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Pharmaceuticals
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Phosphodiesterases as Drug Targets: Development and Challenges
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Phosphodiesterases as Drug Targets: Development and Challenges

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 18288

Special Issue Editor

Prof. Dr. Juraj Mokrý

E-Mail Website
Guest Editor
Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, 03601 Martin, Slovakia
Interests: phosphodiesterase; inhibitors; asthma; COPD; tuberculosis; Mycobacterium; antituberculotics

Special Issue Information

Dear Colleagues,

Recently, several new molecules have been introduced to treat obstructive lung diseases associated with inflammation (e.g., bronchial asthma and chronic obstructive pulmonary disease (COPD)), including long-acting bronchodilators, corticosteroids and monoclonal antibodies. Despite this, some patients may benefit from a more selective approach to treatment (preferentially accompanied by fewer adverse effects), particularly when a combination of drugs is required to manage severe stages of these diseases. Inhibiting certain phosphodiesterase (PDE) isoenzymes (e.g., PDE3 and PDE4) and, thereby, increasing the concentration of cyclic adenosine monophosphate (cAMP) in specific tissues and organs may have therapeutic benefits. PDEs have become attractive drug targets because an increase in cAMP can relax smooth muscle and suppress inflammation and, thus, could be used in COPD, asthma or psoriasis. Moreover, there are many other situations where increased intracellular cyclic nucleotide concentrations could be of benefit. For example, selective inhibition of PDE5 and subsequent increases in intracellular cGMP concentration in vascular smooth muscle may result in vasodilation and, thus, could be used in the therapy of pulmonary hypertension or erectile dysfunction.An integral part of this process is to collect sufficient evidence about the efficacy and safety of these molecules in animal models and in clinical settings of various diseases, as well as by various routes of administration. In this respect, manuscripts that describe recent developments in research on PDEs and  their inhibitors in both experimental and clinical settings are invited.
The journal Pharmaceuticals invites both reviews and original articles that shed light on the challenges and opportunities of targeting PDEs. The collection of manuscripts will be published as a Special Issue of the journal.

Prof. Dr. Juraj Mokrý
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • phosphodiesterase
  • PDE inhibitors
  • selective
  • intracellular
  • receptors
  • bronchial asthma
  • COPD
  • psoriasis
  • apoptosis
  • theophylline
  • roflumilast

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Published Papers (6 papers)

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Research

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13 pages, 1434 KiB  
Article
The Effects of Different Doses of Sildenafil on Coronary Blood Flow and Oxidative Stress in Isolated Rat Hearts
by Nada Banjac, Velibor Vasović, Nebojša Stilinović, Ana Tomas, Lucija Vasović, Nikola Martić, Dušan Prodanović and Vladimir Jakovljević
Pharmaceuticals 2023, 16(1), 118; https://doi.org/10.3390/ph16010118 - 13 Jan 2023
Cited by 2 | Viewed by 4224 | Correction
Abstract
The dose-response relationship of sildenafil effects on cardiac function is not completely elucidated. The aim of this study was to assess the effects of different doses of sildenafil on coronary flow and oxidative stress in isolated rat hearts. Coronary flow and markers of [...] Read more.
The dose-response relationship of sildenafil effects on cardiac function is not completely elucidated. The aim of this study was to assess the effects of different doses of sildenafil on coronary flow and oxidative stress in isolated rat hearts. Coronary flow and markers of oxidative stress, including nitrite outflow, and superoxide anion production in coronary effluent, were determined for isolated rat hearts. The experiments were performed during control conditions and in the presence of sildenafil (10, 20, 50, 200 nM) alone or with Nω-nitro-L-arginine monomethyl ester (L-NAME) (30 μM). Sildenafil was shown to result in a significant increase in coronary flow at lower coronary perfusion pressure (CPP) values at all administered doses, whereas, with an increase in CPP, a reduction in coronary flow was observed. An increase in nitric oxide (NO) was most pronounced in the group treated with the lowest dose of sildenafil at the highest CPP value. After the inhibition of the NO-cyclic guanosine monophosphate (cGMP) signaling (NOS) system by L-NAME, only a dose of 200 nM sildenafil was high enough to overcome the inhibition and to boost release of O2−. That effect was CPP-dependent, with statistical significance reached at 80, 100 and 120 mmHg. Our findings indicate that sildenafil causes changes in heart vasculature in a dose-dependent manner, with a shift from a vasodilatation effect to vasoconstriction with a pressure increase. The highest dose administered is capable of producing superoxide anion radicals in terms of NOS system inhibition. Full article
(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)
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13 pages, 2813 KiB  
Article
Acute Lung Functional and Airway Remodeling Effects of an Inhaled Highly Selective Phosphodiesterase 4 Inhibitor in Ventilated Preterm Lambs Exposed to Chorioamnionitis
by Matthias Christian Hütten, Tim Brokken, Helene Widowski, Tobias Monaco, Jan Philipp Schneider, Markus Fehrholz, Daan Ophelders, Boris W. Kramer and Steffen Kunzmann
Pharmaceuticals 2023, 16(1), 29; https://doi.org/10.3390/ph16010029 - 26 Dec 2022
Cited by 1 | Viewed by 2050
Abstract
Phosphodiesterase (PDE) inhibition has been identified in animal studies as a new treatment option for neonatal lung injury, and as potentially beneficial for early lung development and function. However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental [...] Read more.
Phosphodiesterase (PDE) inhibition has been identified in animal studies as a new treatment option for neonatal lung injury, and as potentially beneficial for early lung development and function. However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental effects and promote lung inflammation in the premature lung. In this study, the effects of a high and a low dose of GSK256066 on lung function, structure and alveolar development were investigated. In a triple hit lamb model of Ureaplasma-induced chorioamnionitis, prematurity, and mechanical ventilation, 21 animals were treated as unventilated (NOVENT) or 24 h ventilated controls (Control), or with combined 24 h ventilation and low dose (iPDE1) or high dose (iPDE10) treatment with inhaled GSK 256066. We found that high doses of an inhaled PDE4 inhibitor impaired oxygenation during mechanical ventilation. In this group, the budding of secondary septae appeared to be decreased in the preterm lung, suggesting altered alveologenesis. Ventilation-induced structural and functional changes were only modestly ameliorated by a low dose of PDE4 inhibitor. In conclusion, our findings indicate the narrow therapeutic window of PDE4 inhibitors in the developing lung. Full article
(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)
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20 pages, 1860 KiB  
Article
Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia
by Rayanne Poletti Guimarães, Danilo Leandro Ribeiro, Keila Bariotto Dos Santos, Carlos Henrique Zanello Talarico, Lívea Dornela Godoy and Fernando E. Padovan-Neto
Pharmaceuticals 2022, 15(8), 947; https://doi.org/10.3390/ph15080947 - 30 Jul 2022
Cited by 2 | Viewed by 2590
Abstract
The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were [...] Read more.
The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID. Full article
(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)
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Review

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21 pages, 1475 KiB  
Review
Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors
by Artem Ovchinnikov, Alexandra Potekhina, Evgeny Belyavskiy and Fail Ageev
Pharmaceuticals 2022, 15(8), 1024; https://doi.org/10.3390/ph15081024 - 19 Aug 2022
Cited by 6 | Viewed by 4114
Abstract
Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated [...] Read more.
Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment. Full article
(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)
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12 pages, 1884 KiB  
Review
Phosphodiesterase-4 Inhibitor Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event of Acute Kidney Injury: A Narrative Review
by Imran Kazmi, Fahad A. Al-Abbasi, Muhammad Afzal, Muhammad Shahid Nadeem, Hisham N. Altayb and Gaurav Gupta
Pharmaceuticals 2022, 15(7), 899; https://doi.org/10.3390/ph15070899 - 20 Jul 2022
Cited by 8 | Viewed by 3468
Abstract
Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock—phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this [...] Read more.
Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock—phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this category to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with chronic bronchitis and a history of COPD exacerbations. Roflumilast has been shown to alleviate inflammatory responses, thus regulating airway inflammation. Additionally, roflumilast therapy dramatically enhanced B-cell lymphoma 2 (Bcl-2) expression, an anti-apoptotic marker lowered in septic animals. Previous research has indicated that roflumilast may help reverse sepsis-induced liver and lung harm, but whether it is also effective in reversing sepsis-induced renal impairment remains unknown. Therefore, this review determines whether roflumilast protects against renal dysfunction, inflammatory response, and apoptosis in sepsis-induced kidney damage. Additionally, we discussed the molecular mechanism through which roflumilast exerts its protective effect to uncover a possible treatment agent for sepsis-induced renal impairment. Full article
(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)
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Other

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1 pages, 141 KiB  
Correction
Correction: Banjac et al. The Effects of Different Doses of Sildenafil on Coronary Blood Flow and Oxidative Stress in Isolated Rat Hearts. Pharmaceuticals 2023, 16, 118
by Nada Banjac, Velibor Vasović, Nebojša Stilinović, Ana Tomas, Lucija Vasović, Nikola Martić, Dušan Prodanović and Vladimir Jakovljević
Pharmaceuticals 2024, 17(4), 439; https://doi.org/10.3390/ph17040439 - 29 Mar 2024
Viewed by 965
Abstract
Prof [...] Full article
(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)
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