生物活性

• 描述Phosphodiesterases (PDEs) are metallo hydrolases which can be found in all tissues. PDES have 11 families which are named from PDE1 to PDE11 respectively^[3]. Sildenafil Citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5, which is a well-tolerated and highly effective treatment for erectile dysfunction. Sildenafil Citrate is orally active with IC50 of 4nM and increases intracellular cGMP concentrations in cultured smooth muscle cells treated with sodium nitroprusside and in rabbit corpus cavernosum in vitro. Sildenafil is metabolized in the liver by cytochrome P450 and is converted into an active metabolite with characteristics similar to the parent compound^[2]. Furthermore, Sildenafil citrate significantly reverses impaired carbachol-stimulated relaxation and inhibits superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits^[7]. Sildenafil improves erectile function in a time- and dose-dependent fashion with maximization of erectile function recovery occurring with daily 20 mg/kg at the 28-day time point in Sprague-Dawley rats, resulting in smooth muscle-collagen ratio protection and CD31 and eNOS expression preservation and reduces apoptotic indices significantly compared with control, and increases phosphorylation of akt and eNOS^[8]. In a recent clinical trial, 46 pregnant women with severe intrauterine growth restriction were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Results showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = 0.001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value=0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value=0.001)^[6].
• 作用机制PDES catalyze the breakdown of cAMP or cGMP into the inactive 5′-AMP or GMP, modulating the duration and intensity of their intracellular response. While sildenafil citrate reversible and selective blocks cGMP hydrolysis of PDE5 (Ki ∼3 nM) ^[2].

• 动物研究
  剂量	Mice: 26 mg/kg - 40 mg/kg[3] (p.o.); 1 mg/kg - 40 mg/kg[4] (i.p.) Rat: 1.4 mg/kg[5] (i.p.); 20 mg/kg[6] (p.o.)
  给药途径	p.o., i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00866463	Erectile Dysfunction	Phase 1	Completed	-	United States, Connecticut ... more >> Pfizer Investigational Site New Haven, Connecticut, United States, 06511 Collapse <<
  NCT00511498	Prostate Cancer	Not Applicable	Completed	-	United States, Maryland ... more >> Johns Hopkins Bayview Medical Center Baltimore, Maryland, United States, 21224 Collapse <<
  NCT01375699	Breast Cancer ... more >> Gastrointestinal Cancer Genitourinary Cancer Sarcoma Gynecologic Cancer Collapse <<	Phase 1	Completed	-	United States, Virginia ... more >> Virginia Commonwealth University/Massey Cancer Center Richmond, Virginia, United States, 23298-0037 Collapse <<

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