sildenafil-citrate and Lung-Diseases

Congenital chylothorax (CC) can result from a congenital malformation or an acquired obstruction or disruption of the thoracic duct. Recently, oral administration of the phosphodiesterase-5 inhibitor, sildenafil, was reported to be effective in resolving non-pulmonary lymphatic malformations in infants and young children. We report a case of CC in a late preterm infant with congenital pulmonary lymphangiectasia where octreotide was not effective, but management with oral sildenafil was successful.

Topics: Chylothorax; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Lung; Lung Diseases; Lymphangiectasis; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tomography, X-Ray Computed

Pulmonary hypertension (PH) can develop secondary to many common cardiopulmonary diseases, and the use of sildenafil has improved care of affected dogs.. To evaluate response to sildenafil in dogs with respiratory-associated PH.. Twenty-five dogs with PH.. Prospective clinical trial. Doppler echocardiography identified dogs with moderate to severe PH, and additional tests were performed to detect underlying diseases. A 17-point quality of life (QOL) questionnaire was completed, and sildenafil was prescribed, along with other medications deemed necessary for the management of clinically diagnosed respiratory diseases. After 30 days, dogs returned to the hospital for repeat echocardiogram and QOL survey.. The median age was 12.4 years, and most dogs were small breed dogs (median weight, 6.5 kg). Syncope (64%), cough (56%), and respiratory difficulty (32%) were the most common presenting complaints. Respiratory diseases associated with PH included tracheobronchomalacia, pulmonary fibrosis, inflammatory airway disease, and brachycephalic syndrome, with multiple diseases in some dogs. Eight of 25 dogs (32%) died or were euthanized within 1 month. In the remaining dogs, tricuspid regurgitation pressure gradient (83.0 ± 17.4 mm Hg before, 55.4 ± 17.4 mm Hg after) and QOL scores were significantly improved after 1 month of sildenafil. Fifty percent mortality was reached 6 months after study entry, with 4 dogs alive 5 years after diagnosis.. Sildenafil responsiveness is variable in dogs with respiratory-associated PH, but improved QOL was demonstrated in dogs surviving >1 month, and long-term survival was noted in some cases.

Topics: Animals; Dog Diseases; Dogs; Female; Hypertension, Pulmonary; Lung Diseases; Male; Quality of Life; Sildenafil Citrate; Survival Analysis; Treatment Outcome; Vasodilator Agents

Pulmonary non-tuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Abnormal mucociliary clearance and abnormal nasal nitric oxide (nNO) have been associated with PNTM disease in other patient cohorts. Mucociliary clearance can be affected by NO-cyclic guanosine monophosphate signalling and, therefore, modulation of the pathway may be possible with phosphodiesterase inhibitors such as sildenafil as a novel therapeutic approach.. To define ex vivo characteristics of PNTM disease affected by sildenafil.. Subjects with PNTM infections were recruited into an open-label dose-escalation trial of sildenafil. Laboratory measurements and mucociliary measurements-ciliary beat frequency, nNO and 24-hour sputum production-were collected throughout the study period. Patients received sildenafil daily during the study period, with escalation from 20 to 40 mg three times per day.. Increased ciliary beat frequency occurred after a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil. The increase ciliary beat frequency was not seen with 20 mg sildenafil dosing. There were no changes in sputum production, nNO production, Quality of Life-Bronchiectasis-NTM module (QOL-B-NTM) questionnaire or the St George's Respiratory Questionnaire during the study period.. Sildenafil, 40 mg, increased ciliary beat frequency acutely as well as with extended administration.

Topics: Aged; Aged, 80 and over; Bronchiectasis; Cilia; Female; Health Surveys; Humans; Lung Diseases; Middle Aged; Mucociliary Clearance; Mycobacterium Infections, Nontuberculous; Nasal Mucosa; Nitric Oxide; Nontuberculous Mycobacteria; Phosphodiesterase 5 Inhibitors; Quality of Life; Sildenafil Citrate; Treatment Outcome

General lymphatic anomaly (GLA) is a very rare disorder, characterised by multifocal lymphatic malformations into various tissues that is due to congenital abnormalities of lymphatic development. No treatment has ever proved its efficiency.We report a 22-year-old man with recurrent bronchial casts due to thoracic involvement of GLA. After a 6-month treatment with sildenafil (20 mg three times a day), a phosphodiesterase 5 inhibitor, chest CT scan showed a complete regression of ground-glass opacities and lung function test results improved substantially and remained stable for 1 year. The treatment was well tolerated.This observation suggests that sildenafil may be a therapeutic approach to be tested in thoracic involvement of GLA.

Topics: Humans; Lung Diseases; Lymphangiectasis; Lymphangioleiomyomatosis; Lymphatic Abnormalities; Male; Phosphodiesterase 5 Inhibitors; Rare Diseases; Respiratory Function Tests; Sildenafil Citrate; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof.

Topics: Acute Disease; Administration, Inhalation; Bronchopulmonary Dysplasia; Cardiac Catheterization; Chronic Disease; Consensus; Constriction, Pathologic; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Lung Diseases; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Pulmonary Veins; Sildenafil Citrate; Tomography, X-Ray Computed

Intravenous sildenafil treatment has recently shown promising results and good tolerability in the treatment of refractory pulmonary hypertension (PH) in term and near-term neonates, while comparable data in preterm infants are still lacking. However, for critically ill preterm infants suffering from PH refractory to conventional treatment, sildenafil may represent a last treatment resort.. We reviewed the records of 6 critically ill extremely preterm infants who had suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment.. To describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome.. 4/6 patients showed resolution of severe PH with full reversal of ductal shunt direction into pure left-to-right shunt within 82 ± 35 h after sildenafil start. Remarkably, 2/6 patients developed pulmonary hemorrhage at a time point when significant improvement of PH had already taken place, both of them survived. Overall 4/6 patients died, two deaths were related to treatment-refractory PH.. Intravenous sildenafil treatment seems effective in improving severe PH and hemodynamic instability in extremely preterm infants with refractory PH. Pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of ductal shunt. Accordingly, sildenafil should be restricted to most severe and refractory cases in this population.

Topics: Female; Hemorrhage; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Infusions, Intravenous; Intensive Care Units, Neonatal; Lung Diseases; Male; Persistent Fetal Circulation Syndrome; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Lung hypoplasia, pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia (CDH). This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling, promotes branching, and improves alveolarization in experimental nitrofeninduced CDH.. Nitrofen (100 mg) was gavage-fed to pregnant rats at post conception day (PCD) 9 to induce CDH. The rats were randomized to 5 groups: 1) control; 2) nitrofen; 3) nitrofen+sildenafil 100 mg/kg per day at PCD 16-20; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16-20, and 5) nitrofen+bosentan+sildenafil, same doses and administration days. After cesarean delivery, the offsprings were sacrificed. The diaphragmatic defect and pulmonary hypoplasia were identified, and the lungs were dissected. Arterial wall thickness, bronchiolar density and alveolarization were assessed.. The offsprings with CDH were characterized by severe pulmonary hypoplasia (lung weight-to-body weight ratio: 0.0263 [95% confidence interval (CI) 0.0242-0.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355-0.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8-3.7) μm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1-4.9) μm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7-15.2) μm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2-9.4) μm in the nitrofen group (P=0.002). More significant differences (P=0.0001) were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group [14.0 (95% CI 12.5-15.4) μm versus 8.5 (95% CI 7.1-9.3) μm]. Pulmonary arterial wall thickness was also decreased in the former group.. In this rat model, antenatal treatment with sildenafil attenuates vascular remodeling. Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.

Topics: Animals; Bosentan; Disease Models, Animal; Female; Hernias, Diaphragmatic, Congenital; Lung; Lung Diseases; Phenyl Ethers; Piperazines; Pregnancy; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides; Vascular Remodeling

To explore the protective effect of the phosphodiesterase-5 inhibitor, sildenafil, on lung ischemia-reperfusion injury, 30 rats were randomly divided into 3 groups of 10: a sham-operated group A, a lung ischemia-reperfusion injury group B, and a sildenafil preconditioned group C. A 0.1% sildenafil solution was administrated orally 2 h before establishing an in-vivo lung ischemia-reperfusion model in group C; 0.9% normal saline solution was used in the controls. The lung wet-to-dry ratio, malondialdehyde content, myeloperoxidase and nitric oxide synthase activity in groups B and C were significant higher than those in group A, while the partial pressure of oxygen in arterial blood and cyclic guanosine-3',5'-monophosphate content in groups B and C were significant lower than those in group A. Compared to group B, lung wet/dry ratio, malondialdehyde content, myeloperoxidase and nitric oxide synthase activity in group C were significantly lower, while arterial O(2) and cyclic guanosine-3',5'-monophosphate content in group C were significantly higher. The expected histological and cytological changes were significantly alleviated in group C. Oral preconditioning with sildenafil prevented rat lung ischemia-reperfusion injury and improved pulmonary function. The mechanisms of this effect might be prevention of cyclic guanosine monophosphate degradation and inhibition of nitric oxide synthase activity.

Topics: Alveolar Epithelial Cells; Animals; Cyclic GMP; Endothelium, Vascular; Lung Diseases; Male; Malondialdehyde; Nitric Oxide Synthase; Peroxidase; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones

Airway inflammation with mucus overproduction is a distinguishing pathophysiological feature of many chronic respiratory diseases. Phosphodiesterase (PDE) inhibitors have shown anti-inflammatory properties. In the present study, the effect of sildenafil, a potent inhibitor of PDE5 that selectively degrades cyclic guanosine 3',5'-monophosphate (cGMP), on acrolein-induced inflammation and mucus production in rat airways was examined. Rats were exposed to acrolein for 14 and 28 days. Sildenafil or distilled saline was administered intragastrically prior to acrolein exposure. Bronchoalveolar lavage fluid (BALF) was acquired for cell count and the detection of pro-inflammatory cytokine levels. Lung tissue was examined for cGMP content, nitric oxide (NO)-metabolite levels, histopathological lesion scores, goblet cell metaplasia and mucin production. The results suggested that sildenafil pretreatment reversed the significant decline of cGMP content in rat lungs induced by acrolein exposure, and suppressed the increase of lung NO metabolites, the BALF leukocyte influx and pro-inflammatory cytokine release. Moreover, sildenafil pretreatment reduced acrolein-induced Muc5ac mucin synthesis at both mRNA and protein levels, and attenuated airway inflammation, as well as epithelial hyperplasia and metaplasia. In conclusion, sildenafil could attenuate airway inflammation and mucus production in the rat model, possibly through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, and, thus, might have a therapeutic potential for chronic airway diseases.

Topics: Acrolein; Analysis of Variance; Animals; Blotting, Western; Bronchoalveolar Lavage; Cyclic GMP; Cytokines; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Leukocytes; Lung Diseases; Male; Mucins; Nitric Oxide; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones

The objective of the present study was to evaluate the effects of inhaled and intravenous sildenafil on the pulmonary endothelium-dependent relaxations, the hemodynamic profile and oxygenation after cardiopulmonary bypass. Five groups of Landrace swine were compared: 1) control; 2) cardiopulmonary bypass: 90 min of normothermic cardiopulmonary bypass; 3) precardiopulmonary bypass sildenafil nebulization; 4) postcardiopulmonary bypass sildenafil nebulization; 5) intravenous sildenafil administration prior to cardiopulmonary bypass. All groups underwent a 60-min period of pulmonary reperfusion after cardiopulmonary bypass. Vascular reactivity of second-degree pulmonary arteries was evaluated in response to acetylcholine and bradykinin. Cardiopulmonary bypass caused a significant decrease in endothelium-dependent relaxations to both agonists; this dysfunction was prevented by administration of sildenafil, both intravenous and inhaled (P < 0.05). Both administration routes prevented the significant increase in mean pulmonary arterial pressure with a safe hemodynamic profile. Moreover, intravenous and inhaled sildenafil after cardiopulmonary bypass also prevented the increase in alveoloarterial gradient (P < 0.05). Both sildenafil formulations of administration prevent the occurrence of pulmonary endothelial dysfunction. Depending on the administration moment and the route, the administration of sildenafil improves the hemodynamic profile and post-cardiopulmonary bypass oxygenation.

Topics: Acetylcholine; Administration, Inhalation; Animals; Blood Pressure; Bradykinin; Cardiopulmonary Bypass; Endothelium, Vascular; Female; Hemodynamics; Injections, Intravenous; Lung Diseases; Male; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Swine; Vasodilation; Vasodilator Agents

We describe four cases of chronic pulmonary hypertension in infants and children with chronic lung disease and pulmonary hypoplasia due to severe congenital diaphragmatic hernia (CDH) or congenital cystic adenomatoid malformation (CCAM). We report data from cardiac catheterization under various conditions: baseline respiratory support and room air, hyperoxic and inhaled nitric oxide challenge. We further report cardiac catheterization measures after chronic pulmonary vasodilator therapy with sildenafil alone or a combination of sildenafil and inhaled nitric oxide (three patients).. Case series.. Tertiary academic center.. Infants and children ages 0-11 yrs with CDH (n = 3) or CCAM (n = 1) with evidence of chronic pulmonary hypertension by echocardiogram and cor pulmonale (n = 3).. Catheterization and pulmonary vasodilator therapy.. Pulmonary vascular resistance, pulmonary arterial pressure, and changes in these measures were assessed. A 20% change in pulmonary vascular resistance was considered a clinically significant response. Ten catheterizations were performed in four patients. All patients had elevated pulmonary vascular resistance and pulmonary arterial pressures at initial catheterizations and significant vasodilation during inhaled nitric oxide.. Chronic lung disease following pulmonary hypoplasia from CDH and CCAM is associated with abnormal pulmonary vascular tone in infants and children with evidence of chronic pulmonary hypertension. Chronic pulmonary vasodilator therapy may improve pulmonary vascular function and enhance lung growth in infants and children who are treated during their period of potential for rapid lung growth.

Topics: Cardiac Catheterization; Child; Child, Preschool; Chronic Disease; Cystic Adenomatoid Malformation of Lung, Congenital; Female; Free Radical Scavengers; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung; Lung Diseases; Male; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Bronchopulmonary dysplasia (BPD), the chronic lung disease of preterm infants, and pulmonary emphysema, both significant global health problems, are characterized by an arrest in alveolar growth/loss of alveoli structures. Mechanisms that inhibit distal lung growth are poorly understood, but recent studies suggest that impaired vascular endothelial growth factor signaling and reduced nitric oxide (NO) production decreases alveolar and vessel growth in the developing lung, features observed in experimental oxygen-induced BPD. NO exerts its biological activity by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production.. Because cGMP is inactivated by phosphodiesterase (PDE) enzymes, we hypothesized that the cGMP-specific PDE5 inhibitor sildenafil would promote angiogenesis and attenuate oxygen-induced lung injury in newborn rats. METHODS, MEASUREMENTS, AND MAIN RESULTS: In vitro, sildenafil (10(-4) M) increased endothelial capillary network formation of human pulmonary endothelial cells exposed to hyperoxia. In vivo, rat pups were randomly exposed from birth to normoxia, hyperoxia (95% O(2), BPD model), and hyperoxia+sildenafil (100 mg/kg/day subcutaneously). Rat pups exposed to hyperoxia showed fewer and enlarged air spaces as well as decreased capillary density, mimicking pathologic features seen in human BPD. These structural anomalies were associated with echographic (decreased pulmonary acceleration time) and structural (right ventricular hypertrophy and increased medial wall thickness) signs of pulmonary hypertension. Sildenafil preserved alveolar growth and lung angiogenesis, and decreased pulmonary vascular resistance, right ventricular hypertrophy and medial wall thickness.. Our findings suggest a role for the NO/cGMP pathway during alveolar development. Sildenafil may have therapeutic potential in diseases associated with impaired alveolar structures.

Topics: Animals; Animals, Newborn; Cells, Cultured; Cyclic GMP; Humans; Hypertension, Pulmonary; Lung; Lung Diseases; Neovascularization, Physiologic; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler

We report a case of severe pulmonary hypertension in a neonate associated with impaired alveolarisation and plexiform pulmonary arteriopathy. Treatment with oral sildenafil in addition to inhaled nitric oxide (NO) resulted in recovery from the pulmonary hypertensive crisis. Long term sildenafil therapy was associated with complete resolution of the pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Lung Diseases; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Aged, 80 and over; Erectile Dysfunction; Fatal Outcome; Hemorrhage; Humans; Lung Diseases; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Pulmonary Fibrosis; Purines; Sildenafil Citrate; Sulfones