Isozyme-selective cyclic nucleotide phosphodiesterase inhibitors: Biochemistry, pharmacology and therapeutic potential in asthma

Raeburn, David; Souness, John E.; Tomkinson, Adrian; Karlsson, J.‐A.

doi:10.1007/978-3-0348-7147-1_3

Cited by 27 publications

(40 citation statements)

References 67 publications

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“…18 PDE5 is ex pres sed in pul mo nary vas cu lar smo oth musc le, bronc hi al blo od ves sels and air way smo oth muscle. 19,20 Air way smo oth musc le plays an im por tant ro le in air way inf lam ma ti on and re mo de ling. 21 The in hi bi ti on of PDE5 le ads to an in cre a se in cGMP le vels and ca u ses pro te in ki na se G de pen dent smooth musc le re la xa ti on.…”

Section: Discussionmentioning

confidence: 99%

“…cGMP cre a te the op por tu nity of new drug de velop ment for tre at ment of ast hma vi a re gu la ti on of cGMP. 8,19,23 PDE4 in hi bi tors ha ve be en re cently in ves ti gated as new tre at ment op ti ons in ast hma. 28 LASS Bio596, a no vel PDE4 and 5 in hi bi tor, ame li o ra ted morp ho met ri cal and mec ha ni cal chan ges of lung in a mo u se mo del of ast hma.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of Nebulized Sildenafil on Lung Histology in a Murine Model of Chronic Asthma

Karaman¹,

Ölmez²,

Babayiğit³

et al. 2010

Turkiye Klinikleri J Med Sci

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A AB BS S T TR RA AC CT T O Ob b j je ec c t ti i v ve e: : Sil de na fil, which is used for the tre at ment of erec ti le dysfunc ti on, has be en shown to in hi bit inf lam ma ti on in an ani mal mo del of ast hma. We ai med to de ter mi ne the im pact of ne bu li zed sil de na fil on lung his to logy in a mu ri ne mo del of chro nic ast hma. M Ma at te er ri ia al l a an nd d M Me et t h ho od ds s: : Forty-two BALB/c mi ce we re di vi ded in to six gro ups; A, B, C, D, E, and the con trol group. All gro ups ex cept con trols we re sen si ti zed and chal len ged with oval bu min. Then, mi ce in Group A re ce i ved ne bu li zed sa li ne. Ne bu li zed sil de na fil cit ra te was administered to Gro up B, C, and D at con cen tra ti ons of 0.035 mg/ml, 0.07 mg/ml, and 0.105 mg/ml res pec ti vely, and ne bu li zed bu deso ni de was administered at a con cen tra ti on of 0.25 mg/ml to Gro up E for 15 mi nu tes on ce a day, for a we ek. Ani mals we re sac ri fi ced 24 ho urs af ter the last in ha la ti o nal ex po su re and the air way samp les we re eva lu a ted his to lo gi cally by light and elec tron mic ros co py. R Re e s su ul lt ts s: : All the his to lo gic para me ters of ast hma in Gro up B we re sig ni fi cantly ame li o ra ted when com pa red to the ones in Gro up A. In Gro ups C and D, all the pa ra me ters ex cept thick nes ses of su be pit he li al smo oth musc le la yers we re sig ni fi cantly im pro ved when com pa red to Gro up A. Thick nes ses of ba se ment mem bra ne, sube pit he li al smo oth musc le, and epit he li um we re sig ni fi cantly smaller in Gro up B than Gro up E. Thick nes ses of ba se ment mem bra ne and su be pit he li al smo oth musc le we re sig ni fi cantly smaller in Gro up C than Gro up E. Thick ness of su be pit he li al smo oth musc le was sig ni fi cantly smaller in Group D than Gro up E. C Co on nc c l lu u s si i o on n: : The res pon ses re gar ding im pro ve ment in ast hma pat ho logy we re fo und bet ter with all do ses of ne bu li zed sil de na fil than pla ce bo and even ne bu li zed ste ro id. K Ke ey y W Wo or rd ds s: : Sil de na fil; ast hma; mi ce, in bred BALB C Ö ÖZ ZE ET T A Am ma aç ç: : Erek til dis fonk si yo nun te da vi sin de kul la nı lan sil de na fi lin bir as tım hay van mo delin de inf la mas yo nu in hi be et ti ği gös te ril miş tir. Biz ilk kez bir kro nik as tım fa re mo de lin de akci ğer his to lo ji si üze ri ne ne bu li ze sil de na fi lin et ki si ni araş tır ma yı amaç la dık. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Kırk iki BALB/c fa re al tı gru ba ay rıl dı; A, B, C, D, E ve kon trol gru bu. Kon trol ler dı şın da ki tüm fa re ler oval bu min ile du yar lı laş tı rıl dı ve pro va ke edil di. Da ha son ra Grup A' da ki fa re ler ne buli ze sa lin, Grup B, C ve D'de ki ler sı ra sı ile 0.035 mg/ml, 0.07 mg/ml ve 0.105 mg/ml kon san trasyon lar da ne bu li ze sil de na fil sit rat, Grup E' de ki fa re ler 0.25 mg/ml kon san tras yon da ne bu li ze bu de so ni di gün de 15 da ki ka ol mak üze re bir haf ta bo yun ca al dı....

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of Nebulized Sildenafil on Lung Histology in a Murine Model of Chronic Asthma

Karaman¹,

Ölmez²,

Babayiğit³

et al. 2010

Turkiye Klinikleri J Med Sci

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“…Airway smooth muscle relaxation is observed following inhibition of PDE3 or PDE4 in canine (Torphy et al, 1988;Torphy and Undem, 1991), guinea pig trachea (Raeburn et al, 1993;Spina et al, 1995), and human airway preparations (de Boer et al, 1992;Rabe et al, 1995), which is primarily thought to be mediated by PDE3 (Cortijo et al, 1993). RPL554 and RPL565 both caused a concentration-and timedependent inhibition of contractile responses elicited by EFS.…”

Section: Discussionmentioning

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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“…The role of isoenzyme-selective phosphodiesterase (PDE) inhibitors as anti-inflammatory agents is currently of great interest (for review see RAEBURN et al [83]). Airway epithelial cells contain PDE types I-V [84].…”

Section: Phosphodiesterase Inhibitorsmentioning

confidence: 99%

“…Airway epithelial cells contain PDE types I-V [84]. Since PDE IV and, possibly, PDE V inhibitors have antiinflammatory actions on mononuclear cells and granulocytes in vitro, and on airways inflammation in vivo [83], they may also act at the epithelium.…”

Section: Phosphodiesterase Inhibitorsmentioning

confidence: 99%

Proinflammatory potential of the airway epithelium in bronchial asthma

Raeburn¹,

Webber²

1994

Eur Respir J

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P Pr ro oi in nf fl la am mm ma at to or ry y p po ot te en nt ti ia al l o of f t th he e a ai ir rw wa ay y e ep pi it th he el li iu um m i in n b br ro on nc ch hi ia al l a as st th hm ma a The epithelium has been suggested to be a target for inflammatory cell mediators and cytokines. Recently, the airway epithelium has itself been shown to produce and release several proinflammatory mediators and cytokines, and to express adhesion molecules for inflammatory cells. The epithelium, thus, may actively participate in the inflammatory changes in asthma, where it may be a source as well as a target.Drug therapy aimed at preventing inflammatory changes in the epithelium, such as cytokine and adhesion molecule expression, may be an important step forward in halting disease progression in asthma.

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Isozyme-selective cyclic nucleotide phosphodiesterase inhibitors: Biochemistry, pharmacology and therapeutic potential in asthma

Cited by 27 publications

References 67 publications

Impact of Nebulized Sildenafil on Lung Histology in a Murine Model of Chronic Asthma

Impact of Nebulized Sildenafil on Lung Histology in a Murine Model of Chronic Asthma

Proinflammatory potential of the airway epithelium in bronchial asthma

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