Dose dependent effects of tadalafil and roflumilast on ovalbumin-induced airway hyperresponsiveness in guinea pigs

Urbanová, Anna; Medvedova, Ivana; Kertys, Martin; Mikolka, Pavol; Kosutova, Petra; Mokrá, Daniela; Mokrý, Juraj

doi:10.1080/01902148.2017.1386735

Cited by 17 publications

(7 citation statements)

References 39 publications

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“…Roflumilast protected against CSE-induced cell death in Beas-2B cells, suggesting that roflumilast might do well in COPD treatment (Kyung et al, 2018 ). In vivo efficacies of roflumilast in airway inflammatory models suggested that roflumilast displayed bronchodilatory activity in spasmogen-challenged rats and guinea pigs and exhibited dose-dependent efficacy in airway hyperresponsiveness associated with eosinophilic inflammation evoked by ovalbumin (OVA) (Urbanova et al, 2017 ). Izikki et al found that roflumilast could also inhibit hypoxia- and monocrotaline-induced severe pulmonary vascular remodeling and hypertension in rats (Izikki et al, 2009 ).…”

Section: Approved Pde4 Inhibitors For the Treatment Of Inflammatory Dmentioning

confidence: 99%

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

2018

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Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.

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Section: Approved Pde4 Inhibitors For the Treatment Of Inflammatory Dmentioning

confidence: 99%

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

2018

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“…The remaining four sensitized groups were treated with theophylline at the doses of 5, 10, or 20 mg/kg, given intraperitoneally for one day (single dose) or for seven days (seven doses) from the 15 th day of sensitization. Detailed information about sensitization procedure can be found in our previous publication (29). Samples of blood were taken to the K 2 EDTA tubes immediately after sacrificing the animals.…”

Section: Application Of the Methodsmentioning

confidence: 99%

Quantification of Theophylline in Guinea Pig Plasma by LC-MS/MS Using Hydrophilic Interaction Liquid Chromatography Stationary Phase: Method Development, Validation, and Application in Study

Kertys

Urbanová

Mokrý

2017

Acta Medica Martiniana

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Theophylline has been used in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD) for over 70 years. In order to maximize the effectiveness and safety of theophylline therapy it is important to individualize the dosage of the drug. In our study we focused on determination of theophylline concentrations in guinea pig plasma. A rapid, specific, and reliable LC-MS/MS-based method was developed and validated according to European Medicine Agency (EMA) guidelines. A hydrophilic interaction liquid chromatography (HILIC) separation mode for reduction time of sample preparation was used. The analysed sample was quantified in a positive ionization mode. Multiple reaction monitoring (MRM) using transition m/z 181.06→124.06 and m/z 187.17→127.06 was performed to quantify theophylline with deuterated internal standard ([2H6]-theophylline), respectively. Modification of collision energies was performed in parallel with chromatographic separation to further eliminate interference from the matrix. The method was validated for a range of 0.5 to 30 μg/mL of plasma sample. The intra-day and inter-day precision and accuracy of the quality control samples at low, me dium, and high concentration levels exhibited relative standard deviations (RSD) of less than 10 %. The method was successfully applied for the quantitation of theophylline in guinea pig plasma for better understanding its effects in a model of ovalbumin-induced allergic inflammation.

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“…34 The significant suppression of both in vivo and in vitro contractile responses to the cumulative doses of acetylcholine and histamine in ovalbumin-sensitized animals was associated with decreased numbers of circulating leukocytes and eosinophils and concentrations of interleukin (IL)-4, IL-5 and TNF-α in the lung homogenate. 35 However, Banner and Page failed to show any significant effects of acute or chronic administration of PDE5 inhibitor in ovalbumininduced eosinophil infiltration in guinea pigs. 36 PDE7 is present in the soluble fraction of T cells, both CD4 + and CD8 + , and controls intracellular levels of cAMP.…”

Section: Dovepressmentioning

confidence: 97%

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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Dose dependent effects of tadalafil and roflumilast on ovalbumin-induced airway hyperresponsiveness in guinea pigs

Abstract: The selective PDE4 and PDE5 inhibitors alleviated allergic airway inflammation, with more significant effects at the higher doses.

Cited by 17 publications

References 39 publications

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

Quantification of Theophylline in Guinea Pig Plasma by LC-MS/MS Using Hydrophilic Interaction Liquid Chromatography Stationary Phase: Method Development, Validation, and Application in Study

New Avenues for Phosphodiesterase Inhibitors in Asthma

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