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At least 685 records · Page 38Linked to original sources
PubMed2002

Cyclic AMP-specific phosphodiesterase 4 inhibitors promote ABCA1 expression and cholesterol efflux.

ATP cassette binding protein 1 (ABCA1) controls the apolipoprotein-mediated cholesterol efflux pathway and determines plasma HDL levels. Although cAMP is known to promote ABCA1 expression and cholesterol efflux from cells, it has not been determined whether cyclic nucleotide phosphodiesterase (PDE) isoforms regulate this pathway. We show that rolipram and cilomilast, inhibitors of cAMP-specific PDE4, increase apolipoprotein A-I (apoA-I)-mediated cholesterol efflux up to 80 and 140% in human THP-1 and mouse J774.A1 macrophages, respectively, concomitant with an elevation of cAMP levels. The EC(50) value was estimated to be 1 to 2 microM for both inhibitors. Rolipram and cilomilast also increase ABCA1 protein expression in THP-1 and J774.A1 macrophages. Thus, PDE4 inhibitors cause parallel increases in cAMP levels, ABCA1 expression and apoA-I-mediated cholesterol efflux. PDE4 inhibitors may provide a novel strategy for the treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Effects of cilomilast, a selective phosphodiesterase 4 inhibitor, on esophageal motility and pH, and orocecal and colonic transit: two single-center, randomized, double-blind, placebo-controlled, two-part crossover studies in healthy volunteers.

BACKGROUND: Phase IIb studies have reported that cilomilast, a selective phosphodiesterase 4 inhibitor being developed for the treatment of chronic obstructive pulmonary disease, is associated with gastrointestinal (GI) adverse effects (AEs) in a small proportion (approximately 5%) of individuals. OBJECTIVES: The aims of these 2 studies were to investigate the effects of cilomilast 15 mg BID on: (1) lower esophageal sphincter pressure (LESP) and esophageal body motility and pH (study 1); and (2) orocecal and whole-gut transit times (OCTT and WGTT, respectively) (study 2) in healthy volunteers. METHODS: These 2 randomized, double-blind, placebo-controlled, 2-part crossover studies were conducted at the Neurogastroenterology Unit, Wythenshawe Hospital, Manchester, United Kingdom (study 1) and GlaxoSmithKline, Harlow, United Kingdom (study 2). In study 1, subjects were randomly assigned to receive either cilomilast (15 mg BID) or matched placebo (control) for 7 days (13 doses; subjects were not given the evening dose on day 7), and in study 2, cilomilast (15 mg BID) or matched placebo (control) for 9 days (18 doses) in each of 2 treatment periods. After study drug administration, combined esophageal motility and pH were recorded for 2 hours before and 4 hours after the administration of a standardized meal (2400 kJ [573 kcal]). Sequences of 6 consecutive 5-mL water swallows (separated by 20 seconds) were carried out 60 and 90 minutes (fasting) and 150, 180, 210, 240, 300, and 360 minutes (fed) after study drug administration. OCTT was determined from the increase in breath hydrogen after the meal. WGTT was determined from the time taken to excrete at least 16 of 20 ingested radiopaque markers, ingested as 2 capsules, each containing 10 radiopaque markers, with 240 mL of water. AEs were elicited at specified times throughout each session using nonleading questions, spontaneously reported AEs, and diary cards. RESULTS: Study 1 enrolled 20 subjects (11 men, 9 women; age range, 20-52 years). Study 2 enrolled 16 subjects (10 men, 6 women; age range, 19-48 years). No clinically significant differences in the amplitude (mean difference in postprandial-preprandial AUC0-t/t, 6.09 mm Hg; 95% CI, -10.66 to 22.84), duration (difference, -0.08 second; 95% CI, -0.54 to 0.37), or velocity of propagation (difference, 0.90 cm/s; 95% CI, -0.66 to 2.46) of esophageal contractions, LESP (difference, -0.39 mm Hg; 95% CI, -5.23 to 4.45), or preprandial or postprandial percentage time pH<4 (median differences: preprandial, 0.47% [95% CI, -0.45 to 1.27]; postprandial, -0.005% [95% CI, -1.30 to 6.27]) were found with cilomilast compared with placebo. No significant differences in OCTT (difference, -0.37 hour; 95% CI, -1.59 to 0.84) or WGTT (difference, -2.96 hours; 95% CI, -20.76 to 14.84) were found with cilomilast compared with controls. In both studies, the most frequently reported AEs with cilomilast use were nausea (8/18 in study 1 and 3/16 in study 2) and headache (8/18 in study 1 and 6/16 in study 2); however, these were generally of mild to moderate intensity. Overall, GI AEs did not correlate with changes in GI motility. CONCLUSION: The results of these 2 studies suggest that cilomilast was not associated with significant changes in esophageal motility and pH or GI transit in these healthy volunteers.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

The mechanisms of action of gabapentin and pregabalin.

Gabapentin and pregabalin are structurally related compounds with recognized efficacy in the treatment of both epilepsy and neuropathic pain. The pharmacological mechanisms by which these agents exert their clinical effects have, until recently, remained unclear. The interaction of gabapentin and pregabalin with conventional antiepileptic and analgesic drug targets is likely to be modest, at best, and has been largely dismissed in favour of a selective inhibitory effect on voltage-gated calcium channels containing the alpha2delta-1 subunit. This mechanism is consistently observed in both rodent- and human-based experimental paradigms and may be sufficiently robust to account for much of the clinical activity of these compounds.

Amines↗
PubMed2005

PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression.

Phosphodiesterase 4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have demonstrated a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells, reactive oxygen species production, and cell adhesion molecule expression in a variety of in vitro and in vivo experimental models. The initially detected side effects, mainly nausea and emesis, appear at least partially overcome by the 'second generation' PDE4 inhibitors, some of which like roflumilast and cilomilast are in the later stages of clinical development for treatment of chronic obstructive pulmonary disease. These new drugs may also offer opportunities for treatment of other inflammatory diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease.

Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive "designer" theophylline, the archetypal non-selective phosphodiesterase inhibitor.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Crystal structure of glutamate-1-semialdehyde aminomutase: an alpha2-dimeric vitamin B6-dependent enzyme with asymmetry in structure and active site reactivity.

The three-dimensional structure of glutamate-1-semialdehyde aminomutase (EC 5.4.3.8), an alpha2-dimeric enzyme from Synechococcus, has been determined by x-ray crystallography using heavy atom derivative phasing. The structure, refined at 2.4-A resolution to an R-factor of 18.7% and good stereochemistry, explains many of the enzyme's unusual specificity and functional properties. The overall fold is that of aspartate aminotransferase and related B6 enzymes, but it also has specific features. The structure of the complex with gabaculine, a substrate analogue, shows unexpectedly that the substrate binding site involves residues from the N-terminal domain of the molecule, notably Arg-32. Glu-406 is suitably positioned to repel alpha-carboxylic acids, thereby suggesting a basis for the enzyme's reaction specificity. The subunits show asymmetry in cofactor binding and in the mobilities of the residues 153-181. In the unliganded enzyme, one subunit has the cofactor bound as an aldimine of pyridoxal phosphate with Lys-273 and, in this subunit, residues 153-181 are disordered. In the other subunit in which the cofactor is not covalently bound, residues 153-181 are well defined. Consistent with the crystallographically demonstrated asymmetry, a form of the enzyme in which both subunits have pyridoxal phosphate bound to Lys-273 through a Schiff base showed biphasic reduction by borohydride in solution. Analysis of absorption spectra during reduction provided evidence of communication between the subunits. The crystal structure of the reduced form of the enzyme shows that, despite identical cofactor binding in each monomer, the structural asymmetry at residues 153-181 remains.

Amino Acid Sequence↗
PubMed2001

Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease.

Cilomilast (Ariflo, SB-207499) is an orally-active, second generation phosphodiesterase (PDE) inhibitor that may be effective in the treatment of asthma and chronic obstructive pulmonary disease (COPD). It has high selectivity for the cyclic AMP-specific, or PDE4, isoenzyme that predominates in pro-inflammatory and immune cells and is ten-fold more selective for PDE4D than for PDE4A, B and C. In vitro, cilomilast suppresses the activity of many pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD and is highly active in animal models of these diseases. Cilomilast demonstrates a markedly improved side effect profile over the archetypal PDE4 inhibitor, rolipram, which has been attributed to its inability to discriminate between the high affinity rolipram binding site and the catalytic domain of the enzyme, and the fact that it is negatively charged which at physiological pH should limit its penetration in to the CNS. In humans cilomilast is rapidly absorbed after oral administration, providing dose-proportional systemic exposure up to 4 mg, completely bioavailable, has a half-life of approximately 7 h and is subject to negligible first pass hepatic metabolism. Cilomilast is extensively metabolised with decyclopentylation, acyl glucuronidation and 3-hydroxylation of the cyclopentyl ring representing the principal routes. Most of the drug is excreted in the urine (approximately 90%) and faeces (6 - 7%) with unchanged cilomilast accounting for less than 1% of the administered dose. Cilomilast has been evaluated in Phase I, Phase II and Phase III trials and dose-response experiments have demonstrated a clinically significant increase in lung function and a perceived improvement in quality of life in patients with COPD. Trials of cilomilast in asthma have been less impressive although a trend towards improved lung function has been reported. Cilomilast is safe and well-tolerated at doses up to 15 mg in both short- and long-term dosing trials with a low incidence of adverse effects. No evidence for drug-drug interactions with commonly prescribed medications for COPD and asthma such as digoxin, corticosteroids, salbutamol, theophylline or warfarin has been found. Moreover, the pharmacokinetics of cilomilast are essentially the same in smokers and non-smokers, indicating that no dose adjustments of cilomilast will be required in patients with COPD. Thus, cilomilast displays a promising clinical profile in the treatment of inflammatory airway diseases, in particular COPD and the results of further Phase III trials are awaited with interest.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1975

The respiratory effects of tilidine hydrochloride.

A standard 50-mg dose of tilidine hydrochloride (Valoron) was administered to 20 patients in the postoperative phase of open-heart surgery. No significant change in respiratory status, as measured by arterial blood gas analysis, was demonstrated with this dosage.

Acid-Base Equilibrium↗
PubMed1983

Bile lipid output and composition in patients fitted with external biliary drainage: activity of cicloxilic acid.

In 7 patients with external biliary drainage for total occlusion of the extrahepatic bile ducts the bile output was measured in 3-day periods, with and without cicloxilic acid treatment (240 mg daily, per os). The output increased markedly during treatment in all cases. In the 3 patients in whom the bile lipid composition was analyzed also, the bile salt and phospholipid concentrations increased while the cholesterol concentration was unchanged--with an consequent lowering of the biliary cholesterol saturation index--during treatment with cicloxilic acid.

Aged↗