Positive Predictors for Response to Ambrisentan Combination Therapy in Pulmonary Arterial Hypertension.

The AMBITION study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil in patients with pulmonary arterial hypertension (PAH). Nevertheless, predictors of treatment response were not assessed.To identify predictors for response to initial combination therapy, we examined data from 302 patients with PAH (World Health Organization Functional Class II or III) who received initial combination therapy from the modified intention-to-treat population of the AMBITION study (n = 605). A responder was defined as not having undergone a clinical failure event. Univariate and multivariate analyses were performed. Multivariate logistic regression with interactive backward selection was used to assess the independent association of potential predictors with response.Treatment responders were younger, more often female, and less likely to have comorbidities or a requirement for oxygen therapy, compared with nonresponders. At multivariate analysis, female sex (odds ratio [OR] 2.67; 95% confidence interval [CI] 1.29, 5.52; P = 0.0081), longer 6-minute walk distance (OR 1.01; 95% CI 1.00, 1.01; P = 0.0039), lower baseline log N-terminal-prohormone of brain natriuretic peptide (OR 0.70; 95% CI 0.52, 0.94; P = 0.0190), and aldosterone antagonist use (OR 2.54; 95% CI 1.03, 6.26; P = 0.0436) independently predicted response to initial combination therapy.Besides demographic factors, the absence of comorbidities and less severe disease state, and the use of aldosterone antagonist therapy identified patients with PAH most likely to respond to initial combination therapy with ambrisentan and tadalafil. Further study to evaluate the role of aldosterone antagonist therapy in PAH is warranted.

Adjuvant daily therapy with L-arginine 2,500 mg and tadalafil 5 mg increases efficacy and duration of benefits of low-intensity extracorporeal shock wave therapy for erectile dysfunction: A prospective, randomized, single-blinded study with 1-year follow-up.

PURPOSE: To investigate a therapeutic protocol for erectile dysfunction (ED) based on the combination of low-intensity extracorporeal shock wave therapy (Li-ESWT), tadalafil, and L-arginine. MATERIALS AND METHODS: Recruited patients completed the International Index of Erectile Function erectile function domain (IIEF-EF) and the Erection Hardness Score (EHS) questionnaires at baseline and were randomly assigned in two groups: A (treatment group) and B (control group). Men in both groups received six weekly applications of Li-ESWT. Group A was prescribed adjuvant oral therapy with tadalafil 5 mg and L-arginine 2,500 mg. Follow-up visits were scheduled 1, 6, and 12 months after the last Li-ESWT application. At each follow-up visit, the IIEF-EF and EHS questionnaires were administered again. The main outcome measures were the changes from baseline to every follow-up visit in IIEF-EF and EHS scores. RESULTS: The mean IIEF-EF score in group A was 16.0±4.0, 24.8±3.4, 23.3±4.6, and 21.6±5.5 at baseline, 1, 6, and 12 months of follow-up, respectively, whereas in group B the mean IIEF-EF score was 16.5±4.1, 22.7±4.2, 21.5±4.5, and 19.5±4.9, respectively. We reported an increase in the mean EHS score in group A from 2.07±0.72 at baseline to 3.39±0.59, 3.17±0.67, and 2.98±0.72 at 1, 6, and 12 months, respectively, and in group B from 2.12±0.80 at baseline to 3.07±0.78 and 2.95±0.76 at 1 and 6 months, respectively. CONCLUSIONS: Adjuvant daily therapy with L-arginine 2,500 mg and tadalafil 5 mg was safe and effective in increasing the efficacy and the duration of benefits of Li-ESWT.

Combination therapy with topical alprostadil and phosphodiesterase-5 inhibitors after failure of oral therapy in patients with erectile dysfunction: a prospective, two-arm, open-label, non-randomized study.

Phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line therapeutic option for erectile dysfunction (ED), while second-line therapy includes the alprostadil. Due to the different pharmacodynamic mechanism of PDE5Is and alprostadil, a synergistic action is conceivable when they are administered in combination. The aim of present study was to evaluate the efficacy and safety of combination therapy with PDE5I and topical alprostadil in patients with ED non-responders to PDE5I alone. We designed a prospective, two-arm, open-label, non-randomized study. Patients over 18 years old, with a stable sexual relationship for at least 6 months, and ED non-responders to PDE5I monotherapy were included in the study. At baseline the variables assessed were 5-item version of the International Index of Erectile Function (IIEF-5), and Sexual Encounter Profile Questions 2 and 3 (SEP-2 and SEP-3). In addition, all subjects underwent penile dynamic duplex ultrasonography. All patients were assigned to the monotherapy group (Group A) or combination therapy group (Group B) based on their preference. Topical alprostadil 300 µg/100 mg (Virirec®) was the treatment assigned to Group A, while the combination therapy with the last PDE5I taken (at the maximum recommended dose) plus topical alprostadil 300 µg/100 mg (Virirec®) was assigned to Group B. After 3 months from assignment to groups were evaluated IIEF-5, SEP-2 and SEP-3 regarding the last sexual intercourse, and Global Assessment Questionnaire-Questions 1 and 2 (GAQ-1 and GAQ-2). All adverse events (AEs) that occurred during the study period were recorded. A total of 170 patients were included in the study (72 in Group A and 98 in Group B). Fifty-two patients were previously treated with sildenafil 100 mg (30.6%), 6 with vardenafil 20 mg (3.5%), 56 with tadalafil 20 mg (32.9%), and 56 with avanafil 200 mg (32.9%). No significant differences among the study groups were found at baseline (p > 0.05). The mean IIEF-5 score increased significantly in Group B after treatment compared to baseline (12.4 ± 3.4 vs. 17.1 ± 4.5; p < 0.001), conversely patients in Group A showed no significant increase (12.2 ± 2.5 vs. 12.7 ± 3.1; p = 0.148). The number of affirmative responses to SEP-2 was significantly higher after treatment compared to baseline only in Group B (57 vs. 78; p < 0.001). The number of affirmative responses to SEP-3 was significantly higher after treatment compared to baseline in both groups (p < 0.001). The number of affirmative responses to GAQ-Q1 and GAQ-Q2 was significantly higher in Group B compared to Group A (p < 0.001). A total of 59 (34.7%) patients experienced AEs. They were mild, self-limited, and did not cause discontinuation of treatment. No episode of priapism was recorded. No statistically significant difference was recorded between the AEs of the two groups, except for facial flushing that was reported only in Group B (p = 0.021). The combination therapy with topical alprostadil and PDE5I seems to be more effective than topical alprostadil alone without worsening the safety of the treatment.

Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension.

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O2) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5-10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 µg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.

A 24-Year-Old Woman With Dyspnea, Chest Pain, and Dry Cough.

CASE PRESENTATION: A 24-year-old woman, a baby-sitter with no known comorbidities, presented to the outpatient department with complaints of modified Medical Research Council grade IV breathlessness for 3 months, chest pain, and dry cough for 2 weeks. There was no known disease history, including respiratory, flu-like illness, or connective tissue disorder. There was no use of chemotherapeutic, oral contraceptive drugs, exposure to toxic substances, or smoking. A review of systems was negative for fever, arthralgia, myalgia, Raynaud phenomenon, skin thickening, rash, or leg swelling. The patient had no family history suggestive of a genetic syndrome.

Sildenafil citrate-loaded targeted nanostructured lipid carrier enhances receptivity potential of endometrial cells via LIF and VEGF upregulation.

The main objective of this research is to prepare sildenafil citrate (SC)-loaded arginyl-glycyl-aspartic acid (RGD)-containing nanostructured lipid carrier (SC-loaded NLC-RGD) and evaluate their effects on the receptivity potential of endometrial cells. Hot homogenization method was used to prepare SC-loaded NLC-RGD. Then, size, drug encapsulation, and morphology of prepared nanoparticles were studied by photon correlation spectroscopy technic, ultrafiltration method, and scanning electron microscopy, respectively. Subsequently, the influence of SC-loaded NLC-RGD on endometrial receptivity was evaluated by in vitro implantation assay. Finally, expression of vascular endothelial growth factor (VEGF), leukemia inhibitory factor (LIF), and integrin beta 3 (as endometrial receptivity markers) was assessed in SC-loaded NLC-RGD-treated endometrial cells by reverse transcription polymerase chain reaction (RT-PCR). Particles with a nano-size diameter (92.7 nm), appropriate polydispersity index (0.21), spherical morphology, and acceptable loading efficiency were prepared. In vitro implantation assay showed that SC, SC-loaded NLC, and SC-loaded NLC-RGD improve the rate of endometrial attachment potential by 1.6 ± 0.4, 1.7 ± 0.3, and 2.3 ± 0.3 times, respectively. Analysis of RT-PCR results showed the enhancing mRNA of LIF and VEGF in SC-treated endometrial cells. Results also confirmed the higher influence of SC-loaded NLC-RGD on gene expression patterns in comparison to SC. Using NLC-RGD as a carrier to deliver SC to endometrial cells is an effective approach to improve endometrial receptivity. Upregulation of LIF and VEGF is the probable mechanism by which SC enhances the endometrial receptivity potential.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Characteristics and Long Term Follow up of Men Who Suffer Ischemic Priapism Secondary to Recreational Use of Intracavernosal Injectable Medications.

OBJECTIVE: To better understand patient experience, risk factors, culture, and ED outcomes surrounding recreational ICI use that led to ischemic priapism. METHODS: After IRB approval, men presenting for ischemic priapism secondary to recreational ICI use from January 2010 to December 2018 were contacted by mail and then via telephone. Standardized questions were asked of all study participants on the topics of erectile function (IIEF-5), sexual practices, and at-risk behavior at the time of priapism. Qualitative data analysis was performed using grounded theory methodology. RESULTS: 14 men age 24-59 were successfully recruited. All men described themselves as men having sex with men (MSM) and one (7.1%) as having both male and female sexual partners. Average follow up IIEF-5 among participants was 13 (SD 4.0). Eleven men (78.6 %) described illicit drug use at the time of priapism. Qualitative data analysis yielded several preliminary themes: concomitant drug use, naivety, peer pressure, and delay in seeking treatment. Men frequently reported illicit drug use in group sex scenarios and ICI use under pressure to perform sexually or to counteract effects of illicit substances. CONCLUSIONS: Recreational ICI in this cohort was part of a lifestyle of risky behavior. Methamphetamine use and group sex encounters strongly motivate recreational ICI use. Substance abuse centers may offer an entry point into this population for counseling and primary prevention.

A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TPN171H, a Novel Phosphodiesterase Type 5 Inhibitor, in Healthy Subjects.

PURPOSE: TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H. METHODS: The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. RESULTS: In Part I, AUC and Cmax were proved to be linear within the 5-30 mg dose range. T1/2 of TPN171H was 8.02-10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease Cmax, prolong Tmax, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and Cmax indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination. CONCLUSION: TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.

Effects of different vardenafil doses on bone healing in a rat fracture model.

OBJECTIVES: We aimed to investigate the radiological, biomechanical, histopathological, histomorphometric, and immunohistochemical effects of different doses of vardenafil on fracture healing. MATERIALS AND METHODS: Fifty-one rats were divided into three groups. Group V5 was given 5 mg/kg/day of vardenafil; Group V10 was given 10 mg/kg/day of vardenafil; and the control group was given the same volume of saline. Six rats from each group were sacrificed on Day 14 (early period) and the remaining rats were sacrificed on Day 42 (late period). Callus/femoral volume and bone mineral density were measured using micro-computed tomography. Five femurs from each group in the late period were examined by biomechanical tests. In addition to the histopathological and histomorphometric evaluations, immunohistochemical analyses were performed to examine the levels of inducible nitric oxide synthase (iNOS), transforming growth factor-3 (TGF-ß3), and nuclear factor kappa B (NF-κB) proteins. RESULTS: Both doses of vardenafil increased primary bone volume and maximal bone fracture strength in late period, compared to the control group (p<0.05). Histological healing scores of vardenafil groups were significantly higher in early period (p<0.001). While cartilaginous callus/total callus ratio in early period was higher, callus diameter/femoral diameter ratio in late period was lower in vardenafil groups (p<0.01). The NF-κB immunopositivity in V10 group decreased in early period, compared to control group (p<0.001). The TGF-ß3 and iNOS immunopositivity increased in both V5 and V10 groups, compared to the control group in early period, but returned to normal in late period. CONCLUSION: During the first period of fracture healing process in which vasodilation is mostly required with increasing inflammation, vardenafil has ameliorating effects on the bone union and supports fracture healing.

Influencing Factors for Erectile Dysfunction of Young Adults with No Response to PDE5i.

Erectile dysfunction (ED) is a common male disorder. Although orally-administered phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are now recognized as the primary pharmacological treatment method for ED, 20%-30% of the patients treated with PDE5 inhibitors exhibit no significant effects. This study aims to investigate the influencing factors of ED in young adults with no response to PDE5 inhibitors. ED patients who would take PDE5 inhibitors were included and investigated with a questionnaire. Patients with no response to PDE5 inhibitors (tadalafil and sildenafil) served as study group, and those with response to PDE5 inhibitors as control group. Then Chi square test and logistic regression analysis were applied to find the potential influencing factors. In total, 378 ED patients were included. Ninety-three (24.6%) cases were non-responsive to PDE5 inhibitors, and the remaining 285 (75.4%) responded to PDE5 inhibitors. In multiple logistic regression analysis, we found that history of drinking (OR=3.152; 95%CI 1.672-6.975), spousal noncooperation (OR=2.994; 95%CI 1.589-5.638), number of fixed sex partners (OR=0.358; 95%CI 0.132-0.651), duration of ED (OR=3.356; 95%CI 1.352-8.333), and depression (OR=3.689; 95%CI 1.579-8.979) could be the influencing factors for ED patients' non-response to PDE5 inhibitors. In conclusion, history of drinking, spousal noncooperation, number of fixed sex partner, long duration of ED, and depression could be the influencing factors for ED patients' non-response to PDE5 inhibitors. Patients and doctors should pay attention to these factors.

High frequency of potential phosphodiesterase type 5 inhibitor drug interactions in males with HIV infection and erectile dysfunction.

OBJECTIVES: We sought to determine the prevalence of phosphodiesterase type 5 inhibitor (PDE-5) mediated drug-drug interactions (DDIs) in males with HIV infection receiving antiretroviral therapy (ART) and identify factors associated with PDE-5-mediated DDIs. METHODS: Male US Military HIV Natural History Study participants diagnosed with erectile dysfunction (ED) and having a PDE-5 inhibitor and potentially-interacting ART co-dispensed within 30 days were included. DDIs were defined according to criteria found in published guidelines and drug information resources. The primary outcome of interest was overall PDE-5 inhibitor-mediated DDI prevalence and episode duration. A secondary logistic regression analysis was performed on those with and without DDIs to identify factors associated with initial DDI episode. RESULTS: A total of 235 male participants with ED met inclusion criteria. The majority were White (50.6%) or African American (40.4%). Median age at medication co-dispensing (45 years), duration of HIV infection (14 years), and duration of ED (1 year) did not differ between the two groups (p>0.05 for all). PDE-5 inhibitors included sildenafil (n = 124), vardenafil (n = 99), and tadalafil (n = 14). ART regimens included RTV-boosted protease inhibitors (PIs) atazanavir (n = 83) or darunavir (n = 34), and COBI-boosted elvitegravir (n = 43). Potential DDIs occurred in 181 (77.0%) participants, of whom 122 (67.4%) had multiple DDI episodes. The median DDI duration was 8 (IQR 1-12) months. In multivariate analyses, non-statistically significant higher odds of DDIs were observed with RTV-boosted PIs or PI-based ART (OR 2.13, 95% CI 0.85-5.37) and in those with a diagnosis of major depressive disorder (OR 1.74, 95% CI 0.83-3.64). CONCLUSIONS: PDE-5-mediated DDIs were observed in the majority of males with HIV infection on RTV- or COBI-boosted ART in our cohort. This study highlights the importance of assessing for DDIs among individuals on ART, especially those on boosted regimens.

Erectile dysfunction post radical cystectomy. The role of early rehabilitation with pharmacotherapy in nerve sparing and non-nerve sparing group: A randomized, clinical trial.

OBJECTIVES: No clinical studies testing erectile function (EF) post radical cystectomy (RC) were done. Our objective was to assess the effect of early pharmacologic therapy after RC using intracorporeal injection (ICI), phosphodiesterase inhibitor (PDE5i) and PDE5i+ICI. MATERIALS AND METHODS: In our randomized, double-blinded study, we prospectively enrolled 160 potent male patients with invasive bladder cancer. Patients were operated by RC using the nerve-sparing (NS) or non-nerve sparing (NNS) technique. They were treated since 1 month postoperatively by different regimens (PDE5i vs. ICI vs. ICI+PDE5i). Patients were evaluated using the international index of erectile function questionnaire and were followed up regularly at 1, 3, 6, and 12 months using the same parameters. RESULTS: One month after therapy, the mean of EF domain improved in both NS and NNS group. In the NNS group, in patients treated with ICI alone and ICI+PDE5i, the EF domain at 12 months moved to the moderate and to the mild category respectively. In patients treated by the NS approach, the mean value remained in the mild category with or without therapy. CONCLUSIONS: Early pharmacotherapy since one-month post RC using ICI and a combination of ICI+PDE5i can improve the erectile function of patients operated with a NNS approach.

Therapeutic potential of phosphodiesterase inhibitors in the treatment of osteoporosis: Scopes for therapeutic repurposing and discovery of new oral osteoanabolic drugs.

Cyclic nucleotide phosphodiesterases (PDEs) are ubiquitously expressed enzymes that hydrolyze phosphodiester bond in the second messenger molecules including cAMP and cGMP. A wide range of drugs blocks one or more PDEs thereby preventing the inactivation of cAMP/cGMP. PDEs are differentially expressed in bone cells including osteoblasts, osteoclasts and chondrocytes. Intracellular increases in cAMP/cGMP levels in osteoblasts result in osteogenic response. Acting via the type 1 PTH receptor, teriparatide and abaloparatide increase intracellular cAMP and induce osteoanabolic effect, and many PDE inhibitors mimic this effect in preclinical studies. Since all osteoanabolic drugs are injectable and that oral drugs are considered to improve the treatment adherence and persistence, osteogenic PDE inhibitors could be a promising alternative to the currently available osteogenic therapies and directly assessed clinically in drug repurposing mode. Similar to teriparatide/abaloparatide, PDE inhibitors while stimulating osteoblast function also promote osteoclast function through stimulation of receptor activator of nuclear factor kappa-B ligand production from osteoblasts. In this review, we critically discussed the effects of PDE inhibitors in bone cells from cellular signalling to a variety of preclinical models that evaluated the bone formation mechanisms. We identified pentoxifylline (a non-selective PDE inhibitor) and rolipram (a PDE4 selective inhibitor) being the most studied inhibitors with osteogenic effect in preclinical models of bone loss at ≤ human equivalent doses, which suggest their potential for post-menopausal osteoporosis treatment through therapeutic repurposing. Subsequently, we treated pentoxifylline and rolipram as prototypical osteogenic PDEs to predict new chemotypes via the computer-aided design strategies for new drugs, based on the structural biology of PDEs.

Whether Adding Vitamin D to Tadalafil 5 mg Treatment Is Useful in Patients with Erectile Dysfunction and Vitamin D Deficiency?

INTRODUCTION: Numerous factors such as endothelial disease and hormonal disorder cause the development of erectile dysfunction (ED). However, the relationship between vitamin D deficiency (VDD) and ED is unclear. Moreover, the benefit of vitamin D replacement on ED patients with VDD is uncertain. As far as we know, there is no study yet in the literature regarding the addition of vitamin D to phosphodiesterase type 5 inhibitors in the treatment of ED patients with VDD. In this study, we investigated whether adding vitamin D to daily tadalafil treatment would be beneficial in ED patients with VDD. METHODS: A total of 111 patients with VDD accompanying ED were retrospectively evaluated between January 2016 and December 2019. Patients were divided into 2 groups according to the treatment they received. Group 1 (n = 58) was treated with daily oral tadalafil 5 mg, while group 2 (n = 53) received oral tadalafil 5 mg and 4,000 IU vitamin D3. Total International Index of Erectile Function-15 (IIEF-15) scores and vitamin D levels of the groups were compared at the end of the study. RESULTS: The mean vitamin D level was increased statistically significant in group 2, but no difference was seen in group 1 (p < 0.001 and p > 0.05, respectively). There was a significant increase in median erectile function, orgasmic function, sexual desire, sexual satisfaction, and overall satisfaction scores in both groups (p < 0.001). However, the increase in median erectile function and sexual desire scores was significantly higher in group 2 compared to group 1 at the end of the study (p = 0.01 and p < 0.001, respectively). CONCLUSION: We found that adding vitamin D to 5 mg oral daily tadalafil treatment may have an additional positive effect on erectile function and sexual desire in ED patients with VDD.

Studies on metal-organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal-organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2-4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.

Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival.

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32-44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18-26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-expected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance-either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. Conclusions Persistent valvular heart disease-pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.

Dihydrotestosterone (DHT) rapidly increase after maximal aerobic exercise in healthy males: the lowering effect of phosphodiesterase's type 5 inhibitors on DHT response to exercise-related stress.

PURPOSE: Few data exist on dihydrotestosterone (DHT) adaptation to exercise-related stress. The aim of the study was to investigate on serum DHT and other androgens' responses to acute aerobic exercises, and to verify if a long-acting phosphodiesterase's type 5 inhibitors could influence these responses, as previously observed for salivary testosterone. METHODS: In a double-blind cross over study, 12 healthy trained male volunteers were submitted to both an acute sub-maximal and maximal exercise tests on cycle ergometer, after randomly receiving a two days placebo or tadalafil administration (20 mg, Cialis®, Ely-Lilly, Indianapolis, IN, USA). Blood sample collections were performed at different time points before and after exercise. Serum DHT, total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS) and luteinizing hormone (LH), were assayed. RESULTS: Serum DHT increase in placebo treatment immediately post maximal aerobic exercise and return to basal values at 60 min of recovery whereas tadalafil administration significantly reduced the DHT increase after exercise. The values of areas under curves showed the increase of TT after acute sub-maximal and maximal exercise and of DHEAS only after acute maximal aerobic exercise independently from treatment. CONCLUSIONS: In addition to testosterone, also DHT plays an exercise-related adaptive role during high intensity aerobic exercise, but its rapid useful effects during exercise have to be determined. We hypothesized that the increased androgens secretion during exercise could be mainly related to steroidogenic enzymes modifications in peripheral tissues (i.e., muscles). Moreover, the blunting effect of tadalafil on DHT increase support a possible role of peripheral nitric oxide/GMPc related pathways in influencing physical-stress related DHT metabolism.

Regimented Phosphodiesterase Type 5 Inhibitor Use Reduces Emergency Department Visits for Recurrent Ischemic Priapism.

PURPOSE: We evaluated the real-world effectiveness of regimented phosphodiesterase type 5 inhibitor dosing on recurrent ischemic priapism outcomes using emergency department visits as a proxy for therapeutic control of the disorder. MATERIALS AND METHODS: We performed a retrospective chart review of patients with recurrent ischemic priapism who were started on regimented phosphodiesterase type 5 inhibitor therapy from May 2006 to January 2020. We compared the number of emergency department visits per month during a 6-month period before treatment, during treatment and after treatment discontinuation. We extracted and categorized priapism outcomes such as priapism frequency and duration. RESULTS: Of 216 patients identified with all cause priapism 114 were diagnosed with recurrent ischemic priapism and 42 were initiated on regimented phosphodiesterase type 5 inhibitor therapy. Treatment effectiveness was analyzed for 24 evaluable patients. Priapism etiology was idiopathic in 12 patients (50%), sickle cell disease in 11 (46%) and drug-induced in 1 (4%). The median length of regimented phosphodiesterase type 5 inhibitor use was 3 months (IQR 2-7). Treatment decreased emergency department visits per month by 4.4-fold (p <0.001), priapism duration tiers (p <0.001) and priapism frequency tiers (p <0.001). Of 24 patients 22 (92%) reported improvement in priapism outcomes, 9 of whom reported resolution of recurrent ischemic priapism episodes. A subgroup analysis of 17 patients with recurrent ischemic priapism relapse after treatment discontinuation showed a significant increase in priapism duration (p <0.001) and frequency (p <0.001) but no significant change in emergency department visits per month (p=0.91). CONCLUSIONS: Regimented phosphodiesterase type 5 inhibitor therapy was an impactful treatment in managing recurrent ischemic priapism according to objective and subjective parameters. This study provides further support for the use of regimented phosphodiesterase type 5 inhibitor dosing as a preventive strategy for recurrent ischemic priapism.