Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cAMP and/or cyclic guanosine monophosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an antiinflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective antiinflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for patients with COPD with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations, whose disease is not adequately controlled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhibitors include extended indications of roflumilast (1) in patients with COPD, and (2) in other respiratory (e.g., asthma) and nonrespiratory chronic inflammatory/metabolic conditions (e.g., diabetes), as well as (3) the development of new molecules with PDE4 inhibitory properties with an improved efficacy/tolerability profile.
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PMID:Phosphodiesterase-4 inhibitor therapy for lung diseases. 2365 8

Little is known about role of PDE4 in the development and progression of diabetic nephropathy. Here, we investigated the effect of roflumilast, a selective PDE 4 inhibitor in type 1 diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats using streptozotocin (55 mg/kg). Diabetic rats showed elevated plasma glucose, blood urea nitrogen, creatinine and decrease in plasma albumin confirming signs of nephropathy. Roflumilast at 2 and 3mg/kg normalized these alterations. Roflumilast also suppressed oxidative stress and deposition of an extracellular matrix protein such as fibronectin and collagen in kidney of diabetic rats. TUNEL assay revealed apoptosis in diabetic kidney than control and that roflumilast prevents this effect. We show that kidney of diabetic rats displayed a state of p-AMPK and SIRT1 deficiency and that roflumilast, interestingly, was able to restore their levels. Further, roflumilast prevented an increase in HO-1 and loss in the FoxO1 expression in diabetes. However, it did not improve the reduced NRF2 levels in diabetes. This is the first report to show that, like resveratrol and other SIRT1 activators, roflumilast also mimics calorie restriction effects through activation of AMPK/SIRT1 and protects against diabetic nephropathy. This study unveils the unexplored potential of roflumilast which can be used in treatment of metabolic disorders.
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PMID:Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy. 2503 26

The PDE4 enzyme has been proven to be a versatile drug target for therapeutics to treat diverse disease conditions such as asthma, COPD, diabetes, Huntington's disease, and various other inflammatory disorders. The treatment of COPD is the most studied utility for PDE4 inhibitors due to their ability to inhibit inflammatory cell responses. Roflumilast is the only approved drug belonging to this class to treat COPD and has shown significant results in the treatment of asthmatic patients. This perspective highlights the pharmacological details of roflumilast and cilomilast. Moreover, efforts have been made to justify the superiority of roflumilast over cilomilast by detailed comparison of their pharmacological, pharmacokinetic, pharmacodynamic properties and structural features. Several other molecules, with promising PDE4 inhibitory activity have also been highlighted. Commonly associated side effects with this class of compounds, their management, and future direction towards the development of PDE4 inhibitors with improved therapeutic index are the focus of this perspective. More emphasis has been given towards the future development strategies to limit the side effects such as emesis and to achieve better benefit to risk ratio.
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PMID:Phosphodiesterase 4 (PDE4) Inhibitors in the Treatment of COPD: Promising Drug Candidates and Future Directions. 2657 14

COPD is a progressive condition involving chronic inflammation and parenchymal destruction with resulting airflow limitation. COPD is associated with worsening airflow limitation over time and increased frequency of COPD exacerbations, leading to increased mortality and morbidity. The effects of COPD extend beyond the lungs, as multiple comorbidities may occur with COPD, including cardiovascular disease, diabetes mellitus, osteoporosis, depression, and pneumonia. COPD exacerbations are associated with a rapid worsening of baseline symptoms that requires prompt management and may necessitate hospitalization in the case of a severe episode. Patients with COPD exacerbations require urgent management of symptoms to prevent further worsening, and preventative steps may be taken to help reduce the number and frequency of future exacerbations. Roflumilast is a potent and selective inhibitor of the enzyme phosphodiesterase-4 that targets the systemic inflammation associated with COPD. Roflumilast has a variety of anti-inflammatory effects including decreasing inflammatory mediators and the expression of cell surface markers and inhibition of apoptosis. Several clinical trials evaluating roflumilast in the treatment of COPD have demonstrated significant improvements from baseline versus placebo in lung function, including increases in mean pre- and postbronchodilator forced expiratory volume in 1 second and forced vital capacity. Data suggest that roflumilast reduces moderate to severe exacerbations with the benefit most well established in patients with severe disease. Given this evidence, roflumilast, as part of a combination regimen with long-acting bronchodilators, appears to be a reasonable treatment option for patients with severe to very severe COPD associated with chronic bronchitis and a history of exacerbations.
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PMID:Roflumilast: a review of its use in the treatment of COPD. 2679 88