Effects of Roflumilast, a Phosphodiesterase-4 Inhibitor, on Hypoxia- and Monocrotaline-Induced Pulmonary Hypertension in Rats

Izikki, Mohamed; Raffestin, Bernadette; Klar, Jürgen; Hatzelmann, Armin; Marx, Degenhard; Tenor, Hermann; Zadigue, Patricia; Adnot, Serge; Eddahibi, Saadia

doi:10.1124/jpet.108.148742

Cited by 34 publications

(25 citation statements)

References 25 publications

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“…It is noteworthy that similar improvements in Sp,O 2 have previously been reported during exercise following ICS therapy in asthma and were independent of change in pulmonary function [11]. It is therefore possible, but unproven, that anti-inflammatory effects in peripheral airways and the adjacent pulmonary vascular bed may occur in COPD following systemic ROF therapy [28]. Treatment effects on Sp,O 2 may be better uncovered using treadmill exercise, which, in COPD, results in greater arterial oxygen desaturation than weight-supported cycling [29].…”

Section: Pre-specified Subgroup Analysessupporting

confidence: 52%

Physiological effects of roflumilast at rest and during exercise in COPD

O’Donnell¹,

Bredenbröker²,

Brose³

et al. 2011

Eur Respir J

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The purpose of this study was to investigate the effects of 500 mg roflumilast, taken once daily for 12 weeks, on airway physiology during rest and exercise in patients with moderateto-severe chronic obstructive pulmonary disease.This randomised, double-blind, placebo-controlled, parallel-group study was conducted in 250 patients with a post-bronchodilator forced expiratory volume in 1 s (FEV1) of 30-80% predicted and a functional residual capacity of o120% pred. Pre-and post-bronchodilator spirometry and body plethysmography, and pre-bronchodilator constant work rate cycle exercise at 75% of peak work rate were evaluated. Exercise measurements included ventilation, breathing pattern, inspiratory capacity (IC) and arterial oxygen saturation measured by pulse oximetry (Sp,O 2 ).Compared with placebo, 12 weeks of treatment with roflumilast was associated with: small but progressive increases in pre-and post-bronchodilator FEV1 and FEV1/forced vital capacity; small decreases in specific airway resistance; and no significant changes in resting vital capacity, IC or measurements of lung hyperinflation. There was no treatment effect on exercise endurance time. At a standardised exercise time after roflumilast, compared with placebo, IC increased by 0.12 L (p50.008) and Sp,O 2 increased by 0.7% (p50.020); peak ventilation increased by 1.9 L?min -1 (p50.014).Roflumilast treatment was associated with progressive improvement of airway function but not lung hyperinflation. Newly described non-bronchodilator effects of roflumilast included small but consistent improvements in air trapping and Sp,O 2 during exercise.

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Section: Pre-specified Subgroup Analysessupporting

confidence: 52%

Physiological effects of roflumilast at rest and during exercise in COPD

O’Donnell¹,

Bredenbröker²,

Brose³

et al. 2011

Eur Respir J

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“…38 Furthermore, inhibition of cAMP metabolism attenuates acute hypoxic vasoconstriction and monocrotaline-induced and chronic hypoxia-induced PAH and vascular remodeling and potentiates the therapeutic effects of prostacyclin analogues in hypoxic pulmonary vascular remodeling. 39,40 These data suggest that in addition to cyclic guanosine monophosphate, the cAMP-dependent signaling pathway may play important role in regulating pulmonary vascular tone and remodeling. Importantly, our recent study in preglomerular vascular smooth muscle cells, which predominantly express PDE4, indicates that 2ME inhibits cAMP metabolism.…”

Section: Discussionmentioning

confidence: 95%

Synergistic Therapeutic Effects of 2-Methoxyestradiol With Either Sildenafil or Bosentan on Amelioration of Monocrotaline-induced Pulmonary Hypertension and Vascular Remodeling

Tofovic

Jones²,

Bilan³

et al. 2010

Journal of Cardiovascular Pharmacology

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2-Methoxyestradiol (2ME) is a major nonestrogenic metabolite of estradiol. Our previous studies suggest that 2ME, in several models of cardiac and/or vascular injury, strongly inhibits cardiac and vascular remodeling. Furthermore, our most recent study shows that in male rats, 2ME attenuates the development and retards the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH), and in female rats, 2ME eliminates the exacerbation of PAH and the increased mortality due to ovariectomy. The current standard of care of patients with PAH includes treatment with an endothelin receptor antagonist (eg, bosentan) or a phosphodiesterase5 inhibitor (eg, sildenafil). Moreover, combination therapy is often prescribed. Therefore, in the present study, we compared the efficacy of 2ME (10 μg · kg(-1) · h(-1), 2ME-10) to the effects of bosentan (200 mg/kg; BOS), sildenafil (50 mg/kg; SIL), and their respective combinations with 2ME-10 (2ME + BOS and 2ME + SIL groups, respectively). Treatments were initiated 12 days after administration of MCT (60 mg/kg). Twenty-eight days after MCT administration, right ventricular peak systolic pressure was measured and morphometric analysis was conducted. 2ME exhibited beneficial effects in pulmonary hypertensive animals and had efficacy comparable to that of BOS and SIL. Importantly, combination treatments had favorable effects on survival, vascular remodeling, and inflammatory response, and the 2ME + SIL combination was significantly more efficacious than any other treatment. These results indicate that 2ME is effective in experimental PAH and suggests that 2ME may provide additional therapeutic benefit over existing drugs used for the treatment of pulmonary hypertension.

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“…In animal studies, roflumilast mitigates key COPD-related disease mechanisms, such as tobacco smoke-induced lung inflammation [26][27][28][29][30][31], mucociliary malfunction [32][33][34][35], lung fibrotic and emphysematous remodeling [32], oxidative stress [32,34,36] and pulmonary vascular remodeling [32,37].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Roflumilast for the treatment of chronic obstructive pulmonary disease

Rabe¹

2010

Expert Review of Respiratory Medicine

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Roflumilast is a new phosphodiesterase 4 inhibitor that has recently completed Phase III trials for the treatment of chronic obstructive pulmonary disease (COPD). Preclinical studies have shown that roflumilast targets inflammatory processes in COPD, with beneficial effects on tobacco-induced lung inflammation, lung fibrosis and remodeling, mucociliary malfunction and oxidative stress. Two recent, 1-year Phase III trials in COPD have shown that roflumilast reduces exacerbations and improves lung function in patients with COPD who have symptoms of chronic bronchitis and a history of exacerbations. Two other 6-month Phase III trials have demonstrated the beneficial effects of roflumilast in patients already receiving treatment with the long-acting β-agonist salmeterol or the long-acting muscarinic antagonist tiotropium. This article reviews the pharmacology, pharmacokinetics and preclinical pharmacology of roflumilast, the clinical studies supporting its use in COPD and its side-effect profile.

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Effects of Roflumilast, a Phosphodiesterase-4 Inhibitor, on Hypoxia- and Monocrotaline-Induced Pulmonary Hypertension in Rats

Cited by 34 publications

References 25 publications

Physiological effects of roflumilast at rest and during exercise in COPD

Physiological effects of roflumilast at rest and during exercise in COPD

Synergistic Therapeutic Effects of 2-Methoxyestradiol With Either Sildenafil or Bosentan on Amelioration of Monocrotaline-induced Pulmonary Hypertension and Vascular Remodeling

Roflumilast for the treatment of chronic obstructive pulmonary disease

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