ArifloTM(SB 207499), a Second Generation Phosphodiesterase 4 Inhibitor for the Treatment of Asthma and COPD: from Concept to Clinic

Torphy, Theodore J.; Barnette, Mary S.; Underwood, David C.; Griswold, Don E.; Christensen, Siegfried B.; Murdoch, Robert; Nieman, Richard B.; Compton, Christopher

doi:10.1006/pupt.1999.0181

Cited by 152 publications

(124 citation statements)

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“…In contrast to corticosteroids, PDE 4 inhibitors have a potent inhibitory effect on neutrophils [97], indicating that they may be useful anti-inflammatory treatments for COPD. There is preliminary evidence that a PDE 4 inhibitor cilomilast improves lung function and symptoms in patients with COPD, although whether this is due to inhibition of cytokines is not yet certain [98].…”

Section: Phosphodiesterase 4 Inhibitorsmentioning

confidence: 99%

Cytokine modulators as novel therapies for airway disease

Barnes¹

2001

Eur Respir J

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Cytokine modulators as novel therapies for airway disease. P.J. Barnes. #ERS Journals Ltd 2001. ABSTRACT: Cytokines play a critical role in orchestrating and perpetuating inflammation in asthma and chronic obstructive pulmonary disease (COPD), and several specific cytokine and chemokine inhibitors are now in development for the future therapy of these diseases.Anti-interleukin (IL)-5 is very effective at reducing peripheral blood and airway eosinophil numbers, but does not appear to be effective against symptomatic asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in asthma. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, as systemic delivery causes side-effects. Inhibition of tumour necrosis factor-a may be useful in severe asthma and for treating severe COPD with systemic features.Many chemokines are involved in the inflammatory response of asthma and COPD and several low-molecular-weight inhibitors of chemokine receptors are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which block neutrophil and monocyte chemotaxis) are in clinical development for the treatment of asthma and COPD respectively.Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side-effects with these nonspecific inhibitors may be reduced by the use of inhalational route of delivery.

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Section: Phosphodiesterase 4 Inhibitorsmentioning

confidence: 99%

Cytokine modulators as novel therapies for airway disease

Barnes¹

2001

Eur Respir J

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“…The cAMP-specific PDE4 has attracted considerable attention for the treatment of airway inflammatory diseases, since its inhibition results in attenuated inflammatory responses (1,3,4). However, the therapeutic potential of PDE4 inhibitors has been limited by the side effects of nausea and emesis, observed both in humans and in various animal species following the administration of structurally diverse compounds (5-9).…”

Section: Introductionmentioning

confidence: 99%

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Robichaud¹,

Stamatiou²,

Jin³

et al. 2002

J. Clin. Invest.

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IntroductionCyclic nucleotides cAMP and cGMP are degraded by at least 11 families of phosphodiesterases (PDEs 1-11) classified according to their gene sequence, substrate specificity, biochemical regulation, and sensitivity to inhibitors (1, 2). The cAMP-specific PDE4 has attracted considerable attention for the treatment of airway inflammatory diseases, since its inhibition results in attenuated inflammatory responses (1,3,4). However, the therapeutic potential of PDE4 inhibitors has been limited by the side effects of nausea and emesis, observed both in humans and in various animal species following the administration of structurally diverse compounds (5-9). A major challenge in the development of new generations of PDE4 inhibitors is the improvement of the therapeutic index of this class of compounds.PDE4 enzymes use a common binuclear ion center as the core catalytic machinery (10). The reversible binding of the cation cofactors (e.g., Mg 2+ ) results in the presence of two coexisting conformers that bind inhibitors differently: the holoenzyme (enzyme bound with Mg 2+ ) and the apoenzyme (free enzyme) (11,12). In the past, it was observed that the potency of some inhibitors (e.g., rolipram) on PDE activity deviated from their affinity at the high-affinity rolipram binding site (HARBS); this led to the proposal that inhibitors with a reduced potency on the HARBS may have an improved therapeutic index over that of firstgeneration compounds (13-15). It has now been clarified that the HARBS corresponds to the holoenzyme conformer responsible for PDE4 catalysis (11,12).The PDE4 family is composed of four subtypes (PDE4A-D) and multiple splice variants (16). If it were possible to identify the subtype(s) responsible for the beneficial and the side effects associated with PDE4 inhibition, then subtype-selective inhibitors devoid of the tendency to induce nausea and vomiting could be developed. The mechanism of the emetic response associated with PDE4 inhibitors is thought to be a consequence of the inhibition of PDE4 in nontarget tissues (9, 13). It is believed that PDE4 inhibitors produce a pharmacologi- A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing α 2 -adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4- -2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice c...

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“…Recently, attention has focused on the inhibition of phosphodiesterase isoenzyme-4 (PDE4) as a molecular target for COPD (and asthma) (Torphy et al, 1999). Evidence suggests that the subsequent intracellular elevation in cAMP induces airway smooth muscle relaxation, alleviates inflammatory edema, and suppresses immunocompetent cell activation and migration in models of acute pulmonary inflammation (Sekut et al, 1995;Torphy et al, 1999).…”

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confidence: 99%

“…However, in chronically LPS-exposed animals, the airway histology showed extensive migration of neutrophils but little evidence of airway collagen or elastic fiber remodeling, smooth muscle hypertrophy, or epithelial shedding. Both dexamethasone and rolipram were equieffective at attenuating the chronic LPS-induced airway infiltration of inflammatory cells, possibly due to their inhibitory effect on TNF-␣ production (Barnes et al, 1999;Torphy et al, 1999).…”

mentioning

confidence: 99%

“…Both dexamethasone and rolipram attenuated goblet cell hyperplasia after chronic LPS exposure. Suppression of inflammatory cell activity with rolipram or dexamethasone reduces the production of reactive oxygen species, eicosanoids, and protease, which stimulate goblet cell secretion and contribute to the etiology that induces a hypersecretory phenotype and edema after chronic LPS (Barnes and Adcock, 1993;Torphy et al, 1999).…”

mentioning

confidence: 99%

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Goblet Cell Hyperplasia, Airway Function, and Leukocyte Infiltration after Chronic Lipopolysaccharide Exposure in Conscious Guinea Pigs: Effects of Rolipram and Dexamethasone

Toward¹,

Broadley²

2002

J Pharmacol Exp Ther

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The effects of chronic exposures (nine, 48 h apart) of conscious guinea pigs to lipopolysaccharide (LPS) (30 g ⅐ ml Ϫ1 , 1 h) on airway function, airway histology (in particular, goblet cell numbers), and inflammatory cell infiltration of the lungs were examined as a model of chronic inflammatory lung disease, such as chronic obstructive pulmonary disease. The sensitivity of these parameters to treatment with the corticosteroid, dexamethasone, or the phosphodiesterase-4 (PDE4) inhibitor, rolipram, was determined. As the number of LPS exposures increased, there was a progressively persistent bronchoconstriction after each exposure. After nine LPS exposures, there was evidence on histological examination of airway infiltration of, predominantly, neutrophils in perivascular, peribronchial, and alveolar tissues. After chronic LPS exposure, the airway epithelium possessed a marked goblet cell hyperplasia and evidence of inflammatory edema, features contributory to reduced airway caliber. Treatment with dexamethasone (20 mg ⅐ kg Ϫ1 ) or rolipram (1 mg ⅐ kg Ϫ1 ), administered (i.p.) 24 and 0.5 h before exposure and 24 and 47 h after each subsequent exposure, attenuated the inflammatory cell infiltration into the airway, goblet cell hyperplasia, and inflammatory edema. Dexamethasone exacerbated, whereas rolipram reversed, the chronic LPS-induced bronchoconstrictions. This study demonstrates that chronic LPS causes persistent bronchoconstriction, neutrophilic airway inflammation, goblet cell hyperplasia, and edema. These rolipram-sensitive features suggest the potential of PDE4 inhibitors in chronic inflammatory lung diseases.Chronic mucus hypersecretion is an important symptomatic and pathological feature of a heterogeneous group of chronic respiratory diseases that includes chronic bronchitis, chronic obstructive pulmonary disease (COPD), and asthma (Rogers, 1994;Jackson, 2001). Persistent mucus overproduction contributes to reduced airway caliber and the occlusion of small airways (reduced FEV 1 ), productive cough, and labored breathing (Jackson, 2001). Individuals with chronic mucus hypersecretion also suffer from an increased frequency and duration of respiratory infection, causing further exacerbation of their original respiratory pathology (Jackson, 2001).The two major sources of mucus secretion in the respiratory tract are the surface epithelial goblet cells and mucous cells of the submucosal glands. In normal lungs, goblet cells are present in the large bronchi, becoming increasingly sparse toward the bronchioles. The submucosal glands are restricted to the large airways with their density decreasing with airway caliber, such that they are absent in the bronchioles. In chronic respiratory diseases, such as COPD and asthma, submucosal glands increase in size (hypertrophy), and the number of goblet cells is increased (hyperplasia), becoming more dense in the peripheral airways, via a phenotypic conversion of nongoblet epithelial cells (metaplasia) (Rogers, 1994;Jackson, 2001). The increased ratio of goble...

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ArifloTM(SB 207499), a Second Generation Phosphodiesterase 4 Inhibitor for the Treatment of Asthma and COPD: from Concept to Clinic

Cited by 152 publications

References 1 publication

Cytokine modulators as novel therapies for airway disease

Cytokine modulators as novel therapies for airway disease

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Goblet Cell Hyperplasia, Airway Function, and Leukocyte Infiltration after Chronic Lipopolysaccharide Exposure in Conscious Guinea Pigs: Effects of Rolipram and Dexamethasone

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