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Drugs of Today (Barcelona, Spain : 1998) Apr 2017Atopic dermatitis (AD) is an extremely common condition affecting as many as 10-20% of children and 2-10% of adults. A particularly distressing symptom of AD is... (Review)
Review
Atopic dermatitis (AD) is an extremely common condition affecting as many as 10-20% of children and 2-10% of adults. A particularly distressing symptom of AD is pruritus. One of the important aspects of AD is inflammation associated with increased activity of phosphodiesterase 4 (PDE4), resulting in decreased intracellular levels of cyclic adenosine monophosphate, which in turn causes increased production of inflammatory cytokines. Crisaborole was developed as a small-molecule, boron-based, selective PDE4 inhibitor that can be used topically. Clinical trials have demonstrated its efficacy in treating patients with mild to moderate AD, resulting in significant relief of pruritus. Unlike PDE4 inhibitors that act systemically, crisaborole does not cause significant gastrointestinal adverse effects. The most common adverse effect has been temporary stinging and burning in about 4% of patients upon application of the 2% ointment. To date there is no evidence of atrophy, telangiectasia or hypopigmentation resulting from its use. Crisaborole is the first topically applied PDE4 inhibitor to be approved by the FDA for use in AD.
Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Dermatitis, Atopic; Humans; Phosphodiesterase Inhibitors
PubMed: 28492291
DOI: 10.1358/dot.2017.53.4.2604174 -
Postepy Higieny I Medycyny... Mar 2017Ibudilast (IBD) is a non‑selective (3, 4, 10, 11) phosphodiesterase (PDE) inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a... (Review)
Review
Ibudilast (IBD) is a non‑selective (3, 4, 10, 11) phosphodiesterase (PDE) inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response) by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro‑inflammatory cytokines (IL‑6, IL‑1β, TNF‑α), toll‑like receptor 4 blockade (TLR‑4), inhibition of a macrophage migration inhibitory factor (MIF), up‑regulation the anti‑inflammatory cytokine (IL‑10), and promotion of neurotrophic factors (GDNF, NGF, NT‑4). Recent data indicate that the efficacy of IBD appears to be independent from PDE inhibition activity and rather linked to glial activity attenuation. Additional advantages of IBD, such as crossing the blood-brain barrier, good tolerance and activity by oral administration, makes it a promising therapeutic candidate for treating neuroinflammatory conditions, where the currently available treatment remains unsatisfying due to poor tolerability and/or sub‑optimal efficacy. IBD has no direct receptor affinity with exemption of some undefined effect on adenosine receptors that makes the drug devoid of its receptors‑mediated adverse effects. Current article provides an overview of the pharmacology of IBD with a focus on preclinical and clinical data supporting its potential neuroprotective benefits for neurological conditions, including multiple sclerosis, neuropathic pain, medication overuse headache, stroke, opioid, alcohol and methamphetamine abuse.
Topics: Animals; Brain Diseases; Brain Edema; Brain Infarction; Humans; Nervous System Diseases; Neurons; Phosphodiesterase Inhibitors; Pyridines
PubMed: 28258674
DOI: No ID Found -
The Journal of Rheumatology Apr 1995
Review
Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Humans; Pentoxifylline; Phosphodiesterase Inhibitors; Rheumatic Diseases
PubMed: 7791149
DOI: No ID Found -
Drug Design, Development and Therapy Jul 2010In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4... (Review)
Review
In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4 inhibitor, for the "maintenance treatment of severe chronic obstructive pulmonary disease (COPD, FEV(1) postbronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment". This decision was based, in part, on the results of several large, international, multicenter, randomized, placebo-controlled trials of either six or 12 months' duration that had been undertaken in COPD patients. Roflumilast 500 mug daily improved lung function and reduced exacerbations in patients with more severe COPD, especially those with chronic bronchitis, frequent exacerbations, or who required frequent rescue inhaler therapy in the placebo-controlled trials. It also improved lung function and reduced exacerbations in patients with moderately severe COPD treated with salmeterol or tiotropium. Advantages of roflumilast over inhaler therapy are that it is an oral tablet and only needs to be taken once daily. While taking roflumilast, the most common adverse effects patients experienced were gastrointestinal upset and headache. Weight loss, averaging 2.2 kg, occurred in patients treated with roflumilast. Patients taking roflumilast were more likely to drop out of the trials than patients in the control groups. Patients who discontinued therapy usually did so during the first few weeks and were more likely to have experienced gastrointestinal side effects. Roflumilast is the first selective phosphodiesterase 4 inhibitor and will offer physicians another treatment option for patients with more severe COPD.
Topics: Adult; Aminopyridines; Animals; Benzamides; Cyclopropanes; Humans; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Severity of Illness Index
PubMed: 20689641
DOI: 10.2147/dddt.s7667 -
BJU International Apr 2003
Review
Topics: Carbolines; Erectile Dysfunction; Humans; Imidazoles; Male; Patient Compliance; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride
PubMed: 12656917
DOI: 10.1046/j.1464-410x.2003.04115.x -
The Korean Journal of Internal Medicine Jun 2012
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hypoxia; Kidney Tubules; Male; Pentoxifylline; Phosphodiesterase Inhibitors
PubMed: 22707885
DOI: 10.3904/kjim.2012.27.2.151 -
Journal of Molecular Modeling Dec 2021Understanding the selectivity mechanism of inhibitors towards homology proteins helps to design selective candidates. Phosphodiesterase (PDE) family members act in the...
Understanding the selectivity mechanism of inhibitors towards homology proteins helps to design selective candidates. Phosphodiesterase (PDE) family members act in the degradation of cAMP and cGMP, among which some isoforms such as PDE9A are attracting interest for Alzheimer's disease treatment, while PDE10A is used as target for treating schizophrenia. In this study, computational methods were used to investigate the major features of PDE9A/10A, with the purpose to provide deep understanding of the molecular mechanism of selective inhibition towards these two isoforms. Our result revealed that two conserved residues Gln453 and Phe456 were proven to be crucial for the binding affinity and inhibitory selectivity of PDE9A inhibitors. In addition, the high-affinity PDE9A inhibitors always interact with the conservative hydrophobic pocket as well as Tyr424 and Ala452 of PDE9A, while PDE10A selective inhibitors need to have two hydrophobic groups and two hydrogen bond donors to interact with the conservative Tyr693, Gln726, and Phe729 of PDE10A. This study provides valuable insights into the underlying mechanism of selective inhibition targeting PDE9A and PDE10A, for further search for potent and highly selective PDE9A/10A inhibitors.
Topics: Algorithms; Amino Acid Sequence; Catalytic Domain; Humans; Isoenzymes; Models, Molecular; Molecular Conformation; Molecular Structure; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Protein Binding; Structure-Activity Relationship
PubMed: 34907481
DOI: 10.1007/s00894-021-04934-7 -
Cardiovascular Drug Reviews 2002Olprinone is a newly developed phosphodiesterase III inhibitor characterized by several properties. First, olprinone has positive inotropic and vasodilator actions and... (Review)
Review
Olprinone is a newly developed phosphodiesterase III inhibitor characterized by several properties. First, olprinone has positive inotropic and vasodilator actions and improves myocardial mechanical efficiency. Second, olprinone augments cerebral blood flow by a direct vasodilatory effect on cerebral arteries. The cerebrovascular reactivity to olprinone is marked in patients with impaired cerebral circulation. Third, olprinone selectively improves carotid artery distensibility, which may be attributable to differences in the arterial structural components or the reactivity of smooth muscle cells to olprinone. Fourth, olprinone improves inadequate redistribution of brain perfusion and may prevent cerebral metabolic abnormalities in heart failure.
Topics: Carotid Arteries; Cerebrovascular Circulation; Heart Failure; Humans; Imidazoles; Muscle, Smooth, Vascular; Myocardial Contraction; Phosphodiesterase Inhibitors; Pyridones; Treatment Outcome; Vasodilation
PubMed: 12397365
DOI: 10.1111/j.1527-3466.2002.tb00085.x -
International Journal of Impotence... 2007Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their... (Review)
Review
Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) relationships and their relevance to dose selection and applied pharmacotherapy. It is followed by a detailed comparative discussion on the pharmacokinetics and exposure-response relationship of the currently available PDE5 inhibitors, including known drug-drug interactions and dosage adjustments in special populations. The review is aimed at providing a critical assessment of the pharmacokinetics of PDE5 inhibitors, which may assist clinicians in tailoring drug and/or treatment regimens to the unique needs of each individual patient with erectile dysfunction.
Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors
PubMed: 16988721
DOI: 10.1038/sj.ijir.3901522 -
Current Medical Research and Opinion Dec 2007Erectile dysfunction (ED) is increasingly being recognized as a sentinel marker of future subsequent cardiovascular disease (CVD). Predicted increases in the prevalence... (Review)
Review
BACKGROUND
Erectile dysfunction (ED) is increasingly being recognized as a sentinel marker of future subsequent cardiovascular disease (CVD). Predicted increases in the prevalence of ED are due to a combination of an aging population and the increasing presence of comorbid conditions (hypertension, dyslipidemia, and diabetes). The dichotomy of the situation is that ED is often associated with these comorbidities, potentially leading to greater CVD risk, and conversely, these comorbidities have also been shown to increase the risk of developing ED. The successful treatment of ED with phosphodiesterase type 5 (PDE5) inhibitor therapy, therefore, is of paramount importance because it not only plays a critical role in restoring erectile function, but also provides clinicians with the opportunity to mitigate existing cardiovascular comorbidities or prevent the occurrence of CVD in this patient population.
METHODS
This review is based on an electronic literature search of databases, including MEDLINE/PubMed, with information selected for its relevance to PDE5 inhibitor therapy comprising efficacy (e.g., first-dose success) in men with ED with or without comorbidities, onset and duration of action at specific time points, and patient preference.
RESULTS
The introduction of PDE5 inhibitors represented a major advance in the treatment of ED. In spite of the availability of these agents, a large percentage of men are still not being treated, in many cases because of their reluctance to seek medical help. Moreover, many men who start treatment with PDE5 inhibitors discontinue treatment. Reasons for discontinuation are many and complex, including lack of initial or first-time success. Although of major concern to both patients and clinicians, there remains limited published clinical data on this specific parameter in the pertinent patient population and from prospective, randomized clinical studies.
CONCLUSION
Data from studies suggests that the available PDE5 inhibitor therapies are effective in treating men with ED, including those who have increased CVD risk and those who have clinically identified cardiovascular comorbidities such as hypertension, dyslipidemia, and/or diabetes. According to data from studies, the attributes of PDE5 inhibitor therapy that matter more to clinicians and patients and that hold influence over treatment compliance include effectiveness in patients with cardiovascular comorbidities, first dose effectiveness or early success, rapid onset of action, reliability, and tolerability.
Topics: Cardiovascular Diseases; Erectile Dysfunction; Humans; Male; Patient Selection; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Treatment Outcome
PubMed: 17991309
DOI: 10.1185/030079907X242656