Zardaverine

Zardaverine is a newly developed dual-selective phosphodiesterase (PDE) III and IV inhibitor. Zardaverine inhibited the cyclic GMP-inhibitable PDE III from human platelets and the rolipram-inhibitable PDE IV from canine trachea and human polymorphonuclear (PMN) cells with IC50-values of 0.58, 0.79 and 0.17 μM, respectively. The pyridazinone derivative affected the calmodulin-stimulated PDE I, the cyclic GMP-stimulated PDE II and the cyclic GMP-specific PDE V only marginally at concentrations up to 100μM. Zardaverine inhibits the ADP-induced aggregation of human platelets with an IC50 of 1.6 μM. This inhibition was synergistically increased by activators of adenylate cyclase such as PGE1 and forskolin. In human PMN cells, Zardaverine inhibited the zymosan-induced superoxide anion generation with an IC50 of 0.40 μM. Again, this effect was increased by activators of adenylate cyclase. Zardaverine acted in synergy with the adenylate cyclase activators prostaglandin E2 and CG 4203, a prostacyclin analog, and super-additive effects of combinations were observed. Zardaverine and dexamethasone prevent bronchial eosinophilia and neutrophilia with similar dosage of 30 microM/kg orally, suggesting that this PDE III/IV inhibitor may be useful for both, bronchorelaxation and reduction of inflammation in asthma therapy.

Effects of the mixed phosphodiesterase III/IV inhibitor, zardaverine, on airway function in patients with chronic airflow obstruction.[Pubmed:7644776]

Respir Med. 1995 Jul;89(6):441-4.

Zardaverine is a selective inhibitor of phosphodiesterase (PDE) III and IV isozymes. It has been shown to exert potent bronchodilator effects in animals. In order to study the efficacy and safety in man, a phase II clinical trial in 10 patients with partially reversible chronic airflow obstruction was carried out. The trial was designed as a double-blind, randomized, five-period change-over study. Zardaverine (at single doses of 1.5 mg, 3.0 mg, or 6.0 mg), salbutamol (0.3 mg) and placebo were administered by metered dose inhaler on separate days. As evaluated by spirometry over a time period of 4 h, salbutamol induced a significant bronchodilatation. In contrast, Zardaverine did not improve airway function in these patients. Unwanted effects of the study medication were not observed.

Comparative investigation of the effects of zardaverine and theophylline on pulmonary function in rats.[Pubmed:7925141]

Exp Lung Res. 1994 May-Jun;20(3):235-50.

Zardaverine (Byk Gulden, Konstanz, Germany) is a new selective phosphodiesterase (PDE) III/IV inhibitor. The bronchodilating and bronchoprotective potency of Zardaverine and the nonselective PDE inhibitor theophylline was compared by measuring typical spontaneous and forced respiratory function parameters in anesthetized female Wistar rats using whole-body plethysmography. Zardaverine (3, 10, 30 mumol/kg) and theophylline (30, 100, 300 mumol/kg), respectively, were given orally in 4% Methocel/0.9% saline solution 20 min before measurement. One week before treatment, control measurements were performed in the same animals after administration of the vehicle. When spontaneously breathing, the 30 mumol/kg Zardaverine- (300 mumol/kg theophylline-) treated animals showed significant changes: a 23% (14% ns) decrease in lung resistance and a 43% (25%) increase in dynamic compliance. These changes can be interpreted as an indication of bronchodilation, since quasistatic lung compliance was unchanged. In the acetylcholine challenge test, treatment with only 10 mumol/kg Zardaverine (but 300 mumol/kg theophylline) revealed significant changes compared to control measurement: a 37% (28%) lower resistance and 85% (44%) higher compliance. It has been determined that Zardaverine is more than 30 times as potent as theophylline in inhibiting acetylcholine-induced bronchospasms, which is also supported by forced expiratory flow data.

Phosphodiesterase 3/4 inhibitor zardaverine exhibits potent and selective antitumor activity against hepatocellular carcinoma both in vitro and in vivo independently of phosphodiesterase inhibition.[Pubmed:24598942]

PLoS One. 2014 Mar 5;9(3):e90627.

Hepatocellular carcinoma (HCC) is the fifth common malignancy worldwide and the third leading cause of cancer-related death. Targeted therapies for HCC are being extensively developed with the limited success of sorafinib. In the present study, we investigated the potential antitumor activity of Zardaverine, a dual-selective phosphodiesterase (PDE) 3/4 inhibitor in HCC cells both in vitro and in vivo. Although all Zardaverine, PDE3 inhibitor trequinsin and PDE4 inhibitor rolipram increased intracellular cAMP levels through inhibiting PDE activity, only Zardaverine significantly and selectively inhibited the proliferation of certain HCC cells, indicating that the antitumor activity of Zardaverine is independent of PDE3/4 inhibition and intracellular cAMP levels. Further studies demonstrated that Zardaverine induced G0/G1 phase cell cycle arrest of sensitive HCC cells through dysregulating cell cycle-associated proteins, including Cdk4, Cdk6, Cdk2, Cyclin A, Cyclin E, p21 and Rb. Notably, Rb expression was reversely related to the cell sensitivity to Zardaverine. The present findings indicate that Zardaverine may have potential as targeted therapies for some HCC, and the likely mechanism of action underlying its selective antitumor activity may be related to its regulation of Rb or Rb-associated signaling in cell cycles.

Zardaverine and aerosolised iloprost in a model of acute respiratory failure.[Pubmed:12952271]

Eur Respir J. 2003 Aug;22(2):342-7.

In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor Zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane-A2-mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from approximately 2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 microg x kg(-1) for 15 min caused a decrease in pulmonary artery pressure (Ppa) and a limitation of maximum shunt flow to approximately 37%. When nebulised PGI2 was combined with subthreshold intravascular Zardaverine, which did not affect pulmonary haemodynamics per se, the duration of the PGI2 effect was increased. Aerosolisation of 3 microg x kg(-1) PGI2 resulted in a transient decrease in Ppa and a reduction in shunt flow. In the presence of subthreshold Zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 microg x kg(-1)) for 15 min caused a more sustained decrease in Ppa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to approximately 32%. Most impressively, when combined with subthreshold Zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to approximately 8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.

Actions of the phosphodiesterase inhibitor zardaverine on guinea-pig ventricular muscle.[Pubmed:1700309]

Naunyn Schmiedebergs Arch Pharmacol. 1990 Aug;342(2):221-7.

The positive inotropic action of the phosphodiesterase inhibitor Zardaverine was investigated in guinea-pig heart muscle. In right papillary muscles, 1-30 microM Zardaverine reversibly increased the force of contraction in a concentration-dependent manner. This effect was accompanied by a shortening of contraction and relaxation times. Resting membrane potential was unchanged, whereas action potential amplitude was significantly increased and duration was reduced. In papillary muscles partially depolarised with 22 mM K+, Zardaverine (10 and 30 microM) restored slow action potentials, which were not influenced by cimetidine, propranolol or prazosin but were blocked by the calcium channel blocker (+)-nitrendipine or the muscarinic agonist carbachol. cAMP-specific phosphodiesterase III, isolated from guinea-pig ventricular muscle was inhibited by Zardaverine as was cAMP-specific phosphodiesterase IV, isolated from dog trachea (IC50s: 0.5 and 0.8 microM, respectively). The results suggest that the observed positive inotropic and electrophysiological effects result from an inhibition of cellular phosphodiesterase.