Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cells transfected to express wild-type PDE4A4 cAMP phosphodiesterase (PDE), the PDE4 selective inhibitor rolipram caused PDE4A4 to relocalise so as to form accretion foci. This process was followed in detail in living cells using a PDE4A4 chimera formed with Green Fluorescent Protein (GFP). The same pattern of behaviour was also seen in chimeras of PDE4A4 formed with various proteins and peptides, including LimK, RhoC, FRB and the V5-6His tag. Maximal PDE4A4 foci formation, occurred over a period of about 10 h, was dose-dependent on rolipram and was reversible upon washout of rolipram. Inhibition of protein synthesis, using cycloheximide, but not PKA activity with H89, inhibited foci generation. Foci formation was elicited by Ro20-1724 and RS25344 but not by either Ariflo or RP73401, showing that not all PDE4 selective inhibitors had this effect. Ariflo and RP73401 dose-dependently antagonised rolipram-induced foci formation and dispersed rolipram pre-formed foci as did the adenylyl cyclase activator, forskolin. Foci formation showed specificity for PDE4A4 and its rodent homologue, PDE4A5, as it was not triggered in living cells expressing the PDE4B2, PDE4C2, PDE4D3 and PDE4D5 isoforms as GFP chimeras. Altered foci formation was seen in the Deltab-LR2-PDE4A4 construct, which deleted a region within LRZ, showing that appropriate linkage between the N-terminal portion of PDE4A4 and the catalytic unit of PDE4A4 was needed for foci formation. Certain single point mutations within the PDE4A4 catalytic site (His505Asn, His506Asn and Val475Asp) were shown to ablate foci formation but still allow rolipram inhibition of PDE4A4 catalytic activity. We suggest that the binding of certain, but not all, PDE4 selective inhibitors to PDE4A4 induces a conformational change in this isoform by 'inside-out' signalling that causes it to redistribute in the cell. Displacing foci-forming inhibitors with either cAMP or inhibitors that do not form foci can antagonise this effect. Specificity of this effect for PDE4A4 and its homologue PDE4A5 suggests that interplay between the catalytic site and the unique N-terminal region of these isoforms is required. Thus, certain PDE4 selective inhibitors may exert effects on PDE4A4 that extend beyond simple catalytic inhibition. These require protein synthesis and may lead to redistribution of PDE4A4 and any associated proteins. Foci formation of PDE4A4 may be of use in probing for conformational changes in this isoform and for sub-categorising PDE4 selective inhibitors.
...
PMID:Occupancy of the catalytic site of the PDE4A4 cyclic AMP phosphodiesterase by rolipram triggers the dynamic redistribution of this specific isoform in living cells through a cyclic AMP independent process. 1287 9

Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic index compared with the weak, non-selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by poor efficacy and an unfavourable safety and tolerability profile, the selective PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in improving lung function, decreasing the rate of exacerbations and improving quality of life, with proven anti-inflammatory effects in patients with COPD. Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications. In contrast, the selective PDE4 inhibitors are convenient medications for both patient and physician alike. Hence these agents represent a therapeutic advance in the treatment of COPD, due to their novel mechanism of action and potent anti-inflammatory effects, coupled with a good safety and tolerability profile.
...
PMID:PDE4 inhibitors in COPD--a more selective approach to treatment. 1519 Oct 33

The pharmacokinetic profile of cilomilast (Ariflo), a selective phosphodiesterase 4 (PDE4) inhibitor, was investigated in three separate studies. Two of these studies explored the drug interaction potential of cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of cilomilast in smokers and nonsmokers. Repeated administration of cilomilast had no effect on the steady-state pharmacokinetics of theophylline in either a pilot dose-ranging or definitive therapeutic study. At therapeutic doses, the point estimate and 90% confidence interval for theophylline AUC(0-12) and C(max) were completely contained within the range (0.8, 1.25). Similarly, repeated administration of theophylline had little clinically relevant effect on the steady-state pharmacokinetics of cilomilast when compared to placebo, as only slight average increases in cilomilast AUC(0-12) and C(max) (6% and 3%, respectively) were observed. In addition, mean cilomilast exposure (AUC(0- infinity )) was found to be similar in both smokers and nonsmokers (8.47 +/- 2.20 microg*h/mL and 7.70 +/- 2.25 microg*h/mL, respectively). Throughout all three studies, cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitors, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate cilomilast from theophylline for drug-drug liability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.
...
PMID:Lack of pharmacokinetic interactions between cilomilast and theophylline or smoking in healthy volunteers. 1531 32

Phosphodiesterase enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 inhibitors have been well documented both in vitro and in vivo in a variety of animal models. The potential use of PDE4 inhibitors as anti-inflammatory agents for the treatment of asthma and other inflammatory disorders has received considerable attention from the pharmaceutical industry, but to date, there are no selective PDE4 inhibitors on the market. Early PDE4 inhibitors, typified by rolipram, suffered from dose-limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second generation compounds, including CDP840 and SB207499 (Ariflo), have been identified with reduced side effect liability. Recent evidence suggests a correlation between side effects and the ability of compounds to bind at the so-called high affinity rolipram binding site (HPDE), whilst beneficial effects appear to correlate with binding at the catalytic site. A number of companies are actively pursuing compounds which exhibit improved affinity for the catalytic site and reduced affinity for the HPDE, in the expectation that this will provide compounds with an improved therapeutic index.
...
PMID:The therapeutic potential of PDE4 inhibitors. 1599 51

This meeting underscored advances in the exploitation of cyclic nucleotide phosphodiesterases (PDEs) as drug targets. One highlight of the meeting was the disclosure of a new PDE isozyme, bringing to 11 the total number of genetically distinct isozyme families thus far identified. Also reported was the phenotypic characterization of a PDE4D murine genetic knockout. With respect to drug discovery and development, the most encouraging information presented centered on advances in targeting PDE4 with therapeutically useful inhibitors. Historically, the therapeutic utility of isozyme-selective PDE4 inhibitors has been limited by class-associated side effects, namely nausea and dyspepsia. New PDE4 inhibitors are being designed with the specific intent of improving upon the therapeutic ratio of first-generation agents. The profiles of two second-generation PDE4 inhibitors, SB-207499 (Ariflo; Smithkline Beecham plc) and PD-189659, were presented. SB-207499 demonstrated marked efficacy in phase II clinical trials in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), a disease of very high unmet medical need. PD-189659 has yet to enter clinical trials, but its preclinical profile indicates that this agent can produce substantial anti-inflammatory effects without producing class-associated side effects in animal models. A number of presentations were also given on the utility of PDE5 inhibitors in the treatment of male erectile dysfunction (MED). The widespread use of Viagra (sildenafil; Pfizer Inc) over the last year has reinforced the perception that PDE5 inhibitors are safe and effective agents for the treatment of MED. The overall tenor of the meeting was distinctly upbeat, with most participants believing that PDE isozymes are becoming ever more accessible as targets for drug discovery in a variety of therapeutic areas.
...
PMID:PDE inhibitors--Second William Harvey Research Conference. Drugs with an expanding range of therapeutic uses. 1-3 December 1999, Nice, France. 1610 32

Cyclic AMP has been shown to have a critical role in learning and memory in invertebrates. Here we use the rat pup odor preference learning model in which odor acts as a conditioned stimulus and beta-adrenoceptor stimulation acts as an unconditioned stimulus to test the role of cyclic AMP in an associative mammalian paradigm. A phosphodiesterase inhibitor that prevents cyclic AMP breakdown (cilomilast) makes a low, learning-ineffective dose of a beta-adrenoceptor agonist (isoproterenol, 1mg/kg) an effective unconditioned stimulus in pup odor preference learning. A dose of the phosphodiesterase inhibitor (cilomilast, 1 mg/kg) that induces learning with a weak unconditioned stimulus interferes with learning using a normally optimal unconditioned stimulus (isoproterenol, 2 mg/kg). Cilomilast (3 mg/kg) paired with peppermint odor during learning, prolonged memory at least four times longer than without the drug (24 h vs. 96 h). These data demonstrate a causal role for cyclic AMP in the acquisition and duration of odor preference learning in the rat pup.
...
PMID:Potentiation and prolongation of long-term odor memory in neonate rats using a phosphodiesterase inhibitor. 1611 26

Metabotropic glutamate receptors (mGluRs), acetylcholinesterase inhibitors (AChE-Is) and phosphodiesterase-4 (PDE4) inhibitors were amongst the topics for discussion on the second day of the EPHAR congress. A novel mGlu1 receptor antagonist, CPCCOEt, was described, along with new in vitro and in vivo data on a number of other promising mGluR1 antagonists. The potential of AChE-Is as therapeutics in Alzheimer's disease was thoroughly reviewed. With the search now on for a brain-selective AChE-I, which will improve the cholinergic transmitter effects in Alzheimer's disease, improvements and limitations with the second generation of AChE-Is were discussed. There was also an extensive review of PDE4 inhibitors and their place in asthma and COPD treatment. An overview of the characterization and immunomodulatory properties of PDEs was given, along with a discussion on the possible reasons for the failure of a promising PDE4 inhibitor, RP-73401 (Rhone-Poulenc SA), in the clinic, and the promise shown by SmithKline Beecham plc's Ariflo in COPD.
...
PMID:mGLuRs, AChE-Is and PDE4. 1612 Dec 93

Ariflo (SB-207499) is a phosphodiesterase (PDE)4 inhibitor under development by SmithKline Beecham and in phase III and II clinical trials as a potential treatment for chronic obstructive pulmonary disease (COPD) and asthma, respectively [284490]. It has commenced phase II trials as a treatment for bronchial asthma in Japan [248285,300145]. In February 1999, Merrill Lynch predicted that Ariflo would be launched by the end of 2000 or early 2001 with first year sales of UK pounds sterling 25 million rising to UK pounds sterling 175 million in 2003 [300257,314372]. In February 1999 ABN Amro predicted sales of UK pounds sterling 52 million in 2001 rising to UK pounds sterling 254 million in 2005 [317577,328676].
...
PMID:Ariflo (SmithKline Beecham plc). 1612 6

Chronic obstructive pulmonary disease (COPD) is a multicomponent, chronic inflammatory disease of the lungs with systemic complications. The majority of the inflammation occurs in the peripheral airways and lung parenchyma. It is a progressive disease, leading to disability and eventual death, despite conventional therapy. Inflammatory activity can be reduced by increasing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) through inhibition of phosphodiesterase (PDE) IV, the principal PDE isoenzyme within pro-inflammatory cells, including eosinophils, mast cells, macrophages, lymphocytes, neutrophils and epithelial cells. PDE IV inhibition also has other effects, including relaxation of airway smooth muscle, suppression of smooth muscle mitogenesis and modulation of excitatory activity in pulmonary nerves. Cilomilast is a systemically available, second-generation, selective PDE IV inhibitor. It retains the therapeutic activity of the first-generation PDE IV inhibitors but lacks their profound emetic effect. Cilomilast is the first drug to demonstrate a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with stable COPD. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits linear pharmacokinetics, with low between-subject variability. Cilomilast is highly protein bound (99.4%), but this binding is concentration-independent at clinically relevant doses, and it has a small volume of distribution at steady state (17L). Plasma clearance (approximately 2 L/h) is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours and steady state is rapidly achieved with twice-daily administration. The most abundant metabolite, formed by the action of cytochrome P450 2C8, has <10% of the activity of the parent molecule. Cilomilast pharmacokinetics in COPD patients were consistent with those in healthy subjects. Smoking, age and ethnicity had no clinically relevant effects. Total plasma cilomilast pharmacokinetic parameters did not change significantly with renal or hepatic impairment, but concentrations of unbound cilomilast increased with declining renal or hepatic function. Cilomilast had no clinically relevant interactions with a range of drugs likely to be coadministered to patients with COPD, with the exception of erythromycin where concurrent administration with cilomilast was associated with an increased incidence of gastrointestinal adverse events, a pharmacodynamic interaction predicted by their secondary pharmacology. Nausea was the principal adverse reaction seen in healthy subjects taking cilomilast, but this was reduced by administration with food or by use of simple dose-escalation regimens. Cilomilast has not shown a propensity for any of the serious cardiac or neurological adverse effects associated with theophylline. Cilomilast exhibits favourable and predictable pharmacokinetics, has few clinically relevant drug-drug interactions and has demonstrated effects on measures of inflammation of potential benefit in the treatment of COPD. It is generally well tolerated and has not generated safety concerns in any clinical study.
...
PMID:Clinical pharmacology of Cilomilast. 1650 57

The central role of cyclic nucleotides as intracellular second messengers dates back almost 50 years. The importance of phosphodiesterase in regulating this system was recognized early, and the potential therapeutic role of phosphodiesterase inhibitors in modulating pathologic conditions was also suggested. At that time, the methylxanthines represented major pharmacologic agents capable of inhibiting cyclic nucleotides and were widely used in respiratory medicine. Initially, bronchodilator effects were considered their major mechanism of action, but subsequent studies suggested other potential roles including an anti-inflammatory one. A number of developments led to the decline in popularity of this class of agents, the foremost being their side-effect profile. The discovery of multiple phosphodiesterase isoforms paired with a better understanding of the physiologic and clinical properties of the phosphodiesterases has re-awakened interest in therapeutic agents in this area and in particular the potential for the development of selective phosphodiesterase inhibitors. Cilomilast is a systemically available, second- generation, selective phosphodiesterase-4 inhibitor. It retains the therapeutic activity of the first generation phosphodiesterase-4 inhibitors (such as rolipram) but is believed to have less of an emetic effect. Cilomilast causes a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease is now considered a chronic inflammatory disease of the lungs resulting from prolonged exposure to inflammatory agents in cigarette smoke and other environmental and occupational pollutants, and it is currently the principal target of cilomilast. It is characterized by progressive destruction of parenchymal tissue and punctuated by acute exacerbations. The inflammation is thought to begin in the peripheral airways and lung parenchyma. Chronic obstructive pulmonary disease is a progressive disease, leading to disability and eventual death despite conventional therapy. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits low between-subject variability. Cilomilast is predominantly protein bound. Plasma clearance is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours, and steady state is rapidly achieved. A dose of 15 mg twice daily has been found to be clinically effective. Smoking and age have no clinically relevant effects on cilomilast pharmacokinetics. Most drugs frequently used in patients with chronic obstructive pulmonary disease do not alter its side effect profile. Initial concerns of arteritis involving the gastrointestinal tract in rodent animal models have not been reported in clinical trials. Nausea, presumably of central origin, is the principal adverse reaction seen in healthy subjects taking cilomilast. It has not been associated with the serious cardiac or neurological adverse effects seen with theophylline. Preliminary clinical studies suggest a favorable clinical effect in chronic obstructive pulmonary disease. Cilomilast is generally well tolerated and has not generated safety concerns in reported clinical studies.
...
PMID:Cilomilast. 1670 20


<< Previous 1 2 3 Next >>

---