Repurposing of the PDE5 inhibitor sildenafil for treatment of persistent pulmonary hypertension in neonates

2020 ◽  
Vol 27 ◽  
Author(s):  
Erika L. Poitras ◽  
Stephen L. Gust ◽  
Paul M. Kerr ◽  
Frances Plane
Keyword(s):  
Pulmonary Hypertension ◽  
Erectile Dysfunction ◽  
Soluble Guanylate Cyclase ◽  
Vascular Endothelial Cells ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Effector Proteins ◽  
Guanosine Monophosphate ◽  
Persistent Pulmonary Hypertension ◽  
Current Evidence

: Nitric oxide (NO), an important endogenous signalling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is) such as sildenafil prolong the availability of cGMP and so enhance NO-mediated signalling. PDE5is are the first line treatment for erectile dysfunction but are also now approved for treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO but this is an expensive option and around 1/3 of newborns are unresponsive resulting in the need for alternative approaches. Here we summarize the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, and then critically review current evidence for the utility of further repurposing of sildenafil as a treatment for PPHN.

Plasma Cyclic Guanosine Monophosphate Reflecting the Severity of Persistent Pulmonary Hypertension of the Newborn

Neonatology ◽  
2001 ◽  
Vol 80 (2) ◽  
pp. 107-112 ◽  
Author(s):  
M. Turanlahti ◽  
E. Pesonen ◽  
M. Pohjavuori ◽  
P. Lassus ◽  
F. Fyhrquist ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Persistent Pulmonary Hypertension

scholarly journals Switching to riociguat: a potential treatment strategy for the management of CTEPH and PAH

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401983784
Author(s):  
Raymond L. Benza ◽  
Paul A. Corris ◽  
Hossein-Ardeschir Ghofrani ◽  
Manreet Kanwar ◽  
Vallerie V. McLaughlin ◽  
...  
Keyword(s):  
Life Experience ◽  
Soluble Guanylate Cyclase ◽  
Real Life ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Cyclic Guanosine Monophosphate ◽  
Initial Therapy ◽  
Guanosine Monophosphate ◽  
Current Evidence ◽  
Off Label ◽  
Insufficient Response

Currently, five classes of drug are approved for the treatment of pulmonary arterial hypertension (PAH): phosphodiesterase 5 inhibitors (PDE5i); endothelin receptor antagonists; prostacyclin analogs; the IP receptor agonist selexipag; and the soluble guanylate cyclase (sGC) stimulator riociguat. For patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), riociguat is currently the only approved pharmacotherapy. Despite the development of evidence-based guidelines on appropriate use of specific drugs, in clinical practice patients are often prescribed PAH-targeted therapies off label or at inadequate doses. PDE5i are the most often prescribed class of drugs as initial therapy, either alone or in combination with other drug classes. However, a proportion of patients receiving PAH therapies do not reach or maintain treatment goals. As PDE5i and riociguat target different molecules in the nitric oxide-sGC-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway, for patients with PAH without an initial or sustained response to PDE5i, there is a biological rationale for switching to riociguat. However, robust data from randomized controlled trials on the safety and efficacy of switching are lacking, as is formal guidance for clinicians. Here we review studies of sequential combination therapy, and trial data and case studies that have investigated switching between PAH-approved therapies, particularly from PDE5i to riociguat in patients with PAH with an insufficient response to PDE5i, and in patients with CTEPH who were receiving off-label treatment. These studies summarize the current evidence and practical real-life experience on the concept of switching treatments.

Sildenafil Is a Pulmonary Vasodilator in Awake Lambs with Acute Pulmonary Hypertension

2000 ◽  
Vol 92 (6) ◽  
pp. 1702-1712 ◽  
Author(s):  
Jörg Weimann ◽  
Roman Ullrich ◽  
Jonathan Hromi ◽  
Yuji Fujino ◽  
Martin W. H. Clark ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Pulmonary Vasculature ◽  
No Production ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator ◽  
Acute Pulmonary Hypertension ◽  
Inhaled No

Background Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction. Methods In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). Results Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation. Conclusions Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

scholarly journals Nitrogen oxide biochemical pathway in pulmonary arterial hypertension therapy and REPLACE trial results

2018 ◽  
Vol 15 (2) ◽  
pp. 72-76 ◽  
Author(s):  
A A Shmalts ◽  
S V Gorbachevsky
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Controlled Trial ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Controlled Study ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Hypertension Therapy

Endogen nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) deficiency in pulmonary vessels walls plays essential role in pulmonary arterial hypertension (PAH) pathogenesis. Soluble guanylate cyclase stimulator riociguat and phosphodiesterase-5 (PDE5) inhibitor sildenafil increase cGMP content and have proven clinical efficacy in PAH treatment. The potentially beneficial mechanisms of riociguat mechanism of action include endogen NO independence in cGMP synthesis and its independence from other phosphodiesterase isoferments (other than PDE5). Clinical options, safety and effectiveness of iPDE5 - riociguat transition in patients with PAH were for the first time shown in non-controlled study RESPITE and the assessment is continued in randomized placebo-controlled trial REPLACE.

Synthesis of isotope – labeled selective PDE5 inhibitor sildenafil (UK 92480-10)

2018 ◽  
Vol 106 (10) ◽  
pp. 851-855
Author(s):  
R. Sekhar Bolla ◽  
Kali Charan Gulipalli ◽  
N. Murthy Gandikota ◽  
Srinu Bodige ◽  
I. V. Kasi Viswanath
Keyword(s):  
Erectile Dysfunction ◽  
Pulmonary Arterial Hypertension ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Selective Inhibitor ◽  
Guanosine Monophosphate ◽  
Isotopic Abundance ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type ◽  
Male Erectile Dysfunction

Abstract Sildenfil a vasodilating agent is a selective inhibitor of cyclic guanosine monophosphate – specific phosphodiesterase type 5 which is used for the treatment of male erectile dysfunction and pulmonary arterial hypertension. We presented a detailed approach for the synthesis of [2H3]sildenafil, [2H8]sildenafil and N-desmethyl [2H8]sildenafil. By using the approach we successfully synthesized [2H3]sildenafil, [2H8]sildenafil and N-desmethyl [2H8]sildenafil with good isotopic abundance.

Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?

2019 ◽  
Vol 19 (18) ◽  
pp. 1544-1557 ◽  
Author(s):  
Sijia Xiao ◽  
Qianbin Li ◽  
Liqing Hu ◽  
Zutao Yu ◽  
Jie Yang ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Smooth Muscle Relaxation ◽  
Secondary Messenger ◽  
Physiological Processes ◽  
Cgmp Pathway ◽  
Preclinical And Clinical Studies

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.

scholarly journals Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3418
Author(s):  
Grzegorz Grześk ◽  
Alicja Nowaczyk
Keyword(s):  
Guanylate Cyclase ◽  
Natriuretic Peptides ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Pharmacological Intervention ◽  
First Line ◽  
Phosphodiesterase Type ◽  
Activity Mechanism

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

scholarly journals Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2514
Author(s):  
Santiago Andrés Plano ◽  
Fernando Martín Baidanoff ◽  
Laura Lucía Trebucq ◽  
Sebastián Ángel Suarez ◽  
Fabio Doctorovich ◽  
...  
Keyword(s):  
Soluble Guanylate Cyclase ◽  
Phase Locking ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Circadian Phase ◽  
Subjective Night ◽  
Circadian Time ◽  
Electron Reduction ◽  
Locomotor Rhythms ◽  
The One

The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli’s salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator.

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