Oral Tadalafil in Children with Pulmonary Arterial Hypertension

Shiva, Atena; Shiran, Mohammad Reza; Rafati, Mohammadreza; Zamani, Hossein; Babazadeh, Kazem; Saeedi, Majid; Ala, Shahram

doi:10.1055/s-0034-1395510

Cited by 17 publications

(29 citation statements)

References 21 publications

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“…This approach has a high sensitivity and specificity for detecting BA, albeit with a low positive predictive value, in keeping with the rarity of the disease. Given the severity and progressive nature of BA, and that both NAC and PDE5 inhibitors are well tolerated in infants (65)(66)(67)(68)(69), combining treatments at this time point may be the most effective strategy, particularly if confirmatory studies can be performed allowing for treatment discontinuation in non-responders and those found not to have BA. Going forward, substitution of PDE5i with activators or stimulators of cGMP might be considered.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Thus, the discontinuation rate for tadalafil therapy in children was 6% (30). In a study by Shiva et al conducted on 25 patients aged two months to five years, a significant improvement was seen in MPAP (P < 0.01) (29). They used tadalafil 1 mg/kg daily.…”

Section: Discussionmentioning

confidence: 99%

“…After changing from sildenafil to tadalafil, a significant clinical improvement was seen (P < 0.05). It was also obvious that the use of an oral tadalafil suspension was safe and well-tolerated (29). Unlike sildenafil, the longer halflife of tadalafil makes serum levels more consistent, which may have an advantage with regard to hemodynamics in patients with PAH (30).…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Tadalafil and Sildenafil in Controlling Neonatal Persistent Pulmonary Hypertension

et al. 2016

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Background: Persistent pulmonary hypertension of the newborn (PPHN) occurs in post-term neonates with an incidence of 1 in 500 -1,500 live births. The survival rate is approximately 69% after conventional management of infants suffering from PPHN. Extracorporeal membrane oxygenation (ECMO) therapy improves survival up to 86%. Methods: A total of 32 neonates with PPHN participated in this study. These neonates were randomly assigned into two 16-case groups: group A received tadalafil while group B received sildenafil. A random simple sampling method was used for the selection of subjects. The severity of tricuspid regurgitation (TR), main pulmonary artery (MPA) diameter, mean pulmonary artery pressure (MPAP), and right ventricular end-diastolic diameter (RVEDD) were assessed by echocardiography before and 6 months after treatment. Results: MPAP decreased after treatment in both groups, but the mean of changes in PAP in the two groups was not significantly different (P = 0.48). Both tadalafil and sildenafil significantly reduced the TR severity, RVEDD, and MPA diameter (P < 0.05), but the mean of the changes in TR, RVEDD, and MPA in both groups was similar (P = 0.05). Conclusions: Tadalafil and sildenafil can similarly reduce MPAP, TR severity, RVEDD, and MPA diameter.

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“…Tadalafil has also been evaluated in children with PAH . These open‐label, uncontrolled trials, some of which included patients previously treated with sildenafil, suggested that tadalafil improves hemodynamics and exercise capacity, and is generally well tolerated (Table ). While tadalafil is licensed for use in adults with PAH in Europe and the USA, it is not licensed for use in children in either region.…”

Section: Current Management Of Pediatric Pahmentioning

confidence: 99%

Treatment of pediatric pulmonary arterial hypertension: A focus on the NO‐sGC‐cGMP pathway

Beghetti¹,

Gorenflo

Ivy

et al. 2019

Pediatric Pulmonology

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Objective While pulmonary arterial hypertension (PAH) is rare in infants and children, it results in substantial morbidity and mortality. In recent years, prognosis has improved, coinciding with the introduction of new PAH‐targeted therapies, although much of their use in children is off‐label. Evidence to guide the treatment of children with PAH is less extensive than for adults. The goal of this review is to discuss the treatment recommendations for children with PAH, as well as the evidence supporting the use of prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (PDE5i) in this setting. Data Sources Nonsystematic PubMed literature search and authors’ expertise. Study Selection Articles were selected concentrating on the nitric oxide (NO)‐soluble guanylate cyclase (sGC)‐cyclic guanosine monophosphate (cGMP) pathway in PAH. The methodology of an ongoing study evaluating the sGC stimulator riociguat in children with PAH is also described. Results Despite recent medical advances, improved therapeutic strategies for pediatric PAH are needed. The efficacy and tolerability of riociguat in adults with PAH have been well trialed. Conclusion The pooling of data across trials, supplemented by registry data, will help to confirm the safety and tolerability of prostanoids, ERAs, and PDE5i in children. Ongoing studies will clarify the place of sGC stimulators in the treatment strategy for pediatric PAH.

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Oral Tadalafil in Children with Pulmonary Arterial Hypertension

Abstract: Oral tadalafil was administered easily and tolerated well and improved mean pulmonary artery pressure (MPAP) in children with PAH, which suggests that oral tadalafil may be more effective and safer than sildenafil in the treatment of PAH.

Cited by 17 publications

References 21 publications

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

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

Comparison of Tadalafil and Sildenafil in Controlling Neonatal Persistent Pulmonary Hypertension

Treatment of pediatric pulmonary arterial hypertension: A focus on the NO‐sGC‐cGMP pathway

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