更新于：2024-11-01

PDE4B x PDE7A x PDE4D

更新于：2024-11-01

基本信息

关联

项与 PDE4B x PDE7A x PDE4D 相关的药物

TPI-1100

靶点

PDE4B x PDE4D x PDE7A

作用机制

PDE4B调节剂 [+2]

在研机构-

原研机构

Syntara Ltd.

在研适应症-

非在研适应症

慢性阻塞性肺疾病

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 PDE4B x PDE7A x PDE4D 相关的临床试验

NCT00914433 / Withdrawn临床1期

A Phase 1,Randomized, Double--blind, Placebo-controlled Study Assessing the Safety and Tolerability, the Pharmacodynamics and Pharmacokinetics of Single-ascending and Repeated Doses of Inhaled TPI 1100 in Healthy Subjects

This study will look at the safety and tolerability of TPI 1100 in healthy volunteers and look at pharmacodynamic (PD) effect on mRNA expression of PDE 4B/D & 7A in blood and in sputum.

开始日期2009-04-01

申办/合作机构

Syntara Ltd.

100 项与 PDE4B x PDE7A x PDE4D 相关的临床结果

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100 项与 PDE4B x PDE7A x PDE4D 相关的转化医学

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0 项与 PDE4B x PDE7A x PDE4D 相关的专利（医药）

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项与 PDE4B x PDE7A x PDE4D 相关的文献（医药）

2017-12-01·BMC Urology4区 · 医学

Expression and function of phosphodiesterases (PDEs) in the rat urinary bladder

4区 · 医学

ArticleOA

作者: Zhai, Kui ; Zhu, Xiaofei ; Ji, Guangju ; Mi, Yue

BACKGROUNDIt has been shown that hosphodiesterases (PDEs) play an important role in mediating the smooth muscle tone of rat urinary bladder. However, the gene expression profiles of them were still unknown.METHODSUrinary bladder Strips were obtained from both neonatal and adult Sprague-Dawley rats. RT-PCR/western blot and organ bath were used to measure the expression and function of PDEs.RESULTSAdult rat urinary bladder expressed various PDE mRNA with the following rank order: PDE5A ≈ PDE9A ≈ PDE10A > PDE2A ≈ PDE4A ≈ PDE4D > PDE4B ≈ PDE3B ≈ PDE8B ≈ PDE7A ≈ PDE7B > PDE1A. PDE1B, PDE1C, PDE3A, PDE4C, PDE8A, and PDE11A were not detected. Of interest, the mRNA and protein of PDE3A were significantly decreased in adult rat urinary bladder compared to neonatal rat urinary bladder. Cilostamide, a specific inhibitor for PDE3, significantly inhibited the amplitude and frequency of carbachol-enhanced phasic contractions of neonatal rat bladder strips by 38.8% and 12.1%, respectively. Compared to the neonatal rat bladder, the effect of cilostamide was significantly blunted in adult rat urinary bladder: the amplitude and frequency of carbachol-enhanced phasic contractions were decreased by 13.4% (P < 0.01 vs neonatal rat bladder) and 4.4%, respectively. However, the mRNA and the protein levels of PDE3B were similar between neonatal and adult rat bladder.CONCLUSIONWe found that several PDE isoforms were expressed in the rat urinary bladder with distinct levels. Moreover, we showed that the function of PDE3 was blunted in adult rat bladder likely due to the decreased expression of PDE3A.

2017-06-01·Journal of Leukocyte Biology3区 · 医学

Leukocyte phosphodiesterase expression after lipopolysaccharide and during sepsis and its relationship with HLA-DR expression

3区 · 医学

Article

作者: Vanhamme, Luc ; Uzureau, Pierrick ; Rousseau, Alexandre ; Kox, Matthijs ; Vincent, Jean-Louis ; Akl, Israa ; Piagnerelli, Michael ; Biston, Patrick ; Pickkers, Peter ; Boudjeltia, Karim Zouaoui ; Medfai, Hayfa ; Vanhaeverbeek, Michel ; Lelubre, Christophe ; Leentjens, Jenneke

AbstractPhosphodiesterases (PDEs) may modulate inflammatory pathways, but PDE expression is poorly documented in humans with sepsis. Using quantitative PCR on whole blood leukocytes, we characterized PDE mRNA expression in healthy volunteers (n = 20), healthy volunteers given lipopolysaccharide (LPS; n = 18), and critically ill patients with (n = 20) and without (n = 20) sepsis. PDE4B protein expression was also studied in magnetic-activated cell sorting (MACS)–isolated CD15+ neutrophils (from 7 healthy volunteers, 5 patients without and 5 with sepsis). We studied relationships between PDE expression, HLA-DR (mRNA and expression on CD14+ monocytes), tumor necrosis factor (TNF)-α, and interleukin (IL)-10 levels. LPS administration in volunteers was associated with increases in PDE4B and PDE4D and decreases in PDE4A and PDE7A mRNAs. The observed global down-regulation of the HLA-DR complex was correlated with PDE7A. Critically ill patients had lower TNF-α/IL-10 mRNA ratios than the volunteers had and global down-regulation of the HLA-DR complex. Septic patients had persistently lower mRNA levels of PDE7A, PDE4A, and 4B (also at a protein level) and decreasing levels of PDE4D over time. Low PDE4D mRNA levels correlated negatively with HLA-DMA and HLA-DMB. LPS administration and sepsis are, therefore, associated with different PDE mRNA expression patterns. The effect of PDE changes on immune dysfunction and HLA-DR expression requires further investigation.

2014-02-01·Cellular Signalling3区 · 生物学

Select 3′,5′-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain

3区 · 生物学

Article

作者: Kleiman, Robin J ; Adamowicz, Wendy ; Kelly, Michy P ; Bove, Susan ; Pathak, Geetanjali ; Reinhart, Veronica ; Romegialli, Alison ; Hartman, Alexander J ; Mariga, Abigail

3',5'-cyclic nucleotide phosphodiesterases (PDEs) are the only known enzymes to compartmentalize cAMP and cGMP, yet little is known about how PDEs are dynamically regulated across the lifespan. We mapped mRNA expression of all 21 PDE isoforms in the adult rat and mouse central nervous system (CNS) using quantitative polymerase chain reaction (qPCR) and in situ hybridization to assess conservation across species. We also compared PDE mRNA and protein in the brains of old (26 months) versus young (5 months) Sprague-Dawley rats, with select experiments replicated in old (9 months) versus young (2 months) BALB/cJ mice. We show that each PDE isoform exhibits a unique expression pattern across the brain that is highly conserved between rats, mice, and humans. PDE1B, PDE1C, PDE2A, PDE4A, PDE4D, PDE5A, PDE7A, PDE8A, PDE8B, PDE10A, and PDE11A showed an age-related increase or decrease in mRNA expression in at least 1 of the 4 brain regions examined (hippocampus, cortex, striatum, and cerebellum). In contrast, mRNA expression of PDE1A, PDE3A, PDE3B, PDE4B, PDE7A, PDE7B, and PDE9A did not change with age. Age-related increases in PDE11A4, PDE8A3, PDE8A4/5, and PDE1C1 protein expression were confirmed in hippocampus of old versus young rodents, as were age-related increases in PDE8A3 protein expression in the striatum. Age-related changes in PDE expression appear to have functional consequences as, relative to young rats, the hippocampi of old rats demonstrated strikingly decreased phosphorylation of GluR1, CaMKIIα, and CaMKIIβ, decreased expression of the transmembrane AMPA regulatory proteins γ2 (a.k.a. stargazin) and γ8, and increased trimethylation of H3K27. Interestingly, expression of PDE11A4, PDE8A4/5, PDE8A3, and PDE1C1 correlate with these functional endpoints in young but not old rats, suggesting that aging is not only associated with a change in PDE expression but also a change in PDE compartmentalization.