in our prior publication and per our ongoing randomized trial. - The men would receive up to two additional series per this protocol for a maximum number of cycles being 6 in total. At the time of initial enrollment, partners of study participants will be invited to enroll in the study and will be administered non-validated questionnaires designed to assess the partner's overall support for the ongoing treatment protocol. Assessments and study questionnaires will be administered at baseline, with the 1st injection of each series, 6 weeks after completing the 4th series of CCH injections, and 1 year after completion of the final series of CCH injections.

Safety and Tolerability of TOP-N53 Applied on Digital Ulcers in Patients With Systemic Sclerosis

Nebulized Magnesium Sulfate and Sildenafil for Persistent Pulmonary Hypertension of Newborn

Persistent pulmonary hypertension of newborn (PPHN) is a serious condition that results from failure of the normal postnatal circulatory transition and is associated with significant mortality and morbidity. Advanced medical treatment, such as inhaled nitric oxide (iNO), high-frequency ventilation (HFV), and extracorporeal membrane oxygenation (ECMO) are commonly not available in developing countries. Intravenous magnesium sulfate has been shown to alleviate pulmonary hypertension but is associated with systemic hypotension and is less effective compared with iNO and sildenafil. Nebulized magnesium sulfate has been reported to be more effective and safer compared with intravenous magnesium sulfate in treating neonates with PPHN on mechanical ventilation. Combined nebulized magnesium and sildenafil has been studied in a small trial on spontaneously breathing neonates with PPHN but not on those connected to mechanical ventilation. The aim of this study is to evaluate the effectiveness of nebulized magnesium sulfate combined with sildenafil citrate, compared with sildenafil citrate alone, in treating neonates with severe PPHN on mechanical ventilation. We hypothesize that neonates with severe PPHN connected to mechanical ventilation could benefit from taking continuous nebulization of magnesium sulfate combined besides sildenafil.

Sildenafil Switching to Riociguat

Chronic thromboembolic pulmonary hypertension (CTEPH) results from the obstruction of the pulmonary arteries by organised fibrotic thrombi and the associated microvasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. CTEPH is associated with significant mortality and morbidity, so prompt initiation of treatments are necessary to improve the prognosis. For those with accessible pulmonary arteries occlusions, surgical pulmonary endarterectomy (PEA) is the treatment of choice. Nevertheless, about 40% of CTEPH patients are not considered to be operable due to occlusion of distal pulmonary vessels. For patients with inoperative CTEPH, current treatment options include balloon pulmonary angioplasty (BPA) and medical therapies. Several medical therapies that target microvascular components of CTEPH, such as phosphodiesterase type 5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), have been used off-label, as the efficacy of those medications in inoperable CTEPH has not been proven in randomised controlled trials or registry data. The CHEST-1 randomised controlled trial demonstrated that the soluble guanylate cyclase stimulator (sGCs), riociguat, significantly reduced pulmonary vascular resistance and improved exercise capacity in patients with inoperative CTEPH or persistent or recurrent pulmonary hypertension after PEA. Based on the finding of this study, riociguat has been approved for treatment for symptomatic inoperable patients with CTEPH. Both PDE5i and sGCs act via the same nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, but these two classes of medications target different molecular targets in the same pathway. PDE5i inhibits the degradation of cGMP, so its efficacy is dependent on a functioning NO-sGC-cGMP axis and the presence of intracellular cGMP. In contrast, riociguat stimulates sGC directly, thus it increases intracellular cGMP level regardless the presence of NO. Therefore, based on this biological rationale, it is postulated that riociguat may be more effective in increasing intracellular cGMP compared to PDE5i. Currently there is no head-to-head trials comparing the efficacy of PDE5i and riociguat in treating pulmonary hypertension. Nevertheless, 2 clinical trials have demonstrated improvement in the clinical and biochemical parameters after switching from PDE5i to sGCs in selected patients with pulmonary arterial hypertension (PAH) with insufficient response to PDE5i. It is currently unknown whether this switching will also apply to patients with CTEPH as those 2 clinical trials do not include patients with CTEPH. In addition to medical therapies, BPA, an endovascular procedure to dilate the occlusions and stricture in segmental or subsegmental pulmonary arteries, has emerged as a treatment for patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after PEA. Two randomised controlled trials comparing BPA and riociguat have demonstrated that BPA was associated with a greater improvement in mean pulmonary artery pressure and reduction in pulmonary vascular resistance in inoperable CTEPH patients. Currently, the data of safety and efficacy of switching PDE5i to sGCs after BPA is lacking. Therefore, this study was designed to investigate the safety and efficacy of replacing PDE5i with riociguat in patients with CTEPH who have undergone BPA and remains symptomatic despite treatments with PDE5i.