The Effect of Selective Phosphodiesterase Inhibitors in Comparison with other Anti-asthma Drugs on Allergen-induced Eosinophilia in Guinea-pig Airways

Banner, Katharine H.; Marchini, Francesco; Buschi, A.; Moriggi, Ermanno; Semeraro, C.; Page, Clive

doi:10.1006/pulp.1995.1005

Cited by 23 publications

(11 citation statements)

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“…We recently demonstrated beneficial and life-saving effects of the PDE3 inhibitor enoximone in status asthmaticus (32), which were based on enoximone's known bronchodilatory capacity (20). PDE3 inhibition literature of the 1990s did not show any antiinflammatory effects in animal models of allergic inflammation (33)(34)(35)(36). We suggest that this absence of proof may be due to inadequate dosing, a wrong model, and limited use of PDE3 inhibitors.…”

Section: Introductionmentioning

confidence: 93%

A pathophysiological role of PDE3 in allergic airway inflammation

et al. 2018

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Section: Introductionmentioning

confidence: 93%

A pathophysiological role of PDE3 in allergic airway inflammation

et al. 2018

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“…On closer inspection, PDE4A, PDE4B, PDE4D, and PDE7 were described in CD4 ϩ and CD8 ϩ human T lymphocytes (Giembycz et al, 1996). Functional studies have shown that PDE4 and to a lesser extent PDE3 inhibitors suppress proliferation of human Tlymphocytes in response to mitogen, anti-CD3, or allergen (Robicsek et al, 1991;Giembycz et al, 1996), cytokine generation (Crocker et al, 1996;Giembycz et al, 1996;Hatzelmann and Schudt, 2001), and mononuclear cell proliferation (Banner et al, 1995). The PHA-or anti-CD3-induced proliferation of CD4 ϩ and CD8 ϩ T-lymphocytes was inhibited in a concentration-dependent manner by rolipram, roflumilast, and cilomilast, consistent with the ability of PDE4 inhibitors to elevate intracellular cAMP in these cells (Giembycz et al, 1996;Hatzelmann and Schudt, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Slides were stained with Lendrum's stain, and differential cell counts were performed. In some experiments, the supernatant was collected for determination of eosinophil peroxidase (EPO) levels using a previously published technique (Banner et al, 1995).…”

mentioning

confidence: 99%

The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]

Boswell-Smith

Spina²,

Oxford³

et al. 2006

J Pharmacol Exp Ther

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The pharmacology of two novel, trequinsin-like PDE3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one], has been investigated in a number of in vitro and in vivo assays. Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 M) and RPL565 (10 M) (percentage control; 93 Ϯ 1.2 and 84.4 Ϯ 2.7, respectively). Contractile responses were suppressed for up to 12 h after termination of superfusion with RPL554 demonstrating a long duration of action. RPL554 and RPL565 inhibited, in a concentration-dependent manner, lipopolysaccharide-induced tumor necrosis factor ␣ release from human monocytes [IC 50 ; 0.52 M (0.38 -0.69) and 0.25 M (0.18 -0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [IC 50 ; 0.46 M (0.24 -0.9) and 2.90 M (1.6 -5.4), respectively]. The inhibitory effect of these drugs in vitro was translated into anti-inflammatory activity in vivo. RPL554 (10 mg/kg) and RPL565 (10 mg/kg) administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. Likewise, inhalation of dry powder containing RPL554 by conscious guinea pigs (25% in micronized lactose) 1.5 h before antigen exposure significantly inhibited the recruitment of eosinophils to the airways. Exposure of conscious guinea pigs to inhalation of dry powder containing RPL554 (2.5%) and RPL565 (25%) in micronized lactose significantly inhibited histamine-induced plasma protein extravasation in the trachea and histamine-induced bronchoconstriction over a 5.5-h period. Thus, RPL554 and RPL565 are novel, long-acting PDE 3/4 inhibitors exhibiting a broad range of both bronchoprotective and anti-inflammatory activities.It is now recognized that the second messenger cAMP plays a pivotal role in the regulation of cell function, and cyclic nucleotide phosphodiesterases (PDEs) are a diverse family of enzymes (1-11) responsible for the degradation of cAMP and are therefore potential drug targets for modulating cell function (Essayan, 2001). In the context of lung diseases, it is of particular interest that inhibiting the PDE3 and PDE4 isoenzymes can modulate the function of a variety This work was supported by Vernalis Plc. Article, publication date, and citation information can be found at

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“…4). In addition, all HPAs significantly inhibited the histamine content and activities of PLA 2 and EPO in BALF, whereas BA had fewer effects on the activities of PLA 2 and EPO than on those of OA and UA (Fig. 5).…”

Section: )mentioning

confidence: 90%

“…HTAs AOVA-challenged guinea pigs during LAR showed significant increases in the activities of inflammatory chemical mediators, histamine, EPO and PLA 2 (Fig. 5).…”

Section: Reductions In Inflammatory Chemical Mediators and Enzymes Inmentioning

confidence: 96%

Effects of Hydroxy Pentacyclic Triterpene Acids from Forsythia viridissima on Asthmatic Responses to Ovalbumin Challenge in Conscious Guinea Pigs

Lee

Moon

Kim

2010

Biological & Pharmaceutical Bulletin

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Bronchial asthma is considered to be a chronic inflammatory disease of the airways. Thus, anti-inflammatory therapy is considered central for its long-term asthma management. 1)Inhaled corticosteroids are highly effective chronic treatments, and are capable of suppressing the underlying inflammatory process. Furthermore, combination inhalers containing corticosteroids and long-acting b 2 -agonists are the principle approach to asthma therapy, and are being increasingly used in patients with persistent symptoms.2-3) However, concern persists regarding the use of inhaled corticosteroids, because the fear is irrational long-term side effects, such as, osteoporosis and growth stunting in children.3) Although these effective medications are delivered by inhalation, compliance is surprisingly poor.3,4) But dichromone flavonoid derivative, cromolyn sodium (CRO), which is a similar chemical structure to flavonoids, inhibits the release of chemical mediators, and has been used as anti-asthmatic agent, especially the prophylactic treatment of both allergic and exercise-induced asthma via the first dry-powder inhaler. 5)Forsythiae fructus (FF), the dried fruits of Forsythia viridissima LINDLE (Oleaceae), which are known as Yeon Kyo in Korea, had been reported to have the anti-inflammatory ingredients such as triterpenoids, lignans, flavonoids, and their glycosides, 6,7) and so are used as a herbal medicine due to their anti-inflammatory, diuretic, antidote, extrusion of pus, and antibacterial effects in Korea, China, and Japan. 8) In a previous study, we found that the natural lignans and flavonoids of FF inhibit inflammatory and asthmatic responses. 9,10) In the present study, we isolated three hydroxyl pentacyclic triterpene acids (HTAs), namely, oleanolic acid (OA), ursolic acid (UA), and betulinic acid (BA), from an ethylacetate fraction of FF, and sought to determine their effects and the underlying mechanisms involved on immunoglobulin E (IgE)-mediated asthmatic response induced by an aerosolized ovalbumin (AOVA) challenge in ovalbumin-sensitized guinea pigs. Their anti-asthmatic effects, which were investigated by measuring sRaw during immediate-phase response (IAR) and late-phase response (LAR) in a double-chambered plethysmograph, [10][11][12] were compared with those elicited by the authorized anti-asthmatic drugs, salbutamol (SAL), dexamethasone (DEX), and CRO. In addition, the chemical mediators of inflammation, histamine, eosinophil peroxidase (EPO), phospholipase A 2 (PLA 2 ), and leukocytosis, were quantified in bronchoalveolar lavage fluid (BALF), and accompanying histopathological changes in lung tissues were monitored. For the identification of anti-inflammatory ingredients from Forsythiae fructus (FF), we isolated three hydroxyl pentacyclic triterpene acids (HTAs), namely, oleanolic acid, ursolic acid, and betulinic acid, from an ethylacetate fraction of FF, and evaluated the effect of these triterpene acids on asthmatic guinea pigs by measuring specific airway resistance (sRaw) during both immediate-pha...

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The Effect of Selective Phosphodiesterase Inhibitors in Comparison with other Anti-asthma Drugs on Allergen-induced Eosinophilia in Guinea-pig Airways

Cited by 23 publications

References 0 publications

A pathophysiological role of PDE3 in allergic airway inflammation

A pathophysiological role of PDE3 in allergic airway inflammation

Effects of Hydroxy Pentacyclic Triterpene Acids from Forsythia viridissima on Asthmatic Responses to Ovalbumin Challenge in Conscious Guinea Pigs

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