Effects of phosphodiesterase 5 inhibitors on sperm parameters and fertilizing capacity

The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase （AC） system and the cGMP/guanylate cyclase （GC） system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide （NO） leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil＇s actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assisted reproductive technology （ART） programs. In the future PDE5 inhibitors might serve as adjunct therapeutical agents for the alleviation of male infertility.

Patterns of treatment with PDE5 inhibitors in the clinical practice in Italy： longitudinal data from the Erectile Dysfunction Observational Study

The Erectile Dysfunction Observational Study （EDOS） is a 6-months observational prospective multicentric study enrolling men with erectile dysfunction （ED） who asked, to be started on a treatment or to change a previous treatment. Aims of the study were to analyse the pattern of treatment and compare the efficacy of treatments used. Patients were enrolled during a normal hospital visit and were prescribed a treatment for ED. They were asked at baseline and after 3 and 6 months, to answer a set of questions from the International Index of Erectile Function, Erectile Dysfunction Inventory of Treatment Satisfaction （EDITS） and Short Form of the Psychological and Interpersonal Relationships Scale questionnaires （SF-PAIRS）. Clinicians were free to prescribe any therapy for ED available in the market, and to change therapy at any time during the study. Out of 1 338 patients, available for analysis at 6 months, 624 （47%） changed their treatment during the study and 714 （53%） continued with the drug prescribed at baseline. Patients assuming tadalafil had a significantly higher probability of maintaining the same treatment compared to sildenafil or vardenafil. There was no clinically significant difference in terms of efficacy, patient satisfaction, self-confidence and spontaneity between the different inhibitors of PDE5. The ‘time concerns＇ domain score of SF-PAIRS, was statistically better in patients assuming tadalafil. In conclusion sildenafil, vardenafil and tadalafil show similar efficacy in the clinical practice. However, patients receiving tadalafil display a lower risk to discontinue or change the treatment.

Peptide Inhibitors of HIV-1 Virus Infection Based on Cullin-5

Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expressed in ＂nonpermissive＂ cells and exhibits virus suppressive activity. With the aid of a Cullin-5 E3 ligase, Vif induces h-APOBEC3G degradation and with the destruction of this ligase, Vif is functionally inactive. Therefore, it is expected that blocking this E3 pathway would be a new therapeutic strategy against HIV-1 infection. In this article, the authors＇ took sequence alignment of the N-termini of Cullin-5 and three other members of the Cullin protein family, respectively. A set of small peptides has been synthesized based on the sequence comparison results and possible Vif-Cullin-5 interaction domains. Moreover, it has been demonstrated that several peptides can reduce virus infectivity in ＂nonpermissive＂ cells with a dose-responsive manner, but not in ＂permissive＂ cells. The results also indicate that the loss of viral infectivity may be because of the increase of APOBEC3G amount in the peptide-treated cells. It is concluded that peptides derived from Cullin-5 can block the APOBEC3G degradation induced by Vif and suppress HIV-1 infectivity. Therefore this study starts a novel strategy for the development of a new HIV-1 inhibitor.

Incidence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors： retrospective analysis

The purpose of this study was to determine the incidence rate of prostate cancer among men with erectile dysfunction （ED） treated with phosphodiesterase type 5 inhibitors （PDE-5i） over a 7-year period vs. men with ED of the same age and with similar risk factors who were not treated with PDE-5i. In a retrospective review of electronic medical records and billing databases between the years 2000 and 2006, men with ED between the ages of 50 and 69 years and no history of prostate cancer prior to 2000 were identified. These individuals were divided into two groups： 2362 men who had treatment with PDE-5i, and 2612 men who did not have treatment. Demographic data in each group were compared. During the study period, 97 （4.1%） men with ED treated with PDE-5i were diagnosed with prostate cancer compared with 258 （9.9%） men with ED in the non-treated group （P〈00001）. A higher percentage of African Americans were treated with PDE-5i vs. those who were not （10.5% vs. 7.1%; P〈O.O001）. The PDE-5i group had lower documented diagnosis of elevated prostate-specific antigen （10.0% vs. 13.1%; P=-0.0008） and higher percentage of benign prostatic hyperplasia （38.4% vs. 35.1%; P=0.0149）. Men with ED treated with PDE-5i tended to have less chance （adjusted odds ratio： 0.4; 95% confidence intervals： 0.3-0.5; P〈0.0001） of having prostate cancer. Our data suggest that men with ED treated with PDE-5i tended to have less of a chance of beine diaenosed with orostate cancer. Further research is warranted.

A systematic review of the effects and mechanisms of preoperative 5α-reductase inhibitors on intraoperative haemorrhage during surgery for benign prostatic hyperplasia

5α-reductase inhibitors （5α-RIs）, including finasteride and dutasteride, are commonly used medical therapies for benign prostatic hyperplasia （BPH）. Many studies reported that preoperative 5α-RI had impact on intraoperative haemorrhage during surgery for BPH, but it was still in controversial. So, we conducted a systematic review of the effects and mechanisms of 5α-RIs on intraoperative bleeding for BPH. MEDLINE, EMBASE, the Cochrane Controlled Trail Register of Controlled Trials and the reference lists of retrieved studies were searched in the analysis. Sixteen publications involving 15 different randomized controlled trials （RCTs） and a total of 1156 patients were used in the analysis, including 10 RCTs for finasteride and five RCTs for dutasteride. We found that preoperative finasteride treatment decreases microvessel density （MVD） in resected prostate specimens. Total blood loss, blood loss per gram of resected prostate tissue and decreases in haemoglobin were all greatly reduced in the finasteride group as compared to controls. Dutasteride appeared to have no effect on bleeding. This meta-analysis shows that preoperative finasteride treatment could decrease intraoperative haemorrhage during surgery for BPH. Preoperative dutasteride had no effect on intraoperative haemorrhage, but further high-qualitv prospective studies are still needed to confirm this observation.

The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia(BPH)is characterized by an enlarged prostate,lower urinary tract symptoms(LUTS),and a decreased urinary flow rate.Common in older men,BPH is a progressive disease that can eventually lead to complications including acute urinary retention(AUR)and the need for BPH-related surgery.Both normal and abnormal prostate growth is driven by the androgen dihydrotestosterone(DHT),which is formed from testosterone under the influence of 5-alpha reductase.Thus,5-alpha reductase inhibitors(5-ARIs)effectively reduce the serum and intraprostatic concentration of DHT,causing an involution of prostate tissue.Two 5-ARIs are currently available for the treatment of BPHdfinasteride and dutasteride.Both have been demonstrated to decrease prostate volume,improve LUTS and urinary flow rates,which ultimately reduces the risk of AUR and BPH-related surgery.Therefore,either alone or in combination with other BPH medications,5-ARIs are a mainstay of BPH management.

Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension:A case report with 8 years follow-up

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5(PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based onDoppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.

Evaluation and diagnostic testing of erectile dysfunction in the era of phosphodiesterase type 5 inhibitors

The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.

Medical therapy for clinical benign prostatic hyperplasia:α1 Antagonists,5α reductase inhibitors and their combination

Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.

2D-QSAR Studies on Anthranilic Acid Derivatives: A Novel Class of Allosteric Inhibitors of Hepatitis C NS5B Polymerase

Quantitative structure activity relationship （QSAR） studies were performed on 45 anthranilic acid derivatives for their potent allosteric inhibition activities of HCV NSSB polymerase. Genetic algorithm based genetic function approximation （GFA） method of variable selection was used to generate the model. Highly statistically significant model with r^2 = 0.966 and r^2cv = 0.951 was obtained when the number of descriptors in the equation was set to 5. High r^2pred value of 0.884 indicates the good predictive power of the best model. Spatial descriptors of radius of gyration （RadOfGration）, molecular volume （Vm）, length of molecule in the z dimension （Shadow-Zlength）, thermodynamic descriptors of the octanol/water partition coefficient （LogP） and molecular refractivity index （MR） showed enormous contributions to HCV NS5B polymerase inhibition. The validation of the model was done by leave-one-out （LOO） test, randomization tests and external test set prediction. The model gives insight on indispensable structural requirements for the activity and can be used to design more potent analogs against HCV NSSB polymerase.

PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice

Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,

3D-QSAR Studies on 4-([1,2,4]Triazolo[1,5-α]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole Analogues as Potent Inhibitors of Transforming Growth Factor-β Type Ⅰ Receptor Kinase

The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.

Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis

BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Design,Synthesis,and Biological Evaluation of 5H-Thiazolo[3,2-a]pyrimidine-6-carboxylic Acid Ethyl Ester Derivatives as a Novel Series of Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer＇s drugs. A series of 5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester derivatives as the novel acetylcholinesterase inhibitors was designed based on virtual screening methods. The target compounds were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, ^1H NMR, and ^13C NMR. The biological evaluation against human acetylcholinesterase in vitro indicated all the target compounds show more than 50% inhibition at 10μmol/L by means of the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer＇s disease and lay the foundation of searching for improved acetylcholinesterase inhibitors with the novel scaffolds.

Design and Synthesis of Pyrido[1,2-e]purin-4(3H)-one Derivatives as Potential PDE 5 Inhibitors

A novel series of pyrido[ 1,2-e]purin-4（3H）-one derivatives containing polar substituents on 5＇-position were designed and prepared as potential PDE5 inhibitors. This paper reports the synthetic routes, 1H-NMR data, and the PDE5 inhibitory activities of the target compounds. The polar piperazinyl group contained （on 5＇-position） compound, 3B2, showed the highest activity among the tested derivatives but less potency than sildenafil 1.

Are phosphodiesterase type 5 inhibitors effective for the management of lower urinary symptoms suggestive of benign prostatic hyperplasia?

AIM: To review the efficacy of phosphodiesterase type 5 inhibitors(PDE5-Is) in lower urinary tract symptoms(LUTS) suggestive of benign prostate hyperplasia(LUTS/BPH). METHODS: A comprehensive research was conducted to identify all publications relating to benign prostate hyperplasia and treatment with sildenafil, vardenafil and tadalafil. To assess the efficacy, the changes in total international prostate symptom score(IPSS), IPSS subscore including voiding, storage and quality of life(Qo L), Benign prostatic hyperplasia Impact Index(BII), maximum urinary flow rate(Qmax) and the International Index of Erectile Function(IIEF) were extracted. A meta-analytical technique was used for the analysis of integrated data from the included studies to evaluate the mean difference in the results. RESULTS: Total IPSS score, IIEF and BII showed a significant improvement in trials in which LUTS/BPH with or without erectile dysfunction(ED) were compared with the placebo. For LUTS/BPH, the mean differences of total IPSS score, IIEF and BII are-2.17, 4.88 and-0.43, P < 0.00001, respectively. For LUTS/BPH with comorbid ED, the mean difference are-1.97, 4.54 and-0.52, P < 0.00001, respectively. PDE5-Is appear to improve IPSS storage, voiding and Qo L subscore(mean difference =-0.71,-1.23 and-0.33, P < 0.00001, respectively). Although four doses of tadalafil(2.5, 5, 10 and 20 mg) failed to reach significance in Qmax(mean difference = 0.22, P = 0.10), the 5 mg dose of tadalafil significantly improved the Qmax(mean difference = 0.33, P = 0.03).CONCLUSION: PED5-Is demonstrated efficacy for improving LUTS in BPH patients with or without ED and could be considered to be the first line treatment for LUTS/BPH.

Synthesis and Biological Evaluation of Novel 1, 5-Diarylpyrazole-3- carboxamide Compounds as Inhibitors of ALK5

Ten new 1, 5-diarulpyrazole-3-carboxamide compounds were synthesized and their structures were identified by ^1H-NMR and FAB-MS. The primary biological tests showed that compound 4j exhibited some ALK5 inhibitory activity at concentration of 1μmol/L.

Comparative dissolution study on counterfeit medicines of PDE-5 inhibitors

Counterfeit medicines are a growing problem in both developing and industrialised countries. In general the evaluation of these medicines is limited to the identification and the dosage of the active ingredients. In this study in vitro dissolution tests were conducted on two sets of counterfeit medicines containing PDE-5 inhibitors （sildenafil citrate and tadalafil）. The dissolution profiles were statistically compared to the ones of the genuine products using the f2-method and a comparison at each time point using the Cochran test. The results showed low equivalences between counterfeit and genuine products as well as higher variations around the mean dissolution value at the different time points for the counterfeit products.

Synthesis of 1-aryl-3-(3,4-dihydro-2H-chromen-5-yl) ureas as TNF-αinhibitors

A new series of compounds, 1-aryl-3-（3,4-dihydro-2H-chromen-5-yl） ureas, have been synthesized and their structures were confirmed by FAB-MS and IH NMR. The preliminary pharmacological screening showed that these compounds inhibited TNF-α production in lipopolysaccharide （LPS）-stimulated THP-1 cells.

Synthesis of N1-Substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyra-zolethiocarboxamide as Novel Small Molecule Inhibitors of Cysteine Protease of T.cruzi

A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine protease of T.cruzi..