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Journal of Translational Medicine Sep 2023Non-union formation represents a major complication in trauma and orthopedic surgery. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been shown to exert...
Non-union formation represents a major complication in trauma and orthopedic surgery. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been shown to exert pro-angiogenic and pro-osteogenic effects in vitro and in vivo. Therefore, the aim of the present study was to analyze the impact of sildenafil in an atrophic non-union model in mice. After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. Bone regeneration was analyzed by means of X-ray, biomechanics, photoacoustic and micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses at 2, 5 and 10 weeks after surgery. The animals were treated daily with either 5 mg/kg body weight sildenafil (n = 35) or saline (control; n = 35) per os. Bone formation was markedly improved in defects of sildenafil-treated mice when compared to controls. This was associated with a higher bending stiffness as well as an increased number of CD31-positive microvessels and a higher oxygen saturation within the callus tissue. Moreover, the bone defects of sildenafil-treated animals contained more tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD68-positive macrophages and exhibited a higher expression of the pro-angiogenic and pro-osteogenic markers cysteine rich protein (CYR)61 and vascular endothelial growth factor (VEGF) when compared to controls. These findings demonstrate that sildenafil acts as a potent stimulator of angiogenesis and bone regeneration in atrophic non-unions.
Topics: Animals; Mice; Sildenafil Citrate; Phosphodiesterase 5 Inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 5; Vascular Endothelial Growth Factor A; X-Ray Microtomography; Bone Regeneration; Atrophy
PubMed: 37684656
DOI: 10.1186/s12967-023-04441-8 -
Pediatric Annals Mar 2020Atopic dermatitis (AD) is the most common inflammatory skin condition in pediatric patients. AD has long been associated with comorbidities including food allergies,... (Review)
Review
Atopic dermatitis (AD) is the most common inflammatory skin condition in pediatric patients. AD has long been associated with comorbidities including food allergies, asthma, and allergic rhinitis, but recent literature has expanded this list to include attention-deficit/hyperactivity disorder and depression. AD has tremendous impact on quality of life for both affected children and their families. Improved understanding of AD pathogenesis, particularly regarding skin barrier dysfunction, the role of the cutaneous microbiome, and immune dysregulation, has spawned exciting new therapeutic directions. Although good skin care and appropriate use of topical corticosteroids remain first-line treatment, more precisely targeted treatments hold great promise. A recently approved topical phosphodiesterase inhibitor, crisaborole, and a subcutaneously administered interleukin-4/interleukin-13 blocker, dupilumab, are the first of what will likely be many new treatment options for patients with AD. [Pediatr Ann. 2020;49(3):e140-e146.].
Topics: Antibodies, Monoclonal, Humanized; Asthma; Child; Comorbidity; Dermatitis, Atopic; Food Hypersensitivity; Humans; Phosphodiesterase Inhibitors; Quality of Life; Rhinitis, Allergic
PubMed: 32155280
DOI: 10.3928/19382359-20200217-01 -
Current Topics in Medicinal Chemistry 2016Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby regulating the cyclic nucleotide signalling pathways and biological responses. PDEs... (Review)
Review
Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby regulating the cyclic nucleotide signalling pathways and biological responses. PDEs inhibitors can be used clinically for treatment of several diseases including central nervous system disorders, erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, and inflammatory diseases such as chronic obstructive pulmonary disease. However, the unfavourable risk-benefit ratio and side-effect profiles of non-selective PDEs inhibitors have impeded their therapeutic success and therefore spurred the pharmaceutical industry to develop family-selective PDE inhibitors. Given the recent remarkable advances in structure-based drug design, this review will summarize developments and achievements in structure-based search, design and optimization of PDEs inhibitors, and highlight the challenges that need to be addressed.
Topics: Animals; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Structure-Activity Relationship
PubMed: 26303429
DOI: 10.2174/1568026615666150825142134 -
Expert Review of Clinical Pharmacology Apr 2017Psoriasis is a chronic inflammatory skin disease characterized by erythematous plaques on extensor surfaces, scalp, and back. Current therapies for psoriasis are limited... (Review)
Review
Psoriasis is a chronic inflammatory skin disease characterized by erythematous plaques on extensor surfaces, scalp, and back. Current therapies for psoriasis are limited by route of administration, side effects, and cost. Apremilast is the first oral phosphodiesterase inhibitor approved for moderate-to-severe plaque psoriasis. It is a small molecule inhibitor of phosphodiesterase-4, and decreases the inflammatory activity associated with psoriasis. Areas covered: This review will discuss the pharmacology of apremilast, mechanism of action, results from key clinical trials, and its use in managing psoriasis. Currently approved treatments are also discussed. Expert commentary: The advantages of apremilast include convenient oral administration and dosing, a favorable safety and tolerability profile, and significant efficacy in moderate-to-severe plaque psoriasis.
Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Humans; Phosphodiesterase 4 Inhibitors; Psoriasis; Severity of Illness Index; Thalidomide
PubMed: 28276777
DOI: 10.1080/17512433.2017.1293519 -
Respiratory Physiology & Neurobiology Nov 2018A group of 11 enzyme families of metalophosphohydrolases called phosphodiesterases (PDEs) is responsible for a hydrolysis of intracellular cAMP and cGMP. Xanthine... (Review)
Review
A group of 11 enzyme families of metalophosphohydrolases called phosphodiesterases (PDEs) is responsible for a hydrolysis of intracellular cAMP and cGMP. Xanthine derivatives (methylxanthines) inhibit PDEs without selective action on their single isoforms and lead to many pharmacological effects, e.g. bronchodilation, anti-inflammatory and immunomodulating effects, and thus they can modulate the cough reflex. Contrary, selective PDE inhibitors have been developed to inhibit PDE isoforms with different pharmacological effects based on their tissue expression. In this paper, effects of non-selective PDE inhibitors (e.g. theophylline) are discussed, with a description of other putative mechanisms in their effects on cough. Antitussive effects of selective inhibitors of several PDE isoforms are reviewed, focusing on PDE1, PDE3, PDE4, PDE5 and PDE7. The inhibition of PDEs suggests participation of bronchodilation, suppression of TRPV channels and anti-inflammatory action in cough suppression. Selective PDE3, PDE4 and PDE5 inhibitors have demonstrated the most significant cough suppressive effects, confirming their benefits in chronic inflammatory airway diseases associated with bronchoconstriction and cough.
Topics: Animals; Antitussive Agents; Cough; Humans; Phosphodiesterase Inhibitors
PubMed: 29337269
DOI: 10.1016/j.resp.2018.01.008 -
Medicina (Kaunas, Lithuania) Dec 2023Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and... (Review)
Review
Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil's therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil's broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.
Topics: Male; Humans; Sildenafil Citrate; Piperazines; Purines; Phosphodiesterase 5 Inhibitors; Cyclic GMP
PubMed: 38138293
DOI: 10.3390/medicina59122190 -
Indian Journal of Pharmacology 2015Phosphodiesterases (PDE) are exciting new targets in medical sciences. These enzymes are some of the key mediators of cellular functions in the body and hence are... (Review)
Review
Phosphodiesterases (PDE) are exciting new targets in medical sciences. These enzymes are some of the key mediators of cellular functions in the body and hence are attractive sites for drug-induced modulations. With the finding that Tofisopam, a new anxiolytic, inhibits PDEs, the authors were inspired to look into the role of PDE and drugs acting on them in psychiatry. Hence, the review was undertaken. We found several research materials available highlighting the role of PDE in cellular functions and the possible newer etiological mechanisms of neuropsychiatric illnesses such as schizophrenia, depression/anxiety disorders, and cognitive dysfunction involving PDEs. We also found that there are many molecules acting on PDEs, which have the potential to alter the way we treat mental illnesses today. This article is intended to provide an in-depth look at these enzymes so that more cost-effective therapeutic molecules may be synthesized and marketed in India for managing mental illnesses.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Anxiety; Benzodiazepines; Brain; Cognition Disorders; Depression; Humans; Isoenzymes; Mental Disorders; Models, Neurological; Molecular Targeted Therapy; Nerve Tissue Proteins; Neurons; Nootropic Agents; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Schizophrenia
PubMed: 26729948
DOI: 10.4103/0253-7613.169593 -
Archiv Der Pharmazie Oct 2021A series of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated for their anti-phosphodiesterase-5 (PDE-5) activity. A total of 28 compounds,... (Comparative Study)
Comparative Study
A series of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated for their anti-phosphodiesterase-5 (PDE-5) activity. A total of 28 compounds, containing alkyl and aryl groups at the 1-N and 3-C positions on the pyrazole ring, and also bearing different alkyl substituents on the piperazine ring were synthesized. Four compounds (4d, 5d, 6d, and 5o) were found to have better inhibitory activity against PDE-5 (IC < 10 nM). All four of the most active compounds contain a phenyl ring at the N1 position. Compounds containing a 3,5-dimethylpiperazinyl group show better activity than others. These results suggest that compound 5o can be used as a lead structure for developing new inhibitors of PDE-5.
Topics: Inhibitory Concentration 50; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Sildenafil Citrate; Structure-Activity Relationship
PubMed: 34131943
DOI: 10.1002/ardp.202100145 -
European Journal of Medicinal Chemistry Apr 2018Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many... (Review)
Review
Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development. A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets. This review will give a brief overview of the expression and regulation of PDE families in the process of tumorigenesis and their anti-tumor inhibitors, which may guide the design of novel therapeutic drugs targeting PDEs for anticancer agent.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neoplasms; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Structure-Activity Relationship
PubMed: 29574203
DOI: 10.1016/j.ejmech.2018.03.046 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Oct 2021Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a... (Review)
Review
Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.
Topics: Animals; Colitis; Inflammatory Bowel Diseases; Phosphodiesterase 4 Inhibitors
PubMed: 34986542
DOI: 10.3724/zdxbyxb-2021-0170