更新于：2024-11-01

PDE5A x cGMP-PDE

更新于：2024-11-01

基本信息

关联

项与 PDE5A x cGMP-PDE 相关的药物

Exisulind

依昔舒林

靶点

PDE5A x cGMP-PDE

作用机制

PDE5A抑制剂 [+1]

在研机构-

原研机构

OSI Pharmaceuticals, Inc.

在研适应症-

非在研适应症

腺瘤性结肠息肉病 [+6]

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 PDE5A x cGMP-PDE 相关的临床试验

NCT04823052 / Withdrawn临床2期

A Phase 2, Placebo-controlled, Adaptive Design Study to Explore the Safety and Efficacy of Sulindac (HLX-0201) and Gaboxadol (HLX-0206) and Possible Other Treatments in Adolescent and Adult Males With Fragile X Syndrome (FXS)

This study is to investigate the safety, tolerability and efficacy of Sulindac (HLX-0201) and Gaboxadol (HLX-0206) in males with Fragile X Syndrome (FXS) with confirmed full FMR1 mutation treated over a 10 week period in an outpatient setting.

开始日期2022-05-25

申办/合作机构

Healx Ltd.初创企业

NCT00078910 / Completed临床2期IIT

A Prospective Phase II Study of Preoperative, Controlled Exisulind Therapy Initiated Prior to Radical Prostatectomy: Effect on Apoptosis

RATIONALE: Drugs used in chemotherapy, such as exisulind, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving a chemotherapy drug before surgery may shrink the tumor so that it can be removed.
PURPOSE: This phase II trial is studying how well neoadjuvant exisulind works in treating patients who are undergoing radical prostatectomy for stage II or stage III prostate cancer.

开始日期2003-08-01

申办/合作机构

National Cancer Institute

100 项与 PDE5A x cGMP-PDE 相关的临床结果

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100 项与 PDE5A x cGMP-PDE 相关的转化医学

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0 项与 PDE5A x cGMP-PDE 相关的专利（医药）

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项与 PDE5A x cGMP-PDE 相关的文献（医药）

2024-07-01·Chinese Journal of Natural Medicines

Picroside II promotes HSC apoptosis and inhibits the cholestatic liver fibrosis in Mdr2−/− mice by polarizing M1 macrophages and balancing immune responses

Article

作者: Liao, Hui ; Zhang, Yan ; Liu, Jing ; Feng, Yating ; Li, Rongshan ; Gong, Le ; Han, Zhaodi

Our prior investigations have established that Inonotus obliquus (Chaga) possesses hypoglycemic effects. Persistent hyperglycemia is known to precipitate renal function abnormalities. The functionality of the kidneys is intricately linked to the levels of cyclic guanosine-3',5'-monophosphate (cGMP), which are influenced by the activities of nitric oxide synthase (NOS) and phosphodiesterase (PDE). Enhanced cGMP levels can be achieved either through the upregulation of NOS activity or the downregulation of PDE activity. The objective of the current study is to elucidate the effects of Chaga on disorders of glucolipid metabolism and renal abnormalities in rats with type 2 diabetes mellitus (T2DM), while concurrently examining the NOS-cGMP-PDE5 signaling pathway. A model of T2DM was developed in rats using a high-fat diet (HFD) combined with streptozotocin (STZ) administration, followed by treatment with Chaga extracts at doses of 50 and 100 mg·kg^-1 for eight weeks. The findings revealed that Chaga not only mitigated metabolic dysfunctions, evidenced by improvements in fasting blood glucose, total cholesterol, triglycerides, and insulin resistance, but also ameliorated renal function markers, including serum creatinine, urine creatinine (UCr), blood urea nitrogen, 24-h urinary protein, and estimated creatinine clearance. Additionally, enhancements in glomerular volume, GBM thickness, podocyte foot process width (FPW), and the mRNA and protein expressions of podocyte markers, such as nephrin and wilms tumor-1, were observed. Chaga was found to elevate cGMP levels in both serum and kidney tissues by increasing mRNA and protein expressions of renal endothelial NOS and neural NOS, while simultaneously reducing the expressions of renal inducible NOS and PDE5. In summary, Chaga counteracts HFD/STZ-induced glucolipid metabolism and renal function disturbances by modulating the NOS-cGMP-PDE5 signaling pathway. This research supports the potential application of Chaga in the clinical prevention and treatment of T2DM and diabetic nephropathy (DN), with cGMP serving as a potential therapeutic target.

2023-05-01·Cellular Signalling

Inhibition of phosphodiesterase 5A by tadalafil improves SIRT1 expression and activity in insulin-resistant podocytes

Article

作者: Rachubik, Patrycja ; Myślińska, Dorota ; Angielski, Stefan ; Szrejder, Maria ; Piwkowska, Agnieszka ; Audzeyenka, Irena ; Kulesza, Tomasz ; Rogacka, Dorota

A decrease in intracellular levels of 3',5'-cyclic guanosine monophosphate (cGMP) has been implicated in the progression of diabetic nephropathy. Hyperglycemia significantly inhibits cGMP-dependent pathway activity in the kidney, leading to glomerular damage and proteinuria. The enhancement of activity of this pathway that is associated with an elevation of cGMP levels may be achieved by inhibition of the cGMP specific phosphodiesterase 5A (PDE5A) using selective inhibitors, such as tadalafil. Hyperglycemia decreased the insulin responsiveness of podocytes and impaired podocyte function. These effects were associated with lower protein amounts and activity of the protein deacetylase sirtuin 1 (SIRT1) and a decrease in the phosphorylation of adenosine monophosphate-dependent protein kinase (AMPK). We found that PDE5A protein levels increased in hyperglycemia, and PDE5A downregulation improved the insulin responsiveness of podocytes with reestablished SIRT1 expression and activity. PDE5A inhibitors potentiate nitric oxide (NO)/cGMP signaling, and NO modulates the activity and expression of SIRT1. Therefore, we investigated the effects of tadalafil on SIRT1 and AMPK in the context of improving the insulin sensitivity in podocytes and podocyte function in hyperglycemia. Our study revealed that tadalafil restored SIRT1 expression and activity and activated AMPK by increasing its phosphorylation. Tadalafil also restored stimulating effect of insulin on glucose transport in podocytes with high glucose-induced insulin resistance. Additionally, tadalafil improved the function of podocytes that were exposed to high glucose concentrations. Our results display novel mechanisms involved in the pathogenesis of glomerulopathies in diabetes, which may contribute to the development of more effective treatment strategies for diabetic nephropathy.

2022-11-01·Journal of Thrombosis and Haemostasis

The NO/cGMP/PKG pathway in platelets: The therapeutic potential of PDE5 inhibitors in platelet disorders

Review

作者: Campolo, Federica ; Stefanini, Lucia ; Degjoni, Anisa ; Venneri, Mary Anna

Platelets are the "guardians" of the blood circulatory system. At sites of vessel injury, they ensure hemostasis and promote immunity and vessel repair. However, their uncontrolled activation is one of the main drivers of thrombosis. To keep circulating platelets in a quiescent state, the endothelium releases platelet antagonists including nitric oxide (NO) that acts by stimulating the intracellular receptor guanylyl cyclase (GC). The latter produces the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) that inhibits platelet activation by stimulating protein kinase G, which phosphorylates hundreds of intracellular targets. Intracellular cGMP pools are tightly regulated by a fine balance between GC and phosphodiesterases (PDEs) that are responsible for the hydrolysis of cyclic nucleotides. Phosphodiesterase type 5 (PDE5) is a cGMP-specific PDE, broadly expressed in most tissues in humans and rodents. In clinical practice, PDE5 inhibitors (PDE5i) are used as first-line therapy for erectile dysfunction, pulmonary artery hypertension, and lower urinary tract symptoms. However, several studies have shown that PDE5i may ameliorate the outcome of various other conditions, like heart failure and stroke. Interestingly, NO donors and cGMP analogs increase the capacity of anti-platelet drugs targeting the purinergic receptor type Y, subtype 12 (P2Y12) receptor to block platelet aggregation, and preclinical studies have shown that PDE5i inhibits platelet functions. This review summarizes the molecular mechanisms underlying the effect of PDE5i on platelet activation and aggregation focusing on the therapeutic potential of PDE5i in platelet disorders, and the outcomes of a combined therapy with PDE5i and NO donors to inhibit platelet activation.