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Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising...
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... a porcine model of endotoxemia, endotoxin decreased the cardiac index and hepatic oxygen delivery (DO2H), while oxygen consumption (VO2H) was unchanged. Treatment with PDE3 inhibitor olprinone unchanged cardiac index, but elevated DO2H and VO2H indicating a restoration of hepatic circulation, and prevented LPS-induced reduction of cytochrome aa3 and increase in arterial lactate values [135] (Table 4). Vasodilating effects of olprinone on peripheral and pulmonary vessels in hypoxic conditions were shown in a canine model of hypoxic pulmonary hypertension where intravenous olprinone increased heart rate and decreased mean aortic pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, systemic vascular resistance, and right ventricular stroke work index, without the change in cardiac index [136]. ...Context 2
... all PDE inhibitors, PDE4 inhibitors seem to be the most promising in the treatment of ALI/ARDS (Table 4). PDE4 inhibitors stabilize both the endothelial cells and pulmonary epithelium, and thereby reduce the sepsis-and inflammation-induced elevation in a microvascular permeability [142], as it has been demonstrated in several animal in vivo studies. ...Similar publications
Background: The effects of neuromuscular blocking agents on the clinical performance of supraglottic airway devices and surgical condition in elderly patients undergoing hand surgery have not been
established. We evaluated the effects of rocuronium on the clinical performance of an i-gel® supraglottic device and surgical condition in elderly patien...
Citations
... Aminophylline is a combination of theophylline and ethylenediamine with a ratio of 2: 1. Aminophylline has antihypoxia, anti-inflammatory, bronchodilator, vasodilator, ROS inhibitor effects, reduces oedema formation, stimulates surfactant release and can prevent virus replication (Mokra & Mokry, 2021;Montao et al., 2022). ...
... The therapeutic treatment of ARDS is mainly supportive therapy, which depends on the patient's condition, so there is no specific therapy. Aminophylline is an adjunct therapy in ARDS due to several beneficial effects of aminophylline, namely phrenic nerve and diaphragm activation; aminophylline is a xanthine alkaloid derivative that has a mild stimulant and bronchodilator effect, immunomodulator with an inhibitory effect on T lymphocytes in the respiratory tract, including neutrophil apoptosis and suppression of inflammatory genes at low doses, theophylline also has an antiinflammatory effect with Histone deacetylase-2 (HDAC2) activity, which increases the response to steroid therapy, ROS inhibitors, reduces oedema formation, stimulates surfactant release in the lungs (Mokra & Mokry, 2021). ...
Background: In Acute respiratory distress syndrome (ARDS), invasion and activation of pro- and anti-inflammatory mediators and cytokines result in oxidative damage to the lung tissue. Aminophylline is a combination of theophylline and ethyl diamine, has anti-inflammatory, bronchodilator, ROS inhibitor effects, and stimulates surfactant release. Mortality of ARDS in COVID-19 patients is high; aminophylline is expected to reduce the incidence of mortality. Information regarding the use of aminophylline in COVID-19 patients with ARDS is still limited. Objective: To evaluate the efficacy of aminophylline in inflammatory parameters in COVID-19 patients with ARDS. Methods: It was a retrospective cohort observational study at the Universitas Airlangga Hospital. Samples were hospitalised COVID-19 patients with ARDS who received a loading dose of 240-480 mg and a maintenance dose of 720-960 mg aminophylline. The primary outcomes were improved C-reactive protein (CRP), IL-6, lymphocytes, neutrophils, and Neutrophil-lymphocyte ratio (NLR), which were measured before and after administration of aminophylline with a duration of therapy of 1-5 days. Result: A total of 50 patients with ARDS were enrolled in the study. Lymphocyte and CRP decreased (p = 0.002; p = 0.128). IL-6, neutrophil, and NLR increased (p = 0.255; p = 0.064; p = 0.005). Conclusion: It can be concluded that the administration of aminophylline has not improved inflammatory parameters.
... cAMP is essential for the regulation of various inflammatory responses in innate immune cells [91]. The intracellular levels of these cyclic nucleotides are primarily regulated by enzymes called phosphodiesterases (PDEs), which catalyse the hydrolysis of a cyclic phosphate bond in cAMP and cyclic guanosine monophosphate (cGMP) to produce the inactive 5 ′ -AMP and 5 ′ -GMP [92]. The predominant subtype of PDE in neutrophils is PDE4, which is involved in the pathogenesis of inflammatory diseases [93]. ...
... Bailly et al. suggested that the inhibitory effect of ciprofloxacin on TNF-α and IL-1 may possibly be attributed to its inhibitory effect on phosphodiesterase, resulting in the accumulation of intracellular cAMP [94]. The accumulation of cAMP levels leads to an augmentation in the activity of protein kinase A (PKA), which is known to decrease the TNF-α expression [92]. Several investigations have indicated that this accumulation inhibits TNF-α and IL-1 production in mononuclear phagocytes [94][95][96]. ...
Community-acquired pneumonia is reported as one of the infectious diseases that leads to the development of acute respiratory distress syndrome. The innate immune system is the first line of defence against microbial invasion; however, its dysregulation during infection, resulting in an increased pathogen load, stimulates the over-secretion of chemokines and pro-inflammatory cytokines. This phenomenon causes damage to the epithelial–endothelial barrier of the pulmonary alveoli and the leakage of the intravascular protein into the alveolar lumen. Fluoroquinolones are synthetic antimicrobial agents with immunomodulatory properties that can inhibit bacterial proliferation as well as exhibit anti-inflammatory activities. It has been demonstrated that the structure of fluoroquinolones, particularly those with a cyclopropyl group, exerts immunomodulatory effects. Its capability to inhibit phosphodiesterase activity leads to the accumulation of intracellular cAMP, which subsequently enhances PKA activity, resulting in the inhibition of transcriptional factor NF-κB and the activation of CREB. Another mechanism reported is the inhibition of TLR and ERK signalling pathways. Although the sequence of events has not been completely understood, significant progress has been made in comprehending the specific mechanisms underlying the immunomodulatory effects of fluoroquinolones. Here, we review the indirect immunomodulatory effects of FQs as an alternative to empirical therapy in patients diagnosed with community-acquired pneumonia.
... As explained earlier, pentoxifylline is a phosphodiesterase IV inhibitor that increases cAMP concentration; hence it can suppress inflammatory cytokines and oxidant agents and present antiinflammatory effects (28,30). In addition, pentoxifylline can inhibit nuclear factor kappa-B (NF-κB), a critical inflammation pathway, which reduces leucocyte/platelet interaction and decreases proinflammatory cytokines and ROS (31). Also, pentoxifylline can enhance the response of the A2A adenosine receptor to extracellular adenosine, which elevates cAMP in inflammatory cells and inhibits the inflammatory process (30,32). ...
Background: Inflammation has a remarkable role in Acute Respiratory Distress Syndrome (ARDS) pathophysiology. Pentoxifylline is a phosphodiesterase IV inhibitor with anti-inflammatory and anti-thrombotic properties, which has had positive results in rodents with ARDS. Due to the lack of human studies, we designed this clinical trial to evaluate the pentoxifylline effect on ARDS prevention in high-risk pediatric patients. Methods: We included thirty-four children from Akbar hospital’s pediatric intensive care unit (PICU). These patients were highly susceptible to ARDS progression. Using a randomized, double-blind method, 17 patients received pentoxifylline tablets three times a day for a week, while others received placebo tablets at the same interval for seven days. Lung Injury Prediction Score (LIPS), vital signs, pulse oximetry, PaO2, pH, and PaCO2 were measured at baseline and every day for a week period. CRP was assessed at baseline, then on the third and seventh days. Finally, we imported all the data to SPSS software to compare the treatment and placebo groups. Results: Each placebo and treatment group had seventeen patients who had no statistically significant difference in baseline demographic information or lab data. The variations in LIPS score (P=0.475), CRP (P=0.053), pH (P=0.199), PO2 (P=0.077), PCO2 (P=0.528), Heart rate (P=0.086), Respiratory rate (P=0.512), Diastolic blood pressure (P=0.572), Systolic blood pressure (P=0.517), and SPO2 (P=0.260) were compared between the two groups; and no significant difference was observed. Conclusion: The results of this clinical trial suggest that pentoxifylline had no prophylactic effect on pediatric ARDS, but for confirmation, further clinical trials with different designs and larger sample sizes are required.
... Thus, PDE4 inhibitors have been proven as anti-inflammatory agents against different pulmonary disorders by inhibiting the release of inflammatory signals and cytokines [9]. This inhibition has been addressed for diverse diseases [10], including inflammatory diseases [11], the topical treatment of psoriasis [12] and atopic dermatitis [13], cancer [14], inflammatory bowel diseases [15,16], neurological disorders [17], diabetic nephropathy [18], and pulmonary dysfunctions in COVID-19, such as chronic obstructive pulmonary disease (COPD) [19,20]. Several studies are being carried out on PDE4 inhibitors in order to understand their mechanism of action. ...
... From the data obtained with different degrees of exhaustiveness (4,8,12,14,16,20) for piclamilast and rolipram, we concluded that level 16 was the most favorable, which gave the results most similar to the experimentally obtained structure, and it was therefore chosen for the docking of all the synthetic compounds. ...
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus belonging to the coronavirus family responsible for coronavirus disease 2019 (COVID-19). It primarily affects the pulmonary system, which is the target of chronic obstructive pulmonary disease (COPD), for which many new compounds have been developed. In this study, phosphodiesterase 4 (PDE4) inhibitors are being investigated. The inhibition of PDE4 enzyme produces anti-inflammatory and bronchodilator effects in the lung by inducing an increase in cAMP concentrations. Piclamilast and rolipram are known selective inhibitors of PDE4, which are unfortunately endowed with common side effects, such as nausea and emesis. The selective inhibition of the phosphodiesterase 4B (PDE4B) subtype may represent an intriguing technique for combating this highly contagious disease with fewer side effects. In this article, molecular docking studies for the selective inhibition of the PDE4B enzyme have been carried out on 21 in-house compounds. The compounds were docked into the pocket of the PDE4B catalytic site, and in most cases, they were almost completely superimposed onto piclamilast. Then, in order to enlarge our study, drug-likeness prediction studies were performed on the compounds under study.
... Data were analyzed by unpaired, 2-tailed t test with Welch's correction or Mann-Whitney U test based on normality. Several of these genes, including phosphodiesterase 5A (PDE5A), CNKSR family member 3 (CNKSR3), angiopoietin-2 (ANGPT2), C-X3-C motif chemokine ligand 1 (CX3CL1), interferon regulatory factor 1 (IRF1), IL-1 receptor-associated kinase 2 (IRAK2), Ras association domain family member 2 (RASSF2), TNF-α-induced protein 2 (TNFAIP2), and c-c motif chemokine ligand-2 (CCL2) are known to play critical roles in cell death and/or ALI (21)(22)(23)(24)(25)(26) and their targeting by miR-1 is consistent with the miR-1 protective effects. We did further testing to validate the targeting of these genes. ...
... TNFAIP2 is induced during ALI and higher levels of TNFAIP2 in patients with septic shock is associated with decreased survival (24). PDE5, CX3CL1, and CCL2 are also activated in ALI and contribute to lung dysfunction during this process (22,23,26,75,76). Targeting of these genes by miR-1 confirms its protective role and suggests that miR-1 acts as an orchestrator of the endothelial injury response during ARDS. ...
Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung, and vascular endothelial growth factor (VEGF) is elevated in ARDS. We found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1), were reduced in the lung endothelium after acute injury. Pulmonary endothelial cell-specific (EC-specific) overexpression of miR-1 protected the lung against cell death and barrier dysfunction in both murine and human models and increased the survival of mice after pneumonia-induced ALI. miR-1 had an intrinsic protective effect in pulmonary and other types of ECs; it inhibited apoptosis and necroptosis pathways and decreased capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoietin-2 (ANGPT2), CNKSR family member 3 (CNKSR3), and TNF-α-induced protein 2 (TNFAIP2). We validated miR-1-mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate a previously unknown role of miR-1 as a cytoprotective orchestrator of endothelial responses to acute injury with prognostic and therapeutic potential.
... Therefore, sildenafil could potentially play major therapeutic roles in patients with specific perfusion patterns on sCTA [132]. (21) Recent research suggests that selective and nonselective PDE inhibitors could prove to be a potential intervention in the treatment of ARDS [133], which primarily causes COVID-19 fatalities as illustrated in Figure 1. These PDE5 inhibitors facilitate contraction and remodeling of smooth muscles of the airways and vasculature. ...
... These PDE5 inhibitors facilitate contraction and remodeling of smooth muscles of the airways and vasculature. They also participate in platelet function, neuronal conduction, and inflammatory and oxidative stress [133]. (22) Various PDE5 Inhibitors, such as sildenafil, tadalafil, and the nonselective inhibitor dipyridamole, can potentially be used as treatment options for chronic obstructive pulmonary disease and asthma [134]. ...
Introduction
Despite the ever-increasing occurrences of the coronavirus disease (COVID-19) cases around the world, very few medications have been validated in the clinical trials to combat COVID-19. Although several vaccines have been developed in the past quarter, the time elapsed between deployment and administration remains a major impediment.
Content
Repurposing of pre-approved drugs, such as phosphodiesterase 5 (PDE5) inhibitors, could be a game-changer while lessening the burden on the current healthcare system. Repurposing and developing phosphodiesterase 5 (PDE5) inhibitors could extrapolate their utility to combat the SARS-CoV-2 infection, and potentially aid in the management of the symptoms associated with its newer variants such as BF.7, BQ.1, BQ.1.1, XBB.1.5, and XBB.1.16.
Summary
Administration of PDE5 inhibitors via the oral and intravenous route demonstrates other potential off-label benefits, including anti-apoptotic, anti-inflammatory, antioxidant, and immunomodulatory effects, by intercepting several pathways. These effects can not only be of clinical importance in mild-to-moderate, but also moderate-to-severe SARS-CoV-2 infections. This article explores the various mechanisms by which PDE5 inhibitors alleviates the symptoms associated with COVID-19 as well as well as highlights recent studies and findings.
Outlook
These benefits of PDE5 inhibitors make it a potential drug in the physicians’ armamentarium in alleviating symptoms associated with SARS-CoV-2 infection. However, adequate clinical studies must be instituted to eliminate any untoward adverse events.
... Therefore, sildenafil could potentially play major therapeutic roles in patients with specific perfusion patterns on sCTA [132]. (21) Recent research suggests that selective and nonselective PDE inhibitors could prove to be a potential intervention in the treatment of acute respiratory distress syndrome (ARDS) [133], which primarily causes COVID-19 fatalities as illustrated in Figure 1. These PDE5 inhibitors facilitate contraction and remodeling of smooth muscles of the airways and vasculature. ...
... These PDE5 inhibitors facilitate contraction and remodeling of smooth muscles of the airways and vasculature. They also participate in platelet function, neuronal conduction, and inflammatory and oxidative stress [133]. (22) Various PDE5 Inhibitors, such as sildenafil, tadalafil, and the nonselective inhibitor dipyridamole, can potentially be used as treatment options for chronic obstructive pulmonary disease and asthma [134]. ...
Introduction:
Despite the ever-increasing occurrences of the coronavirus disease (COVID-19) cases around the world, very few medications have been validated in the clinical trials to combat COVID-19. Although several vaccines have been developed in the past quarter, the time elapsed between deployment and administration remains a major impediment.
Content:
Repurposing of pre-approved drugs, such as phosphodiesterase 5 (PDE5) inhibitors, could be a game-changer while lessening the burden on the current healthcare system. Repurposing and developing phosphodiesterase 5 (PDE5) inhibitors could extrapolate their utility to combat the SARS-CoV-2 infection, and potentially aid in the management of the symptoms associated with its newer variants such as BF.7, BQ.1, BQ.1.1, XBB.1.5, and XBB.1.16.
Summary:
Administration of PDE5 inhibitors via the oral and intravenous route demonstrates other potential off-label benefits, including anti-apoptotic, anti-inflammatory, antioxidant, and immunomodulatory effects, by intercepting several pathways. These effects can not only be of clinical importance in mild-to-moderate, but also moderate-to-severe SARS-CoV-2 infections. This article explores the various mechanisms by which PDE5 inhibitors alleviates the symptoms associated with COVID-19 as well as well as highlights recent studies and findings.
Outlook:
These benefits of PDE5 inhibitors make it a potential drug in the physicians' armamentarium in alleviating symptoms associated with SARS-CoV-2 infection. However, adequate clinical studies must be instituted to eliminate any untoward adverse events.
... Furthermore, the ethanol-water extract and the aqueous fraction had an antispasmodic effect against acetylcholine-induced contractions, and the water fraction abrogated potassium ions-induced contraction. Quercetin, 2"-Ogalloylhyperoside, and hyperoside flavonoids were found to be responsible for an impact on smooth muscle, as they accelerated CBF, exerted an inhibitory effect on phosphodiesterases [143], enzymes involved in airway dilatation, vascular and airway smooth muscle contraction, and remodeling, and participated in the regulation of inflammation [144]. ...
Since Charles Darwin and his book carnivorous plants have aroused interest and heated debate. In addition, there is growing interest in this group of plants as a source of secondary metabolites and in the application of their biological activity. The aim of this study was to trace the recent literature in search of the application of extracts obtained from families Droseraceae, Nepenthaceae, and Drosophyllaceae to show their biological potential. The data collected in the review clearly indicate that the studied Nepenthales species have great biological potential in terms of antibacterial, antifungal, antioxidant, anti-inflammatory, and anticancer use. We proposed that further investigations should include: (i) bioactivity-guided investigations of crude plant extract to connect a particular type of action with a specific compound or a group of metabolites; (ii) a search for new bioactive properties of carnivorous plants; (iii) establishment of molecular mechanisms associated with specific activity. Furthermore, further research should be extended to include less explored species, i.e., Drosophyllum lusitanicum and especially Aldrovanda vesiculosa.
... However, nonselective inhibitors of PDEs as Theophylline has been used in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD) for more than 50 years. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelialendothelial barrier and reduction the sepsis-and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters [117]. ...
Background:
This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction.
Methods:
The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework.
Results:
Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability.
Discussion:
Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis.
Conclusion:
A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.
... Effects of PDE inhibitors may be selective, influencing solely one PDE, or non-selective, influencing more PDEs, much as a group of medicaments named methylxanthines. Methylxanthines act through various mechanisms including non-selective PDE inhibition, what is responsible for a wide variety of actions of these drugs [16]. For instance, caffeine is used because of its stimulatory effects on respiration, cognition, and attention while theophylline and theobromine are used in the treatment of bronchial asthma and chronic obstructive pulmonary disease due to their bronchorelaxation, vasorelaxation, and cardiostimulation effects [17,18]. ...
... This may be attributable to the fact that increased intracellular secondary messenger cAMP due to activation of adenylyl cyclase affects a broad spectrum of cellular functions; modulates transcription factor nuclear factor-kappa B (NF-κB) and expression of pro-inflammatory cytokines (e.g. IL-1, IL-6, IL-12, IL-13, and TNFα) and regulates expression of antiinflammatory interleukins [16,[42][43][44]. In addition, significantly decreased level of anti-inflammatory cytokine IL-10 was found in the lung tissue of ARDS animals, likely due to an imbalance between anti-inflammatory response and serious inflammatory response in ARDS animals [45]. ...
Acute respiratory distress syndrome (ARDS) is a common complication of critical illness characterized by lung inflammation, epithelial and endothelial dysfunction, alveolar-capillary leakage, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory effects of non-selective phosphodiesterase (PDE) inhibitor aminophylline. New Zealand white rabbits were randomly divided into 3 groups: animals with respiratory failure defined as PaO2/FiO2 ratio (P/F) below < 26.7 kPa, and induced by saline lung lavage (ARDS), animals with ARDS treated with intravenous aminophylline (1 mg/kg; ARDS/AMINO), and healthy ventilated controls (Control). All animals were oxygen ventilated for an additional 4 h and respiratory parameters were recorded regularly. Post mortem, the lung tissue was evaluated for oedema formation, markers of inflammation (tumor necrosis factor, TNFα, interleukin (IL)-1β, -6, -8, -10, -13, -18), markers of epithelial damage (receptor for advanced glycation end products, RAGE) and endothelial injury (sphingosine 1-phosphate, S1P), oxidative damage (thiobarbituric acid reactive substances, TBARS, 3-nitrotyrosine, 3NT, total antioxidant capacity, TAC). Aminophylline therapy decreased the levels of pro-inflammatory cytokines, markers of epithelial and endothelial injury, oxidative modifications in lung tissue, reduced lung oedema, and improved lung function parameters compared to untreated ARDS animals. In conclusion, non-selective PDE inhibitor aminophylline showed a significant anti-inflammatory activity suggesting a potential of this drug to be a valuable component of ARDS therapy.
