Phosphodiesterase 4 Inhibitors for the Treatment of COPD

Sturton, Graham; Fitzgerald, Mary

doi:10.1378/chest.121.5_suppl.192s

Cited by 110 publications

(44 citation statements)

References 12 publications

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“…Furthermore, respiratory depression in general can be reversed by the administration of cAMP elevating agents (Arata et al 1993). Stimulation of the cAMP pathway reversed ventilatory depression in human studies as well as in vitro and in vivo animal studies (Lipworth, 2005;Ruangkittisakul and Ballanyi 2006;Sturton, 2002). In an in vitro brainstem spinal cord preparation, respiratory depression caused by opioids was reversed by applying the phosphodiesterase-4 specific inhibitor, rolipram (Ruangkittisakul and Ballanyi 2006).…”

Section: Discussionmentioning

confidence: 99%

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

Satkunendrarajah

Goshgarian

2008

Experimental Neurology

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High cervical spinal cord hemisection interrupts the descending respiratory drive from the medulla to the ipsilateral phrenic motoneurons, consequently leading to the paralysis of the ipsilateral hemidiaphragm. Previous studies have shown that chronic oral administration of theophylline, a phosphodiesterase inhibitor and an adenosine receptor antagonist, can restore function to the quiescent phrenic nerve and hemidiaphragm ipsilateral to hemisection. Both of these actions of theophylline result in an increase in 3′-5′-cyclic adenosine monophosphate (cAMP). Furthermore, the chronic theophylline-mediated respiratory recovery persists long after the animals have been weaned from the drug. To date, the precise cellular mechanisms underlying the recovery induced by theophylline are still not known. Since theophylline has two modes of action, in the present study we tested whether chronic administration of pentoxifylline, a non-selective phosphodiesterase inhibitor, rolipram, a phosphodiesterase-4 specific inhibitor, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, would induce recovery similar to that induced by theophylline in male Sprague Dawley rats following a left C2 spinal cord lesion. Recovery of left phrenic nerve activity was assessed at 5 or 10 days after the last drug administrations to assess the persistent nature of the recovery. Pentoxifylline, rolipram and DPCPX, all capable of modulating 3′, 5′-cyclic monophosphate (cAMP) levels, brought about long-term respiratory recovery in the phrenic nerve ipsilateral to the left C2 lesion at 5 and 10 days after the last drug administration. Therefore, these results suggest that compounds capable of regulating cAMP levels may be therapeutically useful in promoting functional recovery following spinal cord injury.

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Section: Discussionmentioning

confidence: 99%

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

Satkunendrarajah

Goshgarian

2008

Experimental Neurology

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“…3). Thus, there is compelling scientific rationale for the use of PDE4 inhibitors in COPD, although their clinical development has been slow [164,165]. Selective PDE4 inhibitors, such as rolipram, cilomilast and roflumilast, are active in several animal models of neutrophil inflammation, confirming their anti-inflammatory potential [166,167].…”

Section: Phosphodiesterase-4 Inhibitors Basic Researchmentioning

confidence: 99%

COPD: current therapeutic interventions and future approaches

Barnes¹

2005

Eur Respir J

233

143

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Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-a.Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kB and phosphoinositide-3 kinase-c. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B 4 antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema.More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.

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“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org Downloaded from animal models may be less sensitive to the anti-inflammatory effects of PDE 4 inhibition and that the clinical doses may be submaximal for efficacy to maintain a therapeutic window, yet side effects remained a problem even at those lower doses (Sturton and Fitzgerald, 2002).…”

mentioning

confidence: 99%

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

McCluskie

Klein²,

Linnevers³

et al. 2006

J Pharmacol Exp Ther

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Phosphodiesterase type 4 (PDE 4 ) inhibitors are currently being evaluated as potential therapies for inflammatory airway diseases. However, this class of compounds has been shown to cause an arteritis/vasculitis of unknown etiology in rats and cynomolgus monkeys. Studies in rodents have demonstrated the anti-inflammatory effects of PDE 4 inhibitors on lipopolysaccharide (LPS)-induced airway inflammation. The aim of this work was to assess the direct effects of PDE 4 inhibitors on inflammatory cells and cytokine levels in the lung in relation to therapeutic effects. The effects of the PDE 4 inhibitors 3-cyclopropylmethoxy-4-difluoromethoxy-N- [3,5-di-chloropyrid-4-yl

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Phosphodiesterase 4 Inhibitors for the Treatment of COPD

Cited by 110 publications

References 12 publications

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

COPD: current therapeutic interventions and future approaches

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

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