Catechin from Anonna senegalensis is a Potential Inhibitor of Erectile Dysfunction: Implication for Its Use in Male Sexual Enhancement.

Erectile dysfunction (ED) is a major challenge for men. The drugs for its treatment are associated with side effects. Hence, in phytomedicinal research, where Anonna senegalensis (A. senegalensis) is a candidate with abundant phytochemicals possessing various pharmacological properties, but the sex-enhancing phytochemical is elusive in the literature. This study aimed to understand the molecular interaction of its potent molecule mediating male sexual enhancement. A library of 69 compounds from A. senegalensis was docked against the ED-targeted proteins. Sildenafil citrate was used as the reference standard. Thereafter, the lead compound was screened for drug-likeness by applying the Lipinski rule of 5 (RO5), pharmacokinetic properties, and bioactivity using SwissADME and Molinspiration web servers, respectively. The results show catechin as the lead phytochemical compound with a stronger binding affinity for most of the proteins of ED. Also, catechin demonstrates good compliance with the RO5, great pharmacokinetic profiles, and could be said to be a polypharmacological molecule with good bioactivity scores. The research findings unravel the potential of catechin (a phytochemical belonging to the flavonoids class) from A. senegalensis leaf as a potential male sexual enhancement molecule via its high binding affinity for most erectile dysfunction-targeted proteins. They may require further toxicity and therapeutic evaluations in vivo.

Management of neonatal pulmonary hypertension-a survey of neonatal intensive care units in India.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs). METHODS: A questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed. RESULTS: There were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1-3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation. CONCLUSION: We found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

Biological activities of African medicinal plants in the treatment of erectile dysfunction: a mechanistic perspective.

The global incidence of erectile dysfunction is increasingly becoming a significant health concern, as its frequency demonstrates a consistent upward trajectory each year. In recent years, FDA-approved drugs like sildenafil among others has been approved to treat this disorder however the drug is not without its own side effects. In a bid to develop alternative therapeutic option, scientists have now turned to traditional medicine in search of a treatment regimen. Africa is blessed with numerous medicinal plants used in the treatment and management of several diseases including erectile dysfunction. Due to limited access to modern medicine and high-quality medical facilities, a significant number of individuals in Africa continue to depend on traditional medicine as a means of addressing critical health issues. Perhaps one of the grossly explored medicinal properties of plants in Africa is for erectile function. Through years of extensive research in medicinal plants, several plants indigenous to Africa have been identified to show profound ability to mitigate erectile dysfunction. While previous reports have indeed corroborated the ability of this plant to abate erectile dysfunction, there is still a dearth of information regarding the mechanistic aspect of these plants. Hence, the current review aims to provide a comprehensive mechanistic perspective to the major African medicinal plant which have been reported to be effective in the treatment of erectile dysfunction.

A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways.

AIMS: The present study aimed to investigate the effect of nano selenium, sildenafil, and their combination on inflammation, oxidative stress, and apoptosis in streptozotocin-induced diabetic nephropathy in rats. Herein, a new anti-inflammatory pathway for sildenafil as a high-mobility group box (HMGB1) inhibitor was proposed using the molecular docking technique. MATERIALS AND METHODS: Rats were divided into 7 groups: normal control, control nano selenium, control sildenafil, control diabetic, diabetic+ nano selenium, diabetic+ sildenafil, diabetic+ nano selenium+ sildenafil. The effects of drugs were evaluated by measuring serum urea, creatinine, lactate dehydrogenase (LDH), levels of tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1ß), HMGB1, receptor advanced glycation end product (RAGE), malondialdehyde (MDA), thioredoxin reductase (TrxR) by biochemical assays, nuclear factor-kappa b (NF-κB), toll-like receptor (TLR4) by immunohistochemistry, gene expressions of caspase 3 and monocyte chemoattractant protein (MCP-1) besides histopathological investigations of renal cells. KEY FINDINGS: Results showed beneficial effects of 8 weeks of treatment by nano selenium and sildenafil supported by improvement in kidney function, histopathological changes, and reduction in all of these parameters. These results supported molecular docking that indicated sildenafil had a high binding score and interactions with the HMGB1 receptor. SIGNIFICANCE: The current study demonstrated a renoprotective effect of nano­selenium and sildenafil by interfering at multiple pathways, especially the HMGB1/NF-κB signaling pathway.

Astragaloside IV ameliorates pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension by restraining the T follicular helper cell response and expanding T follicular regulatory cell response.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder lacking a validated and effective therapy which characterized by elevated pulmonary arterial pressure, vascular remodeling and eventual death. FDA approved sildenafil is being used as a first-line drug for PH, however, neither survival rates nor quality of life have been improved because of side effects and patient noncompliance. Thus, the exploration of novel therapeutic drugs is urgently needed. Astragaloside IV (ASIV) exhibits a protective effect on HPH, but its mechanisms of action is unclear. HYPOTHESIS: CD4+T cell subsets, Tfh and Tfr cells, may contribute to the development of chronic hypoxia-induced PH (HPH). We hypothesized that ASIV could effectively ameliorates pulmonary vascular remodeling of HPH by restraining the Tfh cell response and expanding Tfr cell response. METHODS AND RESULTS: HPH mice model was established by exposure to chronic hypoxia for 21 days. Mice were randomly assigned to six groups: NaCl group, model group, SN group (100 mg/kg of sildenafil), low-dose group (20 mg/kg of ASIV), medium-dose group (40 mg/kg of ASIV) and high-dose group (80 mg/kg of ASIV). Primary culture and identification of distal pulmonary artery smooth muscle cells (PASMCs) in mice were established. Here, we demonstrated that ASIV treatment could significantly ameliorate the increase of mean PAP, RV/ (LV+S) ratio and PAMT in HPH mice. ASIV inhibited Tfh cell differentiation and IL-21 production, but promoted Tfr cell differentiation and TGF-ß, IL-10 production. Chronic hypoxia promoted germinal center B cell responses, which inhibited by ASIV. ASIV regulated Tfh and Tfr cell differentiation by inhibiting the phosphorylation of mTOR signaling pathway, and the effect of ASIV-H was better than that observed in the SN group. ASIV inhibited the proliferation, migration and adhesion of PASMCs in vitro. Moreover, ASIV significantly downregulated the protein level of RhoA and upregulated the protein level of p27 in PASMCs under hypoxic condition. CONCLUSION: Collectively, ASIV may regulate Tfh and Tfr cell responses to subsequently repress pulmonary vascular remodeling and hypoxic pulmonary hypertension.

Structural Determination, Biological Function, and Molecular Modelling Studies of Sulfoaildenafil Adulterated in Herbal Dietary Supplement.

Unapproved ingredients included in herbal medicines and dietary supplements have been detected as adulterated synthetic drugs used for erectile dysfunction. Extraction from a dietary supplement was performed to isolate the compounds by HPLC analysis. The structural characterization was confirmed using mass spectrometry (ESI-TOF/MS and LC-MS/MS), 1H NMR, and 13C NMR spectroscopy techniques. Results identified the thus-obtained compound to be sulfoaildenafil, a thioketone analogue of sildenafil. The biological activities of this active compound have been focused for the first time by the experimental point of view performance in vitro. The results revealed that sulfoaildenafil can affect the therapeutic level of nitric oxide through the upregulation of nitric oxide synthase and phosphodiesterase type 5 (PDE5) gene expressions. This bulk material, which displays structural similarity to sildenafil, was analyzed for the presence of a PDE5 inhibitor using a theoretical calculation. These unique features of the potential activity of PDE5 protein and its inhibitors, sildenafil and sulfoaildenafil, may play a key consideration for understanding the mode of actions and predicting the biological activities of PDE5 inhibitors.

[Possibilities of using sildenafil in patients with cardiovascular comorbidities who underwent transurethral resection of the prostate].

AIM: To study the efficacy and safety of using sildenafil in patients with erectile dysfunction (ED) and concomitant cardiovascular diseases (CVD) who underwent transurethral resection of the prostate (TURP). MATERIAL AND METHODS: A total of 59 patients (age from 50 to 75 years) with a diagnosis of benign prostatic hyperplasia (BPH), requiring surgical treatment due to inefficiency of drug therapy, I-PSS score more than 20 points), who were sexually active, but had erectile dysfunction (IIEF score < 21), coronary heart disease (NYHA class I) and stage 1-2 hypertension with stable blood pressure. All patients underwent bipolar TURP. From the first day after the TURP, therapy was prescribed as following: tamsulosin 0.4 mg once a day for 90 days, ciprofloxacin 500 mg twice a day for 10 days. In addition, the patients received treatment for comorbidities. In the main group (n=30), men additionally received sildenafil (EFFEX Sildenafil Evalar) 50 mg daily for 60 days, starting from the 30th day postoperatively. We have chosen this drug from an economic standpoint. RESULTS: At baseline, all patients in both groups had hemodynamic and microcirculatory disorders in the prostate, which got worse in the early postoperative period. During the long-term follow-up, hemodynamic and microcirculatory impairments decreased. This effect was more pronounced in patients who received sildenafil. In addition, patients had an improvement in sexual function. During follow-up, there was no adverse effects of sildenafil on hemodynamic parameters (blood pressure, heart rate). CONCLUSION: Our results allow to recommend sildenafil in order to restore sexual function postoperatively in patients with BPH, including those with concomitant cardiovascular disorders.

Combined Intravenous Sildenafil and L-Arginine Administration in a Porcine Animal Model: Hemodynamic Safety Profile and Effects on Coronary Blood Flow.

BACKGROUND: Endothelial dysfunction in the nitric oxide-cyclic guanosine monophosphate pathway is a potential contributor to perioperative myocardial ischemia. The nitric oxide precursor, L-arginine, and the cyclic guanosine monophosphate degradation blocker, sildenafil, have vasodilatory effects under high dosage. OBJECTIVE: This study examined the hemodynamic safety and effect profiles of the combined administration of L-arginine and sildenafil using an in-vivo pig model. METHODS: Hemodynamic safety including mean arterial pressure, central venous pressure, heart rate, coronary vascular resistance, and systemic vascular resistance, as well as effect profiles including cardiac output and left anterior descending blood flow were measured in ten female swine after administrations of L-arginine, sildenafil, as well as combined L-arginine and sildenafil. Measurements were compared using repeated-measures analysis of variance and linear mixed models. RESULTS: The combination of L-arginine and sildenafil produced a significant dose-dependent increase in left anterior descending flow and cardiac output. In contrast, mean arterial pressure, heart rate, central venous pressure, coronary vascular resistance, and systemic vascular resistance did not show any significant changes. No significant change in serum osmolality was observed after administrations of L-arginine. CONCLUSIONS: The combined intravenous administration of sildenafil and L-arginine in a porcine animal model was safe, well tolerated, and had at least additive effects on left anterior descending artery blood flow. Simultaneous application of both drugs might have dose-sparing effects leading to desired coronary effects at lower and safer sildenafil and L-arginine plasma concentrations. Hyperosmolality was only a minor factor in L-arginine hemodynamic effects.

Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials.

PURPOSE: Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. HYPOTHESIS: A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID-19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin, and/or nutraceuticals that have been published to support immune function including glutathione, vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and "cytokine storm syndrome" with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to "acute respiratory distress syndrome" (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NF-κB and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione with associated anti-viral effects should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID-19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. CONCLUSION AND IMPLICATIONS: A three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with ivermectin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NF-κB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.

(Curcumin+sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo.

We have extended our analyses of (curcumin+sildenafil) biology. The drug combination caused vascularization and degradation of mutant K-RAS that correlated with reduced phosphorylation of ERK1/2, AKT T308, mTORC1, mTORC2, ULK1 S757, STAT3, STAT5, and NFκB and increased phosphorylation of eIF2α, ATM, AMPKα, ULK1 S317; all concomitant with elevated ATG13 S318 phosphorylation and autophagosome formation. Prior studies with drug combinations utilizing sildenafil have delineated an ATM-AMPK-ULK1 S317 pathway and an AKT-mTOR-ULK1 S757 pathway as modules which control ATG S318 phosphorylation and autophagosome formation. The knockdown of PKG reduced cell killing as well as reducing drug-enhanced phosphorylation of ATM, AMPKα, and ATG13. In the absence of PKG, no significant increase in ULK1 S317 phosphorylation was observed. In a Beclin1-dependent fashion, the drug combination reduced the expression of multiple histone deacetylase (HDAC) proteins, including HDAC2 and HDAC3. Molecular knockdown of HDAC2, HDAC3, and especially (HDAC2+HDAC3) significantly reduced the expression of PD-L1 and elevated expression of Class I human major histocompatibility complex. In vivo, (curcumin+sildenafil) enhanced the efficacy of 5-flurouracil against CT26 colorectal tumors. Prior exposure of established CT26 tumors to (curcumin+sildenafil) significantly enhanced the efficacy of a subsequently administered anti-PD-1 antibody. Collectively our data argue that (curcumin+sildenafil) has the potential in several settings to be an efficacious neoadjuvant therapy for colon cancer.

What is the Best Way to Treat Patients with Raynaud's Phenomenon and a Tendency towards Hypotension?

Episodes of excessive vasospasm are common in patients with Raynaud's phenomenon (RP). Pharmacological treatment may often result in side-effects such as hypotension, leading to discontinuation of treatment. Review of therapeutic interventions with regard to tendency towards hypotension was done in medical databases including PubMed, Scopus, and Medline to summarize the current state of the knowledge. Despite the episodes of blood pressure drops caused by hypotension, calcium channel blockers (CCB) have been widely used in RP as first-line treatment medication. The use of other CCB apart from nifedipine is controversial due to the variety of results in clinical trials. A clinical study comparing the efficacy and tolerability of losartan with nifedipine revealed a significant reduction in RP severity, frequency of episodes, and reported adverse effects. Application of oral sildenafil 100 mg/d as an add-on therapy increased microvascular blood flow in secondary RP, while being well-tolerated and with no withdrawal from the study. Topical vasodilators may be applied as an adjuvant therapy for patients with RP. Clinical studies approved 10% nifedipine cream and 10% nitroglycerine gel as an efficient RP therapy with side-effects comparable with placebo usage. Non-pharmacological interventions, such as cold avoidance, stress management, and smoking cessation are recommended in reducing episodes of RP. Calcium channel blockers, with a particular emphasis on nifedipine, in combination with non-pharmacological management seem to be the optimal way to treat the patients with a tendency to hypotension.

Comparative Randomized Crossover Clinical Study for the Evaluation of Erectile Dysfunction Medications Via Novel Pentagon System.

INTRODUCTION: Due to the chaos in the legislation in the Middle East, male enhancement nutraceuticals may be sold without any registration or evaluation. These products need to be evaluated with respect to safety and efficacy. Furthermore, cultural and social considerations in the Middle East prevent the use of international evaluations schemes for erectile dysfunction. AIM: Evaluating the safety and efficacy parameters of generic and nutraceutical products for erectile dysfunction in the Middle East through a custom-designed, representable and simple system tailored to the regional culture. METHODS: 74 healthy male volunteers were enrolled into a comparative, simple randomized, single dose, double blind, and crossover clinical study incorporated with a tailored-designed questionnaire. Safety assessment included laboratory analysis for liver functions and measuring blood pressure. MAIN OUTCOME MEASURES: Subjective data regarding safety and efficacy were assessed from the validated questionnaire. Blood pressure was measured. Blood samples were collected to assess the drug/adulterants concentration and liver and kidney functions. RESULTS: All tested nutraceuticals showed undeclared Sildenafil citrate in patients. Questionnaire results showed high inter-patient variability with respect to efficacy and comparable safety profile compared to Viagra®. CONCLUSION: The validated tailored-designed questionnaire effectively assessed the efficacy and safety of male enhancement products. The male enhancement nutraceuticals, sold in Egypt, claimed to be 100% natural are adulterated and of questionable safety profile.

New pulmonary hypertension model in conscious dogs to investigate pulmonary-selectivity of acute pharmacological interventions.

PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). RESULTS: The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 ± 4.4 mmHg) and ANP (- 6.4 ± 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. CONCLUSIONS: By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.

A Double-Blind, Randomized Trial on the Efficacy and Safety of Hyperbaric Oxygenation Therapy in the Preservation of Erectile Function after Radical Prostatectomy.

PURPOSE: We evaluated the efficacy and safety of hyperbaric oxygenation therapy to preserve erectile function as part of penile rehabilitation after robot assisted bilateral nerve sparing radical prostatectomy for prostate cancer. MATERIALS AND METHODS: We performed a prospective, randomized, double-blind study from January 2009 to April 2013. Men 40 to 65 years old who underwent robot assisted bilateral nerve sparing radical prostatectomy were randomized 1:1 to the control or the treatment group. Participants were exposed to air as the control or to 100% oxygen as the treatment in hyperbaric conditions. The primary outcome was erectile function at 18 months as measured by IIEF (International Index of Erectile Function). Secondary outcomes were 12-month urinary symptoms, and 18-month sexual, urinary, bowel and hormonal related symptoms as measured by EPIC-26 (Expanded Prostate Index Composite-26). Adverse events and long-term cancer outcomes were monitored. Primary and secondary outcomes in the 2 groups were compared by the independent group t-test, the Wilcoxon rank sum test and the chi-square test of proportion. RESULTS: A total of 109 potent men were randomized to hyperbaric oxygenation therapy or the control group. A total of 43 men in the air group and 40 in the hyperbaric oxygenation therapy group completed the 18-month followup. No statistically significant differences were observed between the 2 groups on any outcome measure. CONCLUSIONS: This study revealed no difference in erectile recovery in men treated with hyperbaric oxygenation therapy vs placebo. Larger studies involving more diverse comorbidities and different hyperbaric oxygenation therapy regimens are needed to better evaluate the usefulness of hyperbaric oxygenation therapy for penile rehabilitation after radical prostatectomy.

Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment.

Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category suggested potential mechanisms underlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment.

Protective effects of Lycium barbarum polysaccharide on male sexual dysfunction and fertility impairments by activating hypothalamic pituitary gonadal axis in streptozotocin-induced type-1 diabetic male mice.

Diabetes-associated male sexual dysfunction and fertility impairments are both common clinical complications with limited therapeutic options; hence it seriously affects the quality of life of the patients, in particular, the patients of reproductive age. Lycium barbarum polysaccharide (LBP) has long being believed to maintain and to promote reproductive functions in the traditional medical practice in China. The current study was to investigate if LBP may contribute to recovery of male sexual dysfunction and fertility impairments in diabetic individuals. The effects of LBP on sexual behaviors and histological changes of testis were studied in the type-1 diabetes male mice induced by intra-peritoneal (i.p.) injection of streptozotocin (STZ). After oral administration of LBP (10, 20 or 40 mg/kg), sildenafil citrate (SC, 5 mg/kg) or saline for 62 consecutive days, the typical abnormal changes in the sperm parameters, in relative weight of reproductive organs and in morphology of testis were observed in diabetic mice. LBP treatment of the diabetic mice considerably reversed those changes and Johnsen's testicular score, serum testosterone (T), follicular stimulating hormone (FSH) and luteinizing hormone (LH) level were also increased to different degrees. Moreover, our data have also shown that a marked improvement in sexual behavior and fertility level after administration of LBP (40 mg/kg) compared to the diabetic group. These results suggested that LBP can exert functional recovery of male sexual dysfunction and fertility damages induced by diabetes in male mice, which is likely to be mediated through regulating the hypothalamus- pituitary-gonadal axis endocrine activity.

Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia-reperfusion injury model treated with sildenafil citrate.

The aim of this study was to better understand the role of apoptosis in a retinal ischaemia-reperfusion injury model and to determine whether sildenafil citrate treatment can prevent retinal cell apoptosis. Thirty-six rats were divided into a control group (n = 6) and two experimentally induced ischaemia-reperfusion groups (7 and 21 days; n = 15 per group). The induced ischaemia-reperfusion groups were treated with sildenafil for 7 and 21 days (n = 10 per group), and 10 animals were treated with a placebo for the same period (n = 5 per group). Paracentesis of the anterior chamber was performed with a 30-G needle attached to a saline solution (0.9%) bag positioned at a height of 150 cm above the eye for 60 min. Intraocular pressure was measured by rebound tonometer (TonoVet® ). The eyes were analysed by histology and morphometry, and by immunohistochemistry and qRT-PCR for expression of Caspase-7, Caspase-6, Caspase-9, Tnf-r2, Fas-l, Bcl-2 and Bax. Sildenafil-treated animals showed lower levels of histopathological changes (inflammatory, cellular and tissue) than their placebo-treated counterparts at both 7 and 21 days. The retinal ganglion cell layer (RGC) was preserved in the sildenafil groups (SG), with a cell count closer to control than in the placebo groups (PG). Caspase-7 expression was significantly higher in both treated groups at 7 days compared to controls. Gene expression levels in both treatment groups differed from the controls, but in SG Bax and Caspase-6 expression levels were similar to control animals. These results suggest that the main mechanism of retinal cell death in this model is apoptosis, as there is an increase in pro-apoptotic factors and decrease in the anti-apoptotic ones. Also, sildenafil seems to protect the retinal ganglion cell layer from apoptosis. Cell survival was evident in the histological and morphometric analyses, and sildenafil treatment had a protective effect in the apoptosis pathways, with gene expression levels in SG similar to the controls.

Sildenafil normalizes bowel transit in preclinical models of constipation.

Guanylyl cyclase-C (GC-C) agonists increase cGMP levels in the intestinal epithelium to promote secretion. This process underlies the utility of exogenous GC-C agonists such as linaclotide for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Because GC-C agonists have limited use in pediatric patients, there is a need for alternative cGMP-elevating agents that are effective in the intestine. The present study aimed to determine whether the PDE-5 inhibitor sildenafil has similar effects as linaclotide on preclinical models of constipation. Oral administration of sildenafil caused increased cGMP levels in mouse intestinal epithelium demonstrating that blocking cGMP-breakdown is an alternative approach to increase cGMP in the gut. Both linaclotide and sildenafil reduced proliferation and increased differentiation in colon mucosa, indicating common target pathways. The homeostatic effects of cGMP required gut turnover since maximal effects were observed after 3 days of treatment. Neither linaclotide nor sildenafil treatment affected intestinal transit or water content of fecal pellets in healthy mice. To test the effectiveness of cGMP elevation in a functional motility disorder model, mice were treated with dextran sulfate sodium (DSS) to induce colitis and were allowed to recover for several weeks. The recovered animals exhibited slower transit, but increased fecal water content. An acute dose of sildenafil was able to normalize transit and fecal water content in the DSS-recovery animal model, and also in loperamide-induced constipation. The higher fecal water content in the recovered animals was due to a compromised epithelial barrier, which was normalized by sildenafil treatment. Taken together our results show that sildenafil can have similar effects as linaclotide on the intestine, and may have therapeutic benefit to patients with CIC, IBS-C, and post-infectious IBS.

Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing.

BACKGROUND: The baseline exercise capacity evaluated by cardiopulmonary exercise testing (CPET) and the change after administration of calcium channel blockers (CCB) therapy in patients with vasodilator-responsive idiopathic pulmonary arterial hypertension (VR-IPAH)are unknown. METHODS: 25 patients with newly diagnosed VR-IPAH from 1 January 2012 to 16 November 2015 were prospectively enrolled, and 28 age, sex and pulmonary vascular resistance matched newly diagnosed patients with vasodilator-nonresponsive idiopathic pulmonary arterial hypertension (VNR-IPAH) were enrolled. CPET was performed before and after 3.5 ± 0.8 months of CCB or sildenafil therapy. RESULTS: Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were significantly higher (lower in V˙E/V˙CO2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. Peak V˙O2 (13.9 ± 2.9 mL kg-1·min-1 vs 16.4 ± 4.1 mL kg-1·min-1, p = 0.001), peak O2 pulse (5.5 ± 0.8 mL min-1·beat-1 vs 6.9 ± 1.3 mL min-1·beat-1, p = 0.001), V˙E/V˙CO2@AT (34.2 ± 5.0 vs 31.6 ± 3.1, p = 0.02) and PETCO2@AT (33.1 ± 4.0 mmHg vs 35.3 ± 3.2 mmHg, p = 0.02) were significantly improved after high dose of CCB therapy, along with improvement of WHO functional class, 6-min walking distance, NT-proBNP and tricuspid regurgitation pressure gradient. CONCLUSIONS: Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNR-IPAH. CCB can improve aerobic capacity and ventilatory efficiency during exercise in patients with VR-IPAH. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov:NCT02061787.

Comparison of the Effects and Mechanism of the Curcumin with Different Drugs in Experimental Vasospasm After Subarachnoid Hemorrhage.

AIM: Cerebral vasospasm following subarachnoid hemorrhage (SAH) is the most important complication that effects the mortality and morbidity of patients with intracranial aneurysm. Today, the mechanisms of vasospasm are not understood in spite of experimental and clinical researches. The aim of our study was to investigate the effects of curcumin on vasospasm following SAH. MATERIAL AND METHODS: In this study, 64 rats (200-250 g weight) were divided into 7 groups. Group 1: having no treatment after SAH; Group 2: treatment with nimodipine after SAH; Group 3: treatment with nicorandil after SAH; Group 4: treatment with sildenafil citrate after SAH; Group 5: treatment with 150 mg/kg curcumin after SAH; Group 6: treatment with 300 mg/kg curcumin after SAH, Group 7: treatment with 600 mg/kg curcumin after SAH. The experimental SAH was induced by injection of autologous blood into the cisterna magna. After medical treatment, in the first hour, blood was taken for quantified the levels of TNF-α, IL-1ß and IL-6. Then, cerebrum and cerebellum were removed for analysis. Basilar artery luminal diameter was measured and apoptotic cell count was performed with tissue samples. RESULTS: Histopathological findings showed that, in sufficient dose, curcumin dilated the basilar artery beside anti-oxidant effect. CONCLUSION: Curcumin can be used for the treatment of vasospasm as a new medical drug.