scholarly journals Multiorgan Drug Action of Levosimendan in Critical Illnesses

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Jian Pan ◽  
Yun-Mei Yang ◽  
Jian-Yong Zhu ◽  
Yuan-Qiang Lu
Keyword(s):  
Clinical Trials ◽  
Intracellular Calcium ◽  
Myocardial Contractility ◽  
Phosphodiesterase Inhibitors ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
New Drugs ◽  
Ion Concentration ◽  
Research Progress ◽  
Calcium Sensitizers

Cardiotonic drugs mainly include digitalis, catecholamines, phosphodiesterase inhibitors, and calcium sensitizers, which have been successively discovered and applied in clinical practice. However, there are only a few new drugs available in this field, and the selection is very limited. Digitalis, catecholamines, and phosphodiesterase inhibitors increase myocardial contractility by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP) and Ca2+, and this increase in intracellular calcium ion concentration enhances myocardial oxygen consumption and causes arrhythmia. For these reasons, the research focus on positive inotropic agents has shifted from calcium mobilization to calcium sensitization. Intracellular calcium sensitizers are more effective and safer drugs because they do not increase the intracellular concentration of calcium ions. However, only three calcium sensitizers have been fully developed and used in the past three decades. One of these drugs, levosimendan, has multiple molecular targets and exerts its pharmacological effects by not only increasing myocardial contractility, but also enhancing respiratory muscle function and liver and kidney protection, and it is useful for patients with severe sepsis and septic shock. Recently, more than 60 randomized controlled clinical trials of levosimendan have been reported; however, these clinical trials have occasionally shown different findings. This article reviews the research progress of levosimendan in critical illnesses in recent years.

scholarly journals Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

2021 ◽  
Vol 22 (4) ◽  
pp. 1929
Author(s):  
Daniela Mokra ◽  
Juraj Mokry
Keyword(s):  
Length Of Hospital Stay ◽  
Phosphodiesterase Inhibitors ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Pharmacological Action ◽  
Lung Damage ◽  
Lung Protective Ventilation ◽  
Ventilatory Parameters ◽  
Pde Inhibitors ◽  
Supportive Interventions

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. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial–endothelial 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. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.

scholarly journals Imiquimod: the biochemical mechanisms of immunomodulatory and anti-inflammatory activity

2013 ◽  
Vol 59 (3) ◽  
pp. 249-266 ◽  
Author(s):  
S.V. Bozrova ◽  
V.A. Levitsky ◽  
S.A. Nedospasov ◽  
M.S. Drutskaya
Keyword(s):  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Direct Interaction ◽  
Cyclic Adenosine Monophosphate ◽  
Clinical Effectiveness ◽  
Adenosine Monophosphate ◽  
New Drugs ◽  
Published Data ◽  
Biochemical Basis ◽  
Immune Modulators

Imidazoquinolins represent a new group of compounds that recently entered into clinical practice as anti-tumor and anti-viral immune modulators. They are low molecular weight synthetic guanosine-like molecules. Although imiquimod, the most widely used imidazoquinolin, is recommended for the treatment of several forms of skin cancer and papillomas, the molecular mechanisms of its action are not fully understood. In particular, imiquimod has been characterized as a specific agonist of Toll-like receptor 7 (TLR7) and is widely used in this capacity in a large number of experimental studies and clinical trials. However, detailed analysis of the published data with the use of imiquimod, suggests that its biological activity can not be explained only by interaction with TLR7. There are indications of a direct interaction of imiquimod with adenosine receptors and other molecules that regulate the synthesis of cyclic adenosine monophosphate. A detailed understanding of the biochemical basis of imiquimod immunomodulating and antitumor effect will increase its clinical effectiveness and accelerate the development of new drugs with similar but improved medical properties. This review summarizes the published data concerning the effects of imiquimod on a variety of intracellular biochemical processes and signaling pathways.

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