Effect of aerosolized administration of KF19514, a phosphodiesterase 4 inhibitor, on bronchial hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea‐pigs

Myou, Shigeharu; Fujimura, Masaki; Kurashima, Kazuyoshi; Tachibana, Hideki; Hirose, Toshiharu; Nakao, Shinji

doi:10.1046/j.1365-2222.2000.00782.x

Cited by 8 publications

(4 citation statements)

References 26 publications

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“…14,16,27) In animal models of asthma, these agents have been shown to inhibit the induction of airway hyperresponsiveness and the accumulation of inflammatory cells including eosinophils elicited by allergen challenge. 14,41,42) It is assumed from our findings that the antiinflammatory effects of theophylline and selective PDE 4 inhibitors in allergic airway inflammation were due, at least in part, to the removal of eosinophils from the inflammatory sites by the induction of apoptosis. It would therefore be of interest to assess further these agents as antiasthma drugs.…”

Section: Discussionmentioning

confidence: 86%

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Wang

Masu

Tamura

et al. 2005

Biological & Pharmaceutical Bulletin

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Bronchial asthma is a disease characterized by chronic airway inflammation associated with the accumulation and activation of inflammatory cells, such as eosinophils, in the bronchial wall and airway lumen. Eosinophils at the site of inflammation release preformed and newly synthesized mediators, including eosinophil cationic protein, major basic protein, leukotriene C 4 , and reactive oxygen. These mediators contribute to the formation of the pathological features of asthmatic airways such as bronchoconstriction, mucus hypersecretion, microvascular leakage, submucosal edema, and epithelial shedding, which lead to the clinical features of asthma, hyperresponsiveness, and airway narrowing. [1][2][3][4][5] Eosinophils cultured in the absence of hematopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5 undergo apoptosis, which is physiologic cell death characterized by morphologic changes such as membrane blebbing and nuclear condensation, and by the degradation of DNA into oligonucleosomesized fragments showing a "ladder" pattern on agarose gel. [6][7][8] Apoptotic eosinophils have been shown to be removed from the tissue without releasing inflammatory mediators after ingestion by macrophages, 8) which is believed to be one of the important mechanisms in the resolution of inflammation.9) GM-CSF and IL-5, which have been detected in sputum, bronchoalveolar lavage fluid, and bronchial tissues from asthmatics, 5) prolong the survival of tissue eosinophils through the prevention of apoptosis, 10,11) leading to the development and maintenance of airway inflammation. Therefore the induction of apoptosis in eosinophils would be beneficial in the treatment of asthma. The induction of apoptosis in airway eosinophils by the administration of anti-Fas antibody or inhaled steroid is reported to be associated with the reduction or termination of asthmatic airway inflammation in vivo. 12,13) cAMP is well known as a second messenger mediating intracellular signal transduction evoked by the binding of agonists to their cell-surface receptors. The concentration of intracellular cAMP is dependent on the catalysis rate of ATP to cAMP by adenylate cyclase and of cAMP to 5Ј-adenosine monophosphate by cyclic nucleotide phosphodiesterases (PDEs).14) PDEs comprise at lease 11 families containing, in total, more than 50 different PDE enzyme variants, the differentiation of which is based on the primary protein and cDNA sequences, substrate specificity, regulation of enzymatic activity, and calcium/calmodulin dependence.15) The increased concentration of intracellular cAMP is known to suppress the functions of inflammatory cells.14,16) With regard to eosinophils of which the PDE isoenzyme is exclusively type 4, 17) selective inhibitors of PDE 4 and theophylline, a nonselective PDE inhibitor, have been shown to inhibit chemotaxis, adhesion, degranulation, and the release of active oxygen by an increase in the cAMP content.14,16,18) Furthermore, PDE 4 inhibitors and theophylline, as well...

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Section: Discussionmentioning

confidence: 86%

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Wang

Masu

Tamura

et al. 2005

Biological & Pharmaceutical Bulletin

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“…KF19514 is a dual PDE4/PDE1 inhibitor that exhibited a potent anti-inflammatory effect in animal models of acute allergen challenge for inhibiting antigen-induced bronchospasm. 91 It was also shown that KF19514 suppressed inflammation and arrest airway remodelling in a murine model of chronic asthma. 92 Thus, simultaneous inhibition of PDE1c and PDE4 could be seen as a potential drug target in asthma treatment, but more precise studies are necessary in both preclinical and, mainly, clinical research.…”

Section: Dual Pde4/pde1 Inhibitorsmentioning

confidence: 99%

New Avenues for Phosphodiesterase Inhibitors in Asthma

Matera¹,

Ora²,

Cavalli³

et al. 2021

JEP

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Introduction: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease. Areas Covered: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma. Expert Opinion: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.

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“…Recently, hybrid molecules combining salmeterol with two different PDE4Is, roflumilast and phthalazinone, and formoterol with the PDE4I, phthalazinone, have been developed [52,53]. Table 2 summarizes the information known about functionality of developing drugs in preclinical phase [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64].…”

Section: Drugs In Preclinical Developmentmentioning

confidence: 99%

“…Oral Inhibits neutrophil recruitment and TNF-a in BAL Prevents alveolar collapse, bronchoconstriction and lung remodeling Inhibits fibroproliferation in chronic asthma [48,61] Dual phosphodiesterase I and IV inhibitor KF19514 (Kyowa Hakko Kogyo) Inhaled # Airway accumulation of neutrophils and eosinophils, epithelial and sub-epithelial collagen thickness in chronic asthma # antigen induced bronchial hyper-responsiveness [49,62,63] Hybrid --Phosphodiesterase 4 inhibitor and muscarinic (M 3 ) antagonist UCB-101333-3 (Union Chimique Belge Pharma) Inhaled # inflammatory cells and murine keratinocyte level (equivalent to interleukin-8 in humans) in BAL fluid [50] Hybrid --Phosphodiesterase 4 inhibitor and LABA GS-5759 (Gilead sciences) Inhaled Induced bronchodilation Inhibits inflammatory cell recruitment and inflammatory cytokine production from mononuclear cells, neutrophils and fibroblasts [51,64] Salmeterol-roflumilast Inhaled " b2-adrenoceptor agonist effect compared with isoprenaline and salmeterol † [52] Salmeterol-phthalazinone Inhaled " b2-adrenoceptor agonist effect compared with isoprenaline and salmeterol † [52] Formoterol-phthalazinone Inhaled " b2-adrenoceptor agonist effect † There are no trials comparing theophylline with roflumilast so the contention that more selective PDE inhibition might be better clinically has not been tested directly. Further, clinical studies of theophylline and roflumilast were performed in different eras of clinical COPD research with different types of end points, study design and size, and different concurrent medications.…”

Section: Inhaledmentioning

confidence: 99%

Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs

Mulhall

Droege

Ernst

et al. 2015

Expert Opinion on Investigational Drugs

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After decades of research in drug development, PDE4Is are a welcomed addition to the COPD therapeutic armamentarium. In its current clinical role, the salubrious clinical effects of PDE4I in reducing exacerbations and stabilizing the frequent exacerbator phenotype have to be cautiously balanced with numerous adverse effects. Developing drugs may provide similar or better clinical benefits while minimizing adverse effects by changing the mode of drug delivery to inhaled formulations, combining dual PDE isoenzyme inhibitors (PDE1/4I and PDE3/4I) and by forming hybrid molecules with other bronchodilators (muscarinic receptor antagonist/PDE4I and β2-agonist/PDE4I).

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Effect of aerosolized administration of KF19514, a phosphodiesterase 4 inhibitor, on bronchial hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea‐pigs

Abstract: The results indicate that inhaled PDE inhibitors might be useful for treatment of bronchial asthma.

Cited by 8 publications

References 26 publications

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

New Avenues for Phosphodiesterase Inhibitors in Asthma

Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs

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