Disease relevance of denbufylline

• In the anaesthetized dog, pentoxifylline and denbufylline both inhibited the E. coli lipopolysaccharide-induced mesenteric blood flow fall, without affecting renal blood flow or cardiac index [1].
• We have reported that denbufylline, a phosphodiesterase 4 (PDE4) inhibitor, inhibits bone loss in Walker256/S tumor-bearing rats, suggesting therapeutic potentiality of a PDE4 inhibitor in osteopenia [2].
• The purpose of the present investigation was to study in animal experiments whether 7-(2'-oxopropyl)-1,3-di-n-butyl-xanthine (BRL 30892) could be of potential value for the treatment of peripheral vascular disease (PVD) [3].

Psychiatry related information on denbufylline

• Evaluations were carried out before and 12 weeks after treatment with either 100 mg denbufylline BID or placebo and included EEG mapping, the Sandoz Clinical Assessment Geriatric (SCAG) score/factors, the Clinical Global Impression (CGI), the Digit Symbol Substitution Test (DSST), the Trail-Making Test (TMT) and the Digit Span Test (DS) [4].
• 5. Denbufylline is being developed as an agent for the therapy of multi-infarct dementia [5].
• Denbufylline in dementia: a double-blind controlled study [6].

High impact information on denbufylline

• Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm [7].
• However, PDE IV inhibitors (rolipram and denbufylline) only induce relaxation of aorta with endothelium, this relaxation being reversed by addition of L-NMMA and restored by addition of L-arginine [8].
• Denbufylline induced a statistically significant and clinically relevant improvement in both SDAT and MID patients, whereas after placebo this was not the case in CGI, the TMT, and the DS, with interdrug differences being significant in all primary target variables such as the CGI, MMS, SCAG, and DSST [4].
• Of these selective compounds, only rolipram, denbufylline and Org 30029 inhibited the IgE-dependent generation of IL-4, IL-13 and histamine from basophils to a statistically significant (P<0.05) degree [9].
• 4. Rolipram (100 microM), denbufylline (100 microM) and BRL 61063 (100 microM) stimulated the release of corticotrophin (ir-ACTH) from pituitary tissue in vitro (P < 0.05) but in lower concentrations they were without significant effect [10].

Biological context of denbufylline

• Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50S) = 0.21 +/- 0.05 microM, 0.67 +/- 0.23 microM, and 0.73 +/- 0.16 microM, respectively] [7].
• Cyclic AMP PDE activity of eosinophil homogenates was inhibited by both zardaverine (IC50 = 515 nM) and rolipram (IC50 = 550 nM) as well as two other PDE IV-selective inhibitors, Ro 20-1724 (IC50 = 3.0 microM) and denbufylline (IC50 = 360 nM), whereas SK&F 94120 was ineffective [11].
• Serial oral administrations of denbufylline inhibited the decrease in the bone mineral density of femurs from Walker 256/S-bearing rats, without influence on the healthy rats [12].
• 5. It is concluded that eosinophil respiratory burst activity induced by OZ can be regulated by intracellular cyclic AMP and that the levels of cyclic AMP are controlled exclusively by a rolipram- and denbufylline-sensitive PDE isoenzyme that resembles a type IV species [13].
• In addition, denbufylline blocked the accommodation of trains of action potentials evoked by the injection of depolarizing current pulses [14].

Anatomical context of denbufylline

• 4. The results suggest that the stimulatory actions of denbufylline on the hypothalamo-pituitary-adrenocortical axis are exerted predominantly at the level of the anterior pituitary gland and that they may be attributed, at least in part, to inhibition of type 4 phosphodiesterase enzymes [15].
• The adrenocortical responses to peripheral injections of denbufylline (1 mg kg-1, i.p.) were reduced in rats in which the secretion of endogenous corticotrophin releasing factors (CRFs) from the hypothalamus was blocked pharmacologically (P < 0.01 vs. controls, Scheffe's test) [15].
• Denbufylline restored the bone mass and the number of osteoclasts and osteoblasts per trabecular surface in the femur metaphysis [12].
• Negative inotropic action of denbufylline through interfering with the calcium channel independently of its PDE IV inhibitory activity in guinea pig ventricle papillary muscles [16].
• The effects of denbufylline, a xanthine derivative with selective inhibitory activity on the phosphodiesterase (PDE) 4 isoenzyme, on bone loss in Walker 256/S-bearing rats and on mineralized nodule formation and osteoclastlike cell formation in bone marrow culture systems were examined [12].

Associations of denbufylline with other chemical compounds

• The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re-uptake site [5].
• Most inhibitors synthesized to date (rolipram, denbufylline nitraquazone, etc.) display high-affinity for HARBS but are much weaker in inhibiting cAMP hydrolysis [17].
• Pretreatment with the non-selective phosphodiesterase inhibitor, pentoxifylline, or selective phosphodiesterase IV inhibitors such as denbufylline or rolipram reduced intestinal haemoconcentration [1].
• The IC50 values were 0.7, 5.8, 330, 3,500, 4,200 and 6,250 nM for DSCG, denbufylline, salmeterol, azelastine, salbutamol and theophylline, respectively [18].
• Effect of [1,3-di-n-butyl-7-(2-oxopropyl)-xanthine] (denbufylline), a low Km phosphodiesterase inhibitor, on striatal acetylcholine release in the rat: analysis using cerebral microdialysis [19].

Gene context of denbufylline

• 1. Denbufylline has been examined for its ability to inhibit cyclic nucleotide phosphodiesterase isoenzymes from rat cardiac ventricle and cerebrum, as well as for its affinity for adenosine A1 and A2 receptors and the re-uptake site [5].
• 5. Since both denbufylline and BRL 61063 possess significant adenosine A1 receptor blocking activity, further studies examined the potential influence of these receptors on the secretion in vitro of CRH-41, AVP and ACTH [10].
• Especially, dl-3,4-dipropyl-8-methyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (dl-7c) exhibited comparable PDE4 inhibitory activity (IC(50)=1.9 microM) to rolipram and denbufylline (DBF) [20].
• Dexamethasone, pentoxifylline and denbufylline inhibited TNF alpha production with IC50s of 6.0 +/- 2.0 nM, 20.6 +/- 8.00 microM and 138.0 nM, respectively [21].

Analytical, diagnostic and therapeutic context of denbufylline

• EEG mapping and psychopharmacological studies with denbufylline in SDAT and MID [4].
• Denbufylline, which has been shown to selectively inhibit a low KM, Ca2+/calmodulin-independent phosphodiesterase isozyme, concentration-dependently increased the amplitude of the extracellularly recorded CA1 population spike evoked by electrical stimulation of the Schaffer collateral/commissural pathway [14].
• The influence of denbufylline, nabumetone and its main metabolite BRL 10,720 on iron stimulated lipid peroxidation (LPO), cytochrome P 450 dependent H2O2 and chemiluminescence (CL) production was investigated in rat liver microsomes in vitro (10(-5)-10(-3) M) and in vivo after treatment of rats (5-300 mg/kg b.m. orally on three consecutive days) [22].

References