Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors

Unegbu, Chinwe; Noje, Corina; Coulson, John D.; Segal, Jodi B; Romer, Lewis H.

doi:10.1542/peds.2016-1450

Cited by 57 publications

(44 citation statements)

References 57 publications

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“…Unegbu et al . () performed a systematic review of the comparative effectiveness and safety of PDE5 inhibitors in the management of paediatric patients with PAH. They found strong evidence that PDE5 inhibitor use improves echocardiography measurements, cardiac catheterization parameters and oxygenation compared with baseline or placebo.…”

Section: Approved Clinical Applications Of Pde5 Inhibitorsmentioning

confidence: 99%

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

2018

British J Pharmacology

370

157

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The discovery of the nitric oxide/cGMP pathway was the basis for our understanding of many normal physiological functions and the pathophysiology of several diseases. Since the discovery and introduction of sildenafil, inhibitors of PDE5 have been the first-line therapy for erectile dysfunction (ED). The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms, and pulmonary arterial hypertension, which are now approved indications. However, PDE5 inhibitors have also been used in several other disorders not discussed in this review, and the fields of clinical use are increasing. In the present review, the pharmacological basis of the NO/cGMP pathway and the rationale and clinical use of PDE5 inhibitors in different diseases are discussed.

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Section: Approved Clinical Applications Of Pde5 Inhibitorsmentioning

confidence: 99%

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

2018

British J Pharmacology

370

157

View full text Add to dashboard Cite

show abstract

“…Regarding the possible benefit of our rather aggressive sildenafil treatment, we cannot assess to what extent a spontaneous improvement of PH would have occurred without such treatment. However, a recent review by Unegbu et al [24] emphasizes the effectivity of sildenafil treatment in pediatric patients suffering from PH.…”

Section: Discussionmentioning

confidence: 99%

An Echocardiographic Screening Program Helps to Identify Pulmonary Hypertension in Extremely Low Birthweight Infants with and without Bronchopulmonary Dysplasia: A Single-Center Experience

Mehler

Cate²,

Keller³

et al. 2017

Neonatology

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Background: Pulmonary hypertension (PH) affects 1 in 6 infants with a birthweight <1,000 g (extremely low birthweight; ELBW) and is frequently associated with bronchopulmonary dysplasia (BPD). If untreated, the mortality rates of the disease are high. Objectives: The aim of this study was to characterize risk factors for PH in ELBW infants and to describe the timing of onset of the disease by setting up a screening program. Methods: ELBW infants treated at the Department of Neonatology (level III neonatal intensive care unit at the University of Cologne Medical Centre, Germany) between January 2010 and March 2015 were included. Echocardiography screening for PH was performed either before discharge or if BPD was diagnosed. Additionally, infants had at least 1 echocardiographic scan after discharge. Survival with PH, age at diagnosis of PH, and risk factors associated with PH were assessed. Results: In total, 34/188 (18%) infants had PH. Of these, 14 (41%) were identified after discharge. Another 11 (32%) were diagnosed with PH without suffering from moderate or severe BPD. The risk factors for diagnosis of PH were moderate (odds ratio, OR 4 [2-8]) or severe BPD (OR 13 [2-71]), prolonged rupture of membranes >7 days (OR 5 [1-19]), and birthweight below the 3rd percentile (OR 3 [1-9]). All infants with PH before discharge and 50% diagnosed after discharge were treated with sildenafil (2.0 mg/kg/day). PH resolved and sildenafil was discontinued in all patients after a median duration of 13 months (IQR 8-20). Conclusions: An echocardiographic screening program may help to identify infants with PH. Examinations should include all ELBW infants irrespective of the presence of BPD and be continued after discharge.

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“…4F, J; Fig.S1E, F, J). In contrast, co-treatment with the adenylate cyclase activator, forskolin 39 , which increases levels of cAMP, but not cGMP, did not reduce biliatresone-toxicity ( Fig. S2) Activation of cGMP signaling had a comparable effect on biliatresone toxicity in two human cholangiocyte cell lines (H69 and NHC) (40,41).…”

Section: Activation Of Cgmp Signaling Rescues Biliatresone-mediated Cmentioning

confidence: 95%

“…The response to trequinsin, on the other hand, was inconsistent (data not shown). Interestingly, two PDE5 inhibitors, vardenafil (Levitra) and tadalafil (Cialis), which block cGMP degradation and are clinically approved for erectile dysfunction and pulmonary hypertension (38,39), had a comparable effect as aminophylline in 60.0% and 49.5% of the larvae examined, respectively ( Fig. 4E, J, S1D, J).…”

Section: Activation Of Cgmp Signaling Rescues Biliatresone-mediated Cmentioning

confidence: 96%

Impaired redox and protein homeostasis as risk factors and therapeutic targets in toxin-induced biliary atresia

Zhao

Lorent

Escobar-Zarate

et al. 2019

Preprint

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Extra-hepatic biliary atresia (BA) is an important pediatric liver disease of unknown etiology. The identification of biliatresone, a plant electrophile with selective toxicity for extra-hepatic cholangiocytes (EHC) and linked to outbreaks of epidemic BA in livestock, demonstrated the feasibility of an environmental trigger for this enigmatic condition. Here, we show that susceptibility of zebrafish EHC to biliatresone arises from their inability to restore stress-induced depletion of glutathione, and that heterozygous mutations in glutathione metabolism genes differentially sensitize EHC and the normally resistant intra-hepatic cholangiocytes (IHC) to biliatresone-mediated injury. Collectively these findings argue that genetic variants in stressresponse genes could be risk factors for human BA. Supporting this idea, we identified de novo loss-of-function mutations in the STIP1 and REV1 gene, both part of the HSP90 pathway, in two children with BA, respectively, and showed that modulation of their expression sensitized zebrafish larvae and human cholangiocytes to biliatresone. Using an in vivo drug screening assay, we identified activators of cGMP signaling as potent enhancers of the anti-oxidant Nacetylcysteine (NAC) in biliatresone-treated larvae and human cholangiocytes that act independently of glutathione and upstream of chaperone-mediated protein quality control (PQC) pathways. Collectively, these data highlighted novel aspects of cholangiocyte injury responses, identified new genetic risk factors for BA, and suggest combined treatment with NAC and cGMP signaling modulators as a rational therapeutic strategy for BA. University of Pennsylvania School of Medicine (Philadelphia, PA) zebrafish facility in accord with protocols approved by the University of Pennsylvania Institutional Animal Care and Use Committee.Generation of targeted mutations in zebrafish using CRISPR/Cas9 system. The target sequences for gclm, abcc2, stip1 were identified using the CHOPCHOP website: http://chopchop.cbu.uib. no/. The single-guide RNA (sgRNA) was generated as described(70). Cas9 protein were obtained from PNABIO. Approximately 60 to 120 pg of sgRNA and 180 pg of Cas9 protein were coinjected into WT embryos at the one-cell stage. Genomic DNAs was extracted from pools of 20 one-day old embryos, and the targeted areas were amplified and sequenced using primers listed in Supplementary Table 1 to confirm somatic mutations. Injected embryos were raised to adulthood (F0) and screened for the germline-transmitting founders. The F0 founders were subsequently outcrossed with WT fish to obtain the heterozygous F1 and F2 offspring. All experiments were performed on the animals of F3 or subsequent generations. The gclm, abcc2 mutants were genotyped using primers listed in Table S1. The gsr and stip1 mutant fish were genotyped using the KASP genotyping assays (KBioscience).Redox-Sensitive GFP Redox Mapping Double transgenic (Tg(ef1a:Grx-roGFP; tp1:mCherry)) larvae in gclm, abcc2, gsr genetic background were used for the redox mapping of hep...

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Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors

Cited by 57 publications

References 57 publications

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

An Echocardiographic Screening Program Helps to Identify Pulmonary Hypertension in Extremely Low Birthweight Infants with and without Bronchopulmonary Dysplasia: A Single-Center Experience

Impaired redox and protein homeostasis as risk factors and therapeutic targets in toxin-induced biliary atresia

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