PDE5 Inhibitors Attenuate Exaggerated Inflammatory Resp

03 Jun 2018 01:26
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PDE5 Inhibitors Correct Transepithelial Chloride Transport in Cystic Fibrosis: Inhalational Administration. Figure 4. Effect of parenteral (i.p.) administration of Fildena (A; 0.7 mg/kg body weight) and of vardenafil (B; 0.14 mg/kg body weight) on CFTR-dependent chloride secretion assessed by means of the nasal potential difference (PD) in wild-type (WT) and F508del-CF mice. In F508del mice, the chloride conductance in the presence of 200 μM DIDS (4-4′-diisothiocyanostilbene-2,2′-disulphonic acid), an inhibitor of alternative chloride channels, was much higher after Fildena injection than following placebo treatment.

This suggests the possibility of accumulation if taken regularly and in short intervals, which may result in an increased risk of side effects with excessive use. Based on their relatively high systemic clearance after intravenous administration, Fildena, and vardenafil can be classified as non-restrictively cleared drugs with intermediate to high hepatic extraction ratio. The major route of elimination for all PDE5 inhibitors is hepatic metabolism, with renal excretion of unchanged drug accounting for 1% or less of the elimination pathways.

Administration of a high-fat meal had no significant effect on the rate and extent of absorption of Fildena but decreased the rate of absorption for Fildena and vardenafil. PDE inhibitors increase cAMP by inhibiting one or more enzymes involved in cAMP degradation. Non-specific PDE inhibitors such as IBMX, theophylline, and DPMX (7-methyl-1,3-dipropylxanthine) have been shown to activate normal and mutated CFTR chloride channels in epithelia ( Chappe et al., 1998 ). Due to impact on the cAMP pathway and activity at low concentrations, studies have looked at the effect of methylxanthines on the cAMP activated CFTR channel.

As an important second messenger signaling molecule, cAMP controls a wide variety of eukaryotic and prokaryotic responses to extracellular cues ( Antoni, 2000 ). As CF is characterized by a defective cAMP-dependent chloride conductance in epithelial cells, it could be expected that modulating intracellular levels of the second messenger would bring beneficial therapeutic effects for patients with CF. PDE Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis. It has been shown that selective PDE7 inhibition or dual PDE4/7 inhibition may provide a novel therapeutic approach for the treatment of chronic lymphocytic leukemia (CLL) by enhancing killing and increasing specificity for CLL cells ( Zhang et al., 2008 ).

PDE7s are characterized by their high affinity and selectivity for cAMP as a substrate ( Gardner et al., 2000 ; Hetman et al., 2000a ; Sasaki et al., 2000 ; Smith et al., 2003 ; Pitts et al., 2004 ; Vergne et al., 2004 ; Zhang et al., 2008 ). Expression is abundant in T cells, eosinophils and neutrophils, epithelial cells, vascular smooth muscle cells, and lung fibroblasts ( Smith et al., 2003 ). Several distinct PDE7 inhibitors have been reported ( Pitts et al., 2004 ; Vergne et al., 2004 ). As PDE7 is simultaneously expressed in inflammatory cells and in the brain highlights the potential role of PDE7 as drug target for neuroinflammation. PDE4 inhibitors have been developed for the treatment of asthma and COPD ( Essayan, 2001 ). Rolipram, a highly selective first generation PDE4 inhibitor, has been used for many years as a research tool to investigate the role of PDE4.

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