Disease relevance of Tocris-1046

• Zardaverine and aerosolised iloprost in a model of acute respiratory failure [1].
• Effects of the mixed phosphodiesterase III/IV inhibitor, zardaverine, on airway function in patients with chronic airflow obstruction [2].

High impact information on Tocris-1046

• The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation [3].
• 6. Addition of forskolin (1 microM) together with the phosphodiesterase inhibitor zardaverine (100 microM) produced a mean 35-fold increase in intracellular cyclic AMP in sheep trachea [4].
• The first crystal structure of PDE4D catalytic domain and a bound inhibitor, zardaverine, was determined [5].
• Zardaverine fills only a portion of the active site pocket [5].
• Non-selective PDE inhibitors (theophylline, 3-isobutyl-1-methylxanthine [IBMX]), a PDE3-selective inhibitor (motapizone), PDE4-selective inhibitors (RP73401, rolipram, AWD 12-281) and a mixed PDE3/4 inhibitor (zardaverine) all significantly relaxed inherent bronchial tone at resting tension and to a similar degree [6].

Biological context of Tocris-1046

• In human PMN cells, zardaverine inhibited the zymosan-induced superoxide anion generation with an IC50 of 0.40 microM [7].
• RESULTS: The type 4 PDE inhibitors (CDP840, rolipram and RO 20-1724), and the mixed PDE3/4 inhibitor, zardaverine, produced a concentration-related inhibition of PHA-stimulated cord blood mononuclear cell proliferation (P < 0.05, ANOVA) [8].
• This study investigates the bronchodilatory properties of zardaverine, administered by inhalation [9].
• Of the three phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methylxanthine (IBMX), zardaverine and rolipram, only the adenosine receptor antagonist, IBMX, increased the amplitudes of the extracellular excitatory postsynaptic potential (EPSP) and population spike (PS) [10].

Anatomical context of Tocris-1046

• The OA-induced pulmonary eosinophil infiltration in these animals was attenuated by all treatments with zardaverine producing the greatest degree of inhibition [11].
• In addition, zardaverine exerts a positive inotropic action on heart muscle in vitro [7].
• In right papillary muscles, 1-30 microM zardaverine reversibly increased the force of contraction in a concentration-dependent manner [12].
• The specific type III and IV phosphodiesterase inhibitor zardaverine suppresses formation of tumor necrosis factor by macrophages [13].
• Murine resident peritoneal macrophages were stimulated with lipopolysaccharide and treated with phosphodiesterase (PDE) inhibitors zardaverine, rolipram and motapizone [13].

Associations of Tocris-1046 with other chemical compounds

• Rolipram or zardaverine (0.1-10 microM), but not siguazodan, inhibited OA-induced contraction of the isolated trachea in a concentration-dependent manner [11].
• 4. Chronic administration of a low dose (3 mg kg-1, i.p., twice daily for 7 days) of the type IV PDE inhibitor, RO 20-1724, and the PDE III/IV inhibitor, zardaverine, produced a significant inhibition of eosinophil accumulation (46% and 59% respectively).(ABSTRACT TRUNCATED AT 250 WORDS)[14]
• In combination with salbutamol, however, both ECP/EDN secretion and chemiluminescence was inhibited by rolipram and zardaverine with IC50 values similar to the IC50 values for inhibition of PDE IV activity [15].
• Combined preincubation of FRA-19 with zardaverine, a cAMP-specific phosphodiesterase III/IV inhibitor, produced a synergistical inhibitory effect of leukocyte histamine release, which might explained by their different sites of action on intracellular cAMP levels [16].
• An antiinflammatory potential in vivo of zardaverine is demonstrated by the inhibition of bronchial cell infiltration following inhalative allergen challenge in sensitized guinea pigs [17].

Gene context of Tocris-1046

• Zardaverine is a novel phosphodiesterase III/IV inhibitor, developed as a potential therapeutic agent for asthma [18].
• The inhibition of anti-IgE-induced HR by zardaverine (a PDE-III/IV-inhibiting compound) was synergistically enhanced in the combined presence of forskolin or the recently synthesized histamine H2-agonist FRA 19) [19].

Analytical, diagnostic and therapeutic context of Tocris-1046

• In this study we evaluated the effect of zardaverine in an in vivo animal model of airway inflammation and hyperresponsiveness [18].
• Sensitive determination of the phosphodiesterase III/IV inhibitor zardaverine in human serum by direct sample injection, automated precolumn clean-up and high-performance liquid chromatography [20].

References