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Food and Chemical Toxicology : An... Dec 2019Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic... (Review)
Review
Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the second messengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involvement in diverse medical conditions, e.g. cardiovascular diseases, autoimmune diseases, Alzheimer's disease (AD), etc. Among them; AD with a complex pathology is a progressive neurodegenerative disorder which affect mostly senile people in the world and only symptomatic treatment particularly using cholinesterase inhibitors in clinic is available at the moment for AD. Consequently, novel treatment strategies towards AD are still searched extensively. Since PDEs are broadly expressed in the brain, PDEIs are considered to modulate neurodegenerative conditions through regulating cAMP and cGMP in the brain. In this sense, several synthetic or natural molecules inhibiting various PDE subtypes such as rolipram and roflumilast (PDE4 inhibitors), vinpocetine (PDE1 inhibitor), cilostazol and milrinone (PDE3 inhibitors), sildenafil and tadalafil (PDE5 inhibitors), etc have been reported showing encouraging results for the treatment of AD. In this review, PDE superfamily will be scrutinized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy.
Topics: Alzheimer Disease; Animals; Humans; Phosphodiesterase Inhibitors
PubMed: 31536753
DOI: 10.1016/j.fct.2019.110822 -
Expert Opinion on Drug Safety Apr 2020: Apremilast is an oral phosphodiesterase inhibitor, approved for moderate to severe psoriasis in adults. Despite the advancement in dermatology, and the introduction of... (Review)
Review
: Apremilast is an oral phosphodiesterase inhibitor, approved for moderate to severe psoriasis in adults. Despite the advancement in dermatology, and the introduction of newer biological drugs, apremilast this is the only novel oral medication that has been introduced to treat psoriasis in the past two decades. Like additional other more traditional oral medications, its advantages and disadvantages should be discussed and compared within this group of oral-systemic medications.: We conducted a review to assess the safety, efficacy, and adherence of apremilast for psoriasis treatment. The aim of this paper was to provide an overview of apremilast regarding its mechanism of action, indications, and adverse events.: Apremilast has been found to be a safe and efficacious drug for moderate-to-severe psoriasis, and despite minor numerous side effects, most of the patients adhere to the therapy. Therefore, overall, it may be easily embraced as the drug of choice for this category. However, for more severe psoriasis cases newer biological drugs seem to be superior to apremilast.
Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Humans; Medication Adherence; Phosphodiesterase 4 Inhibitors; Psoriasis; Thalidomide
PubMed: 32182143
DOI: 10.1080/14740338.2020.1744562 -
Expert Opinion on Therapeutic Patents Jul 2017Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing... (Review)
Review
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing interest in recent years because both the enzyme ATX and the bioactive lipid LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity and impaired glucose homeostasis. Thus, a great effort has been devotd in developing synthetic ATX inhibitors as new agents to treat various diseases including cancer and fibrotic diseases. Areas covered: This review article summarizes the autotaxin inhibitors presented in patent literature from October 2012 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo. Expert opinion: During the recent years, there has been an intensive effort on the discovery of potent and selective ATX inhibitors. Although various synthetic inhibitors have been developed, only limited studies for their in vivo activity have been reported so far. A decade after the first claim of synthetic ATX inhibitors in 2006, one inhibitor has been in clinical trials for idiopapthic pulmonary fibrosis. The use of ATX inhibitors seems an attractive strategy to produce novel medicinal agents, for example anticancer agents.
Topics: Animals; Antineoplastic Agents; Drug Design; Humans; Idiopathic Pulmonary Fibrosis; Lysophospholipids; Neoplasms; Patents as Topic; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
PubMed: 28447479
DOI: 10.1080/13543776.2017.1323331 -
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 -
Journal of Experimental & Clinical... Aug 2023Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA stimulates cell proliferation and migration and promotes...
BACKGROUND
Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA stimulates cell proliferation and migration and promotes wound repair following tissue damage. ATX levels are directly correlated with stage and grade in several human cancers. Several small molecule ATX inhibitors have been developed in recent years. IOA-289 is a potent ATX inhibitor, developed to treat cancers containing fibrosis. In this study, we tested IOA-289 treatment on different gastrointestinal tract tumor cell lines, in order to evaluate its effects on viability and motility.
METHODS
To determine the effects on cell viability and proliferation of treatment with increasing concentrations of IOA-289, we used the crystal violet assay, a clonogenic assay in matrigel, and we evaluated the inhibitor's effect on formation of 3D spheroids in an in vitro model. The effect of IOA-289 on cell cycle phases was analysed with a redox dye reagent. Cell migration capacity was evaluated by wound healing assay and transwell migration assay. To evaluate the pro-apoptotic effect of the inhibitor, cells were stained with Annexin V and immunofluorescence and flow cytometry analysis were performed. An antibody array was also used, to discriminate, in various samples, the differential expression of 43 proteins involved in the apoptosis pathway.
RESULTS
We found that IOA-289 is able to inhibit both growth and migration of gastrointestinal tract tumor cell lines, both in 2D (crystal violet assay) and 3D in vitro models (spheroid formation and clonogenic assay in matrigel). This effect is dose-dependent, and the drug is most effective when administered in FBS-free culture medium. The inhibitory effect on cell growth is due to a pro-apoptotic effect of IOA-289. Staining with FITC-conjugated Annexin V showed that IOA-289 induced a dose-dependent increase in fluorescence following incubation for 24 h, and apoptotic cells were also distinguished in flow cytometry using Annexin/PI staining. The antibody array shows that treatment with IOA-289 causes the increased expression of several pro-apoptotic proteins in all tested cell lines.
CONCLUSIONS
These results indicate that IOA-289 may be an effective drug for the treatment of tumors of the gastrointestinal tract, particularly those characterized by a high degree of fibrosis.
Topics: Humans; Annexin A5; Cell Line, Tumor; Fibrosis; Gastrointestinal Neoplasms; Phosphoric Diester Hydrolases; Phosphodiesterase Inhibitors; Drug Evaluation, Preclinical
PubMed: 37550785
DOI: 10.1186/s13046-023-02780-4 -
Expert Opinion on Investigational Drugs Oct 2016Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive axonal loss.... (Review)
Review
INTRODUCTION
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive axonal loss. Clinically, this is manifest as relapsing and remitting neurological symptoms and progressive accumulation of disability. Ibudilast is a nonselective phosphodiesterase inhibitor which works by blocking the cleavage of cyclic adenosine monophosphate (cAMP). It has been found to have anti-inflammatory and neuroprotective properties in animal studies and in-vitro studies; it is currently being studied in progressive MS.
AREAS COVERED
This article reviews various studies looking at ibudilast as a potential therapy for MS. It summarizes prior and current clinical trials of ibudilast in MS as well as its pharmacology.
EXPERT OPINION
Although ibudilast has not been found to decrease the focal inflammatory activity in relapsing MS, it was shown to have an effect on preserving brain volume and disability progression. Ibudilast may have a role in the treatment of progressive MS phenotypes.
Topics: Animals; Anti-Inflammatory Agents; Brain; Disease Progression; Humans; Multiple Sclerosis; Neuroprotective Agents; Phosphodiesterase Inhibitors; Pyridines
PubMed: 27501293
DOI: 10.1080/13543784.2016.1221924 -
Current Pharmaceutical Design 2015Cyclic AMP and cyclic GMP are essential second messengers that regulate multiple signaling pathways in virtually all cell types. Their accumulation in cells is finely... (Review)
Review
Cyclic AMP and cyclic GMP are essential second messengers that regulate multiple signaling pathways in virtually all cell types. Their accumulation in cells is finely regulated by cyclic nucleotide phosphodiesterases (PDEs), the only enzymes that can degrade these signaling molecules and thus provide exquisite control over intracellular signaling processes. One PDE family, PDE10A, is highly enriched in the brain and its unique expression profile in specific brain regions of interest, in particular to antipsychotic treatment, has made it an attractive therapeutic target for the treatment of schizophrenia. However, after a Phase II trial failure of a selective PDE10A inhibitor for the treatment of schizophrenia, it has encouraged the field to reexamine the role of this enzyme in the brain, and the possible CNS disorders in which PDE10A inhibition could be therapeutic. We will review the localization of PDE10A, both within the brain and the neuron and discuss how its role in regulating cAMP and cGMP accumulation modulates intracellular signaling pathways. Since this cellular signaling has best been documented in the striatum, we will focus our discussion of PDE10A in the context of disorders that affect the basal ganglia, including psychiatric disorders such as bipolar disorder and autism spectrum disorders and the movement disorders, including Parkinson's disease and Huntington's disease.
Topics: Brain Diseases; Clinical Trials as Topic; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Signal Transduction
PubMed: 25159072
DOI: 10.2174/1381612820666140826114744 -
The Journal of Sexual Medicine Jul 2023
Topics: Male; Humans; Phosphodiesterase 5 Inhibitors; Tamoxifen; Penile Induration; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride; Triazines
PubMed: 37524687
DOI: 10.1093/jsxmed/qdad083 -
International Journal of Molecular... Mar 2017A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are... (Review)
Review
A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.
Topics: Animals; Central Nervous System; Central Nervous System Diseases; Cyclic AMP; Cyclic GMP; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Regeneration; Second Messenger Systems; Signal Transduction
PubMed: 28338622
DOI: 10.3390/ijms18040696 -
Journal of Natural Medicines Jun 2020Agarwood has been used as an incense and in traditional medicines as aphrodisiac, sedative, cardiotonic, and carminative. In this study, five new...
Agarwood has been used as an incense and in traditional medicines as aphrodisiac, sedative, cardiotonic, and carminative. In this study, five new 2-(2-phenylethyl)chromones (2, 13-16) and eleven known compounds (1, 3-12) were isolated from the agarwood. The structures of the new compounds were determined by H-, C-, and two-dimensional NMR together with electronic circular dichroism (ECD) spectroscopy. All isolated compounds were evaluated for the phosphodiesterase (PDE) 3A and 5A1 inhibitory activity by the fluorescence polarization method. Dimeric 2-(2-phenylehyl)chromones (13, 14, 16) had potent inhibitory activity to PDE 5A1 with IC values of micro molar range (13: 4.2 μM, 14: 7.9 μM, 16: 4.3 μM), whereas they had weak activity to PDE 3A. In contrast, compound (15), which has a phenylpropionic acid moiety instead of the 2-(2-phenylethyl)chromone moiety in the dimers, showed moderate inhibition of both PDE 3A (IC: 42.6 μM) and PDE 5A1 (IC: 15.1 μM).
Topics: Chromones; Flavonoids; Molecular Structure; Phosphodiesterase Inhibitors; Plant Extracts; Thymelaeaceae
PubMed: 32335822
DOI: 10.1007/s11418-020-01410-z