Search

PurposeTo explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs).MethodsWe queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the adverse drug reactions (ADR) with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the reporting odds ratio (ROR) of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients.ResultsFrom a total of 133 819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n = 550, 0.41%; intracavernousal drugs: n = 82, 9.92%). Priapism disproportionality signals from intracavernousal drugs were 25 times stronger than PDE5is (ROR = 34.7; confidence interval [CI] 95%: 27.12-43.94 vs. ROR = 1.38; 95% CI: 1.24-1.54). For all PDE5i agents, the 12-17 years age group had the highest ROR (9.49, 95% CI: 3.76-19.93) followed by 2-11 years (4.31, 95% CI: 1.57-9.4). Disproportionality signals for consumers under 18 for both all PDE5is as a whole (ROR = 4.57, 95% CI: 2.48-7.73) and sildenafil (ROR = 4.89, 95% CI: 2.51-8.62) were stronger than individuals 18 or older (ROR = 1.06, 95% CI: 0.93-1.21 and ROR = 1.08, 95% CI: 0.91-1.26, respectively).ConclusionsPDE5i use shows disproportionate priapism signals which are higher in young patients.

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Abstract Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFβ1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFβ1 suppression. Overall, TGFβ1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process.

Objective: To investigate mechanism of phosphodiesterase 5 （PDE5） inhibitor Sildenafil in treatment of pain and inflammation in chronic pelvic pain mediated by macrophage polarization. Methods: A total of 32 adult Wistar rats were divided into 4 groups: Sham group, Experimental autoimmune prostatitis （EAP） group, Sildenafil+EAP group, MET+Sildenafil+EAP group, with 8 rats in each group. EAP model was induced by subcutaneous injection of prostate antigen （PAg） and complete Fredrin adjuvant, Sham group was injected with equivalent normal saline. EAP rats were treated with Sildenafil. Metformin was injected on basis of Sildenafil+ EAP. HE staining was used to analyze pathological changes of prostate. Response rate of pelvic pain in rats was measured by von Frey fiber method. Serum cytokines IL-10 and TNF-α levels were determined by ELISA. Numbers of iNOS+ and CD16/32+ macrophages and CD206+ and CD10+ macrophages in serum were detected by flow cytometry. Results: Compared with Sham group, EAP group showed obvious focal or multifocal inflammation in ventral prostate gland tissues, pelvic pain response rate, serum inflammatory factor TNF-α level, and number of M1-type polarization characteristic iNOS+ and CD16/32+ cells in EAP group were significantly increased （all P<0.05）, while M2-type polarization characteristics of macrophages, IL-10 level and number of CD206+ and CD10+ macrophages were significantly decreased （all P<0.05）. Compared with EAP group, pelvic pain response rate, TNF-α level, iNOS+ and CD16/32+ cell number in Sildenafil+EAP group were significantly decreased （all P<0.05）, while IL-10 level and CD206+ and CD10+ macrophage number were significantly increased （all P<0.05）. Compared with Sildenafil+EAP group, pelvic pain response rate, TNF- α level, iNOS+ and CD16/32+ cells in MET+Sildenafil+EAP group were significantly increased （all P<0.05）, while IL-10 level and number of CD206+ and CD10+ macrophages were significantly decreased （all P<0.05）. Conclusion: Sildenafil, a PDE5 inhibitor, blocks chronic pelvic pain and inflammation by promoting polarization of M2 macrophages. [ABSTRACT FROM AUTHOR]

Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFβ1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFβ1 suppression. Overall, TGFβ1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is a major concern in perinatal care. Various medications have been proposed as potential treatments for this serious condition. Nonetheless, there is still no definitive treatment. We studied tadalafil, a phosphodiesterase-5 inhibitor, as a therapeutic agent for FGR in clinical studies and animal experiments. In this review, we summarize our preclinical and clinical data on the use of tadalafil for FGR. Our studies in mouse models indicated that tadalafil improved FGR and hypertensive disorders of pregnancy. A phase II trial we conducted provided evidence supporting the efficacy of tadalafil in prolonging pregnancy (52.4 vs. 36.8 days; p = 0.03) and indicated a good safety profile for fetuses and neonates. Fetal, neonatal, and infant mortality was significantly lower in mothers receiving tadalafil treatment than that in controls (total number: 1 vs. 7, respectively; p = 0.03), and no severe adverse maternal events associated with tadalafil were observed. Although further studies are needed to establish the usefulness of tadalafil in FGR treatment, our research indicates that the use of tadalafil in FGR treatment may be a paradigm shift in perinatal care. [ABSTRACT FROM AUTHOR]

OBJECTIVES The primary outcome of this study was to describe the dosing regimen of tadalafil in neonates and infants diagnosed with pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD). Secondary outcomes included tolerability, efficacy, adverse events, discontinuation of therapy, and changes in echocardiography. METHODS This was a single-center, retrospective review of neonates and infants <1 year of age at initiation of tadalafil for PH secondary to BPD from January 2010 to November 2021. Data collected from the electronic medical record included patient demographics, tadalafil dosing, oxygen support, mechanical ventilation, concomitant PH medications, adverse events, and echocardiography information. RESULTS Forty-two patients--4 neonates and 38 infants--met the inclusion criteria. The postnatal and postmenstrual age (median, IQR) at diagnosis were 121 (35.5-153.5) days and 42.6 (40.6-47.6) weeks, respectively. The initial and highest tadalafil doses (median, range) were 1 (0.25-2) and 1 (0.5-2) mg/kg/day. Only 1 patient experienced pulmonary overcirculation and required tadalafil to be discontinued. Over half (57.1%) of the patients in this study discontinued tadalafil therapy owing to improvements in pulmonary artery pressures. CONCLUSIONS Tadalafil 1 mg/kg/day was the most commonly used dose regimen in neonates and infants. Tadalafil at this dose of 1 mg/kg/day appears well tolerated in neonates and infants with PH secondary to BPD and correlates with improvements in pulmonary artery pressures. Further studies evaluating tadalafil in comparison to other phosphodiesterase-5 inhibitors in neonates with PH secondary to BPD are warranted. [ABSTRACT FROM AUTHOR]

Aim:Renal ischemia-reperfusion injury (RI/RI) damages many organs, especially the kidney. Phosphodiesterase (PDE) 5 inhibitors has antioxidant and anti-inflammatory effects. Avanafil (AVA) is a second-generation PDE 5 inhibitor with greater PDE isoform selectivity. The aim of this study is to investigate the effects of AVA on RI/RI in rats.Materials and Methods:Forty rats were randomly divided into five groups (n=8): Sham; AVA 10; RI/RI; RI/RI + 5 mg/kg AVA, and RI/RI + 10 mg/ kg AVA. RI/RI in rats was established by clamping renal artery. An acute surgical experiment was performed for the induction of renal ischemia for 45 min by renal artery clamping followed by reperfusion for 24 h. Kidney tissues were investigated biochemically [malondialdehyde (MDA) and glutathione (GSH) with ELISA], molecularly [relative quantification of IL-1β, nuclear factor-kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α) mRNA gene expression with qRT-PCR], and histopathologically (staining with Harris hematoxylin and eosin Y).Results:AVA administration ameliorated disturbances in MDA and GSH levels caused by RI/RI. AVA treatment improved the increase in the mRNA expressions of IL-1β, NF-κB, and TNF-α in kidney tissues induced ischemia/reperfusion injury. AVA administration ameliorated histopathologic injury in kidney tissues caused by renal ischemia reperfusion. Moreover, the values closest to those of the sham group were obtained by administering 10 mg/kg AVA to rats with RI/RI.Conclusion:AVA administration improved renal ischemia/reperfusion-induced tissue injury by alleviating oxidative stress and inflammatory cascades that could be important in ischemia-reperfusion injury. These findings may provide a mechanistic basis for using AVA to treat RI/RI.

Objectives. Stroke is an acute cerebrovascular disease with high morbidity and mortality rate. Many stroke management strategies can improve prognosis and quality of life, but only to a certain extent. Phosphodiesterase inhibitor-5 (PDE-5i) has shown benefits in numerous preclinical studies, but human studies have been inconclusive. Material and Methods. For this narrative review, we conducted a systematic search following the PRISMA statement guideline from inception until November 2022. The search was conducted in PubMed, ScienceDirect, EBSCOhost, and ProQuest. We included all human and animal studies on this topic, including preclinical studies, randomized clinical trials, and case studies. All the excluded studies are reviews or non-English studies. Review. Many PDE-5i have shown benefits in anatomical and functional outcomes in preclinical acute experimental stroke models. PF-03049423 was safe and well tolerated in humans but had no significant impact on neurological or functional outcomes. Sildenafil on acute/subacute was deemed safe to use and demonstrated improvement over baseline, but power remains unknown due to the lack of a control group. Tadalafil use resulted in a reduction in regional cerebral blood flow in subjects with a history of stroke. Conclusions. Despite promising results in preclinical studies, current evidence shows that PDE-5i does not affect clinical or functional recovery in people with acute stroke. The disparity in the intricacy of stroke pathophysiology between human and animal models was crucial. Further research in a larger population with more consistent stroke onset, medicines, and doses is required for a more conclusive result.

Copyright of Namık Kemal Tıp Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fetal growth restriction (FGR) is a major concern in perinatal care. Various medications have been proposed as potential treatments for this serious condition. Nonetheless, there is still no definitive treatment. We studied tadalafil, a phosphodiesterase-5 inhibitor, as a therapeutic agent for FGR in clinical studies and animal experiments. In this review, we summarize our preclinical and clinical data on the use of tadalafil for FGR. Our studies in mouse models indicated that tadalafil improved FGR and hypertensive disorders of pregnancy. A phase II trial we conducted provided evidence supporting the efficacy of tadalafil in prolonging pregnancy (52.4 vs. 36.8 days; p = 0.03) and indicated a good safety profile for fetuses and neonates. Fetal, neonatal, and infant mortality was significantly lower in mothers receiving tadalafil treatment than that in controls (total number: 1 vs. 7, respectively; p = 0.03), and no severe adverse maternal events associated with tadalafil were observed. Although further studies are needed to establish the usefulness of tadalafil in FGR treatment, our research indicates that the use of tadalafil in FGR treatment may be a paradigm shift in perinatal care.

Objective: Adding selexipag to the combined treatment of endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitor (PDE5i) reduces the risk of clinical worsening events in patients with pulmonary arterial hypertension (PAH) but at a considerably higher cost. This study evaluated the cost-effectiveness of adding selexipag to the combined treatment of ERA and PDE5i in patients with PAH from a Chinese healthcare system perspective. Methods: A Markov model was developed to assess costs and quality-adjusted life years (QALYs) of macitentan + tadalafil + selexipag vs. macitentan + tadalafil for the treatment of PAH. Markov states included WHO Functional Class (FC) (I-IV) and death. Transition probabilities were based on data from the TRITON trial. Mortality rates, costs, and utilities were obtained from published literature and public databases. Results: In the base case analysis, compared with macitentan + tadalafil, selexipag + macitentan + tadalafil increased costs ($357,807.588 vs. $116,534.543, respectively) and QALYs (7.234 QALYs vs. 6.666 QALYs, respectively). The resulting incremental cost-effectiveness ratio was $424,746.070 per QALY, which was higher than the willingness-to-pay (WTP) of $38,223.339 per QALY. The results were most sensitive to HR for mortality of patients with FC IV relative to the general population, discount rate, and the cost of selexipag. The probability was greater than 50% for the selexipag+ macitentan+ tadalafil only if the WTP was more significant than $426,019.200 per QALY. Conclusion: In China, adding selexipag may not be cost-effective for patients with PAH who failed to control their condition after combined treatment of ERA and PDE5i. Results of the analysis can aid discussions on the value and position of selexipag for the combined treatment of PAH. [ABSTRACT FROM AUTHOR]

The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 inhibitors on ischemia–reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity suggested a possible clinical role for each of these medications; however, attempts to translate these findings to the bedside have resulted in mixed outcomes. In this review, we explore the biologic preclinical effects of PDE5 inhibitors in mediating cardioprotection. We then examine clinical trials investigating PDE5 inhibition in patients with heart failure, coronary artery disease, and ventricular arrhythmias and discuss why the studies likely have yet to show positive results and efficacy with PDE5 inhibition despite no safety concerns. [ABSTRACT FROM AUTHOR]

Objectives. Stroke is an acute cerebrovascular disease with high morbidity and mortality rate. Many stroke management strategies can improve prognosis and quality of life, but only to a certain extent. Phosphodiesterase inhibitor-5 (PDE-5i) has shown benefi ts in numerous preclinical studies, but human studies have been inconclusive. Material and Methods. For this narrative review, we conducted a systematic search following the PRISMA statement guideline from inception until November 2022. The search was conducted in PubMed, ScienceDirect, EBSCOhost, and ProQuest. We included all human and animal studies on this topic, including preclinical studies, randomized clinical trials, and case studies. All the excluded studies are reviews or non-English studies. Review. Many PDE-5i have shown benefi ts in anatomical and functional outcomes in preclinical acute experimental stroke models. PF-03049423 was safe and well tolerated in humans but had no significant impact on neurological or functional outcomes. Sildenafi l on acute/subacute was deemed safe to use and demonstrated improvement over baseline, but power remains unknown due to the lack of a control group. Tadalafi l use resulted in a reduction in regional cerebral blood flow in subjects with a history of stroke. Conclusions. Despite promising results in preclinical studies, current evidence shows that PDE-5i does not aff ect clinical or functional recovery in people with acute stroke. The disparity in the intricacy of stroke pathophysiology between human and animal models was crucial. Further research in a larger population with more consistent stroke onset, medicines, and doses is required for a more conclusive result. [ABSTRACT FROM AUTHOR]

Background and Objective: Pulmonary hypertension is a life‐limiting complication of interstitial lung disease (ILD‐PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD‐PH was associated with improved survival. Methods: Consecutive incident patients with ILD‐PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow‐up and survival data modelled by Bayesian methods. Results: The diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non‐specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint‐modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity‐matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: −0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04). Conclusion: PDE5i treatment in ILD‐PH should be investigated by a prospective randomized trial. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase 5 inhibitors (PDE5i), since their introduction in the late 1990s, have proven their efficacy in treating several conditions, predominantly pulmonary hypertension and erectile dysfunction where they remain the first-line therapeutic option. However, in the recent years, growing evidence from both animal and human studies has emerged to suggest the additional benefits of PDE5i in cardiovascular and metabolic disorders. This is of specific interest to the diabetes population where prevalent cardiovascular disease andmetabolic dysregulation significantly contribute to the increased morbidity and mortality. Objectives: To examine the available data on the non-standard, pleiotropic effects of PDE5i in patients with diabetes mellitus. Materials and methods: The review of the published background research, preclinical studies and clinical trials. Results: In human studies, PDE5 inhibition appeared to be associated with reduced cardiovascular mortality and overall improved clinical outcomes in those with established cardiovascular disease. PDE5i were also consistently found to reduce albuminuria in subjects with diabetic nephropathy. Furthermore, animal data suggest a plausible effect of this group of medication on sensory function and neuropathic symptoms in diabetic neuropathy as well as improved wound healing. A decrease in insulin resistance and augmentation of beta cell function seen in preclinical studies has not been consistently demonstrated in human trials. Discussion and conclusion: In animal models, PDE5 inhibition appears to decrease oxidative stress and reduce some of the micro- and macrovascular complications associated with diabetes. However, data from human trials are limited and largely inconsistent, highlighting the need for adequately powered, randomised-controlled trials in diabetic cohorts in order to fully assess the benefits of PDE5i in this group of patients. [ABSTRACT FROM AUTHOR]

Oral tadalafil (TD) proved promising in treating pediatric pulmonary arterial hypertension (PAH). However, to ensure higher efficacy and reduce the systemic side effects, targeted delivery to the lungs through nebulization was proposed as an alternative approach. This poorly soluble drug was previously dissolved in nanoemulsions (NEs). However, the formulations could not resist aqueous dilution, which precluded its dilution with saline for nebulization. Thus, the current study aimed to modify the previous systems into dilutable TD-NEs and assess their suitability for a pulmonary application. In this regard, screening of various excipients was conducted to optimize the former systems; different formulations were selected and characterized in terms of physicochemical properties, nebulization performance, stability following sterilization, and biocompatibility. Results showed that the optimal system comprised of Capmul-MCM-EP:Labrafac-lipophile (1:1) (w/w) as oil, Labrasol:Poloxamer-407 (2:1) (w/w) as surfactant mixture (Smix) and water. The optimum formulation P2TD resisted aqueous dilution, exhibited reasonable drug loading (2.45 mg/mL) and globule size (25.04 nm), acceptable pH and viscosity for pulmonary administration, and could be aerosolized using a jet nebulizer. Moreover, P2TD demonstrated stability following sterilization and a favorable safety profile confirmed by both in-vitro and in-vivo toxicity studies. These favorable findings make P2TD promising for the treatment of pediatric PAH. [ABSTRACT FROM AUTHOR]

Erectile dysfunction is a common disease of the male reproductive system, which seriously affects the life quality of patients and their partners. At present, erectile dysfunction is considered as a social-psychological-physiological disease with complex etiology and various treatment methods. Oral PDE5I is the first-line treatment for erectile dysfunction with the advantages of high safety, good effect and non-invasiveness. But intracavernosal injection, hormonal replacement therapy, vacuum erection device, penile prosthesis implantation can also be alternative treatments for patients have organic erectile dysfunction or tolerance to PDE5I. With the rapid development of technologies, some new methods, such as low-intensity extracorporeal shock wave and stem cell injection therapy can even repair the organic damage of the corpora cavernosa. These are important directions for the treatment of male erectile dysfunction in the future. In this mini-review, we will introduce these therapies in detail.

Objective: No reports have evaluated the treatment effects of tadalafil by age group in a positive, noninterventional observational study of Japanese men. The present study aimed to evaluate the treatment effects of tadalafil by age group in a positive, noninterventional observational study of Japanese men. We therefore divided patients into 2 groups about the age of 70 years and investigated the treatment effects of tadalafil regarding voiding and storage functions by age group. Methods: Changes from baseline in each parameter (International Prostate Symptom Score [IPSS], quality of life [QOL] score, Overactive Bladder Symptom Score [OABSS], and residual urine volume) at 4, 12, and 24 weeks after initiating tadalafil for benign prostatic hyperplasia (BPH) patients were compared between groups (50–69 years vs. ≥70 years). In addition, side effects of tadalafil were investigated by age group. Results: In the 50–69 years group, significant improvements from baseline were seen in IPSS total and QOL score for all time points. In addition, significant improvements in IPSS storage subscore from baseline were observed at the 4- and 24-week time points. In the ≥70 years group, significant improvements from baseline were seen in IPSS total, IPSS voiding and storage subscores, and QOL score at each time point. Conclusions: Tadalafil 5 mg once daily appeared effective in clinical settings for elderly BPH patients even over 70 years old. [ABSTRACT FROM AUTHOR]

Marcio Carneiro Vieira,1,2 Fernanda Bezerra de Mello Monte,3 Bruno Eduardo Dematte,3 Tadeu Lima Montagnoli,3 Guilherme Carneiro Montes,3 Jaqueline Soares da Silva,3 Rosalia Mendez-Otero,4 Margarete Manhães Trachez,3 Roberto Takashi Sudo,1,3 Gisele Zapata-Sudo1,3 1Programa de Pós-graduação em Ciências Cirúrgicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; 2Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; 3Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; 4Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio De Janeiro, 21941-902, BrazilCorrespondence: Gisele Zapata-SudoInstituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, BrazilTel +55 21 3938 6505Email gsudo@icb.ufrj.brIntroduction: New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3ʹ,5ʹ-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models.Methods and Results: Although no effect was detected on neurogenic phase of formalin test in mice, oral administration of lodenafil carbonate dose-dependently reduced reactivity in the inflammatory phase (200.6 ± 39.1 to 81.9 ± 18.8 s at 10 μmol/kg, p= 0.0172) and this effect was totally blocked by NO synthase inhibitor, L-Nω-nitroarginine methyl ester (L-NAME). Lodenafil carbonate (10 μmol/kg p.o.) significantly reduced nociceptive response as demonstrated by increased paw withdrawal latency to thermal stimulus (from 6.8 ± 0.7 to 10.6 ± 1.3 s, p= 0.0006) and paw withdrawal threshold to compressive force (from 188.0 ± 14.0 to 252.5 ± 5.3 g, p< 0.0001) in carrageenan-induced paw inflammation model. In a spinal nerve ligation-induced neuropathic pain, oral lodenafil carbonate (10 μmol/kg) also reversed thermal hyperalgesia and mechanical allodynia by increasing paw withdrawal latency from 17.9 ± 1.5 to 22.8 ± 1.9 s (p= 0.0062) and paw withdrawal threshold from 26.0 ± 2.8 to 41.4 ± 2.9 g (p= 0.0196). These effects were reinforced by the reduced GFAP (3.4 ± 0.5 to 1.4 ± 0.3%, p= 0.0253) and TNF-alpha (1.1 ± 0.1 to 0.4 ± 0.1%, p= 0.0111) stained area densities as detected by immunofluorescence in ipsilateral dorsal horns.Conclusion: Lodenafil carbonate demonstrates important analgesic activity by promoting presynaptic hyperpolarization and preventing neuroplastic changes, which may perpetuate chronic pain, thus representing a potential treatment for neuropathic pain.Keywords: neuropathic pain, inflammatory pain, phosphodiesterase 5 inhibitor, lodenafil carbonate, spinal cord, GFAP

Oral tadalafil (TD) proved promising in treating pediatric pulmonary arterial hypertension (PAH). However, to ensure higher efficacy and reduce the systemic side effects, targeted delivery to the lungs through nebulization was proposed as an alternative approach. This poorly soluble drug was previously dissolved in nanoemulsions (NEs). However, the formulations could not resist aqueous dilution, which precluded its dilution with saline for nebulization. Thus, the current study aimed to modify the previous systems into dilutable TD-NEs and assess their suitability for a pulmonary application. In this regard, screening of various excipients was conducted to optimize the former systems; different formulations were selected and characterized in terms of physicochemical properties, nebulization performance, stability following sterilization, and biocompatibility. Results showed that the optimal system comprised of Capmul-MCM-EP:Labrafac-lipophile (1:1) (w/w) as oil, Labrasol:Poloxamer-407 (2:1) (w/w) as surfactant mixture (Smix) and water. The optimum formulation P2TD resisted aqueous dilution, exhibited reasonable drug loading (2.45 mg/mL) and globule size (25.04 nm), acceptable pH and viscosity for pulmonary administration, and could be aerosolized using a jet nebulizer. Moreover, P2TD demonstrated stability following sterilization and a favorable safety profile confirmed by both in-vitro and in-vivo toxicity studies. These favorable findings make P2TD promising for the treatment of pediatric PAH.

Pulmonary arterial hypertension (PAH) is a severe disease with a resultant increase of the mean pulmonary arterial pressure, right ventricular hypertrophy and eventual death. Research in recent years has produced various therapeutic options for its clinical management but the high mortality even under treatment remains a big challenge attributed to the complex pathophysiology. Studies from clinical and non-clinical experiments have revealed that the nitric oxide (NO) pathway is one of the key pathways underlying the pathophysiology of PAH. Many of the essential drugs used in the management of PAH act on this pathway highlighting its significant role in PAH. Meanwhile, several novel compounds targeting on NO pathway exhibits great potential to become future therapy medications. Furthermore, the NO pathway is found to interact with other crucial pathways. Understanding such interactions could be helpful in the discovery of new drug that provide better clinical outcomes. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a severe disease with a resultant increase of the mean pulmonary arterial pressure, right ventricular hypertrophy and eventual death. Research in recent years has produced various therapeutic options for its clinical management but the high mortality even under treatment remains a big challenge attributed to the complex pathophysiology. Studies from clinical and non-clinical experiments have revealed that the nitric oxide (NO) pathway is one of the key pathways underlying the pathophysiology of PAH. Many of the essential drugs used in the management of PAH act on this pathway highlighting its significant role in PAH. Meanwhile, several novel compounds targeting on NO pathway exhibits great potential to become future therapy medications. Furthermore, the NO pathway is found to interact with other crucial pathways. Understanding such interactions could be helpful in the discovery of new drug that provide better clinical outcomes.

Objectives: Sickle cell disease‐related pulmonary hypertension (SCD‐PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD‐PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. Methods: We performed a retrospective chart review of patients with SCD‐PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5‐I) therapy for ≥4 months between 2008 and 2019 at two institutions. Results: Thirty‐six patients were included in the analysis. The median age (IQR) upon PDE5‐I initiation was 47.5 years (35‐51.5 years); 58% were female and twenty‐nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism, and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25 months (IQR 13‐60 months). Use of PDE5‐I was associated with a significant improvement in symptoms as assessed by NYHA Class (P =.002). Conclusions: In SCD patients with PH defined by RHC, PDE5‐I therapy was tolerated long‐term and may improve physical activity. [ABSTRACT FROM AUTHOR]

Objective: The present study assesses whether phosphodiesterase type 5 (PDE-5) inhibitor or carnitine exert nephroprotective effects against clinical contrast-induced nephropathy (CIN). Materials and Methods: The present study consisted of three groups of CKD patients. The first group was control group, who were treated with N-acetyl-L-cysteine 1 day before and on the day of radiocontrast administration. The second one was carnitine group, where the patients were infused with carnitine over 10 min 2 h prior to the radiocontrast administration and 24 h post CT. The third one was PDE-5 inhibitor group, where patients were given tadalafil 2 h prior to the administration of the radiocontrast and in the subsequent day. Urine and blood samples were collected before and at the following time sequence: 2, 6, 12, 24, 48, and 120 h after the contrast administration, for creatinine and NGAL determination. Results: Pretreated with N-acetyl-L-cysteine prior to administration of contrast media (CM) to CKD patients caused a significant increase in urinary but not of plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum creatinine (SCr). In contrast, pretreatment with carnitine prevented the increase in urinary NGAL and reduced SCr below basal levels. Similarly, tadalafil administration diminished the elevation of CM-induced urinary NGAL. Conclusions: These results indicate that carnitine and PDE-5 inhibitors may comprise potential therapeutic maneuvers for CIN.

Background: Conversion of quiescent resident fibroblasts to activated myofibroblasts by transforming growth factor-beta 1 (TGF-β1) is the hallmark of fibrotic pathogenesis of systemic sclerosis (SSc). Myofibroblasts are characterized by increased alpha smooth muscle actin (α-SMA) expression and extracellular matrix (ECM) proteins production. Objective: The aim of this study is to evaluate anti-fibrotic potential of dual inhibition by phosphodiesterase5 (PDE5) inhibitor, sildenafil plus 5-HT2B inhibitor, SB204741 in human adult dermal fibroblasts (HADFs) isolated from mid-forearm skin of a scleroderma patient. Materials and Methods: In disease-mimicking strategy, HADFs were incubated with TGF-β1 (10 ng/ml) for 1 hour, followed by TGF-β1 (10 ng/ml)/[sildenafil (10 µM) or SB204741 (1 µM)] or combination of the two for 24 hours. In pretreatment strategy, HADFs were pretreated with sildenafil (10 µM) or SB204741 (1 µM) or combination of the two for 1 hour and later with only TGF-β1 (10 ng/ml) for 24 hours. Real time quantitative polymerase chain reaction for pro-fibrotic (COL1A1, COL1A2, ACTA2, CCN2 and FN1) and anti-fibrotic genes (MMP2, TIMP1) was performed. Results: In TGF-β1 stimulated HADFs, upregulated expression of pro-fibrotic genes was observed (P < 0.05). Expression of pro-fibrotic genes in HADFs stimulated with TGF-β1 were significantly (P < 0.05) reduced by dual inhibition strategy with complete amelioration of ACTA2 in comparison to their respective individual treatments. Ratio of anti-fibrotic genes (MMP2/TIMP1) was restored significantly (P < 0.05). Conclusion: Dual inhibition strategy with sildenafil plus SB204741 leads to near complete amelioration of conversion of fibroblasts to myofibroblasts and thus may have the potential to treat fibrosis in scleroderma. [ABSTRACT FROM AUTHOR]

Introduction: Erectile dysfunction is often a consequence of stressful situations, lack of adequate sleep and rest, and sedentary lifestyles. The profession of locomotive engineer implies the presence of these negative factors, which in addition provoke high blood pressure and the development of hypertension., Materials and Methods: A total of 85 patients of the urological and therapeutic departments of the "Clinical Hospital "Russian Railways Medicine" in the city of Barnaul", working as locomotive drivers or assistant drivers, were examined. 65 men with erectile dysfunction and hypertension of 1-2 stages (all received antihypertensive therapy) were randomly divided into 3 groups: in the group 1, an activator of endogenous nitric oxide synthase (NOS) was added to the treatment of hypertension; in group 2, a combination of an endogenous NOS activator and a phosphodiesterase-5 inhibitor (PDE-5) was used. Patients of group 3 did not receive additional treatment. The efficiency of treatment was assessed using markers of endothelial dysfunction, including plasminogen activator inhibitor type 1 (PAI-1), endothelin-1 (ET-1), homocysteine, high-selective C-reactive protein (hs-CRP). In addition, the International Index of Erectile Function and male copulatory function scores were filled out. Moreover, laser doppler flowmetry (LDF) with determination of blood flow in penile vessels was done. Follow-up examination was carried out after 2 and 4 months. Twenty of the persons were healthy and referred to the control group., Results: There were no significant changes in markers and LDF values after 2 months in groups 1 and 3. In group 2, ET-1 and hs-CRP returned to the reference limits, which indicated a decrease in ischemia. After 4 months, there was an improvement in hemodynamics and marker values in group 2. The mean blood flow increased in group 1, while hs-CRP returned to the reference limits. In patients of group 2, a higher total IIEF and male copulatory function scores was documented. In group 3, there was no improvement., Conclusion: The combination of hypotensive drugs, PDE-5 inhibitor and NOS activator showed the best effect, improving blood flow, reparative properties of endothelium with preventing of thrombus formation. Treatment with an NO synthase activator partially eliminates pathological processes in the endothelium.

Introduction: Tadalafil improves lower urinary tract symptoms (LUTS) including nocturia. However, the effect of tadalafil on the nocturia-related quality of life (QoL) is still unknown. Objective: The effects of tadalafil on nocturia and nocturia-related QoL were evaluated prospectively in patients with benign prostatic hyperplasia (BPH) as a multicenter study. Methods: Eligible men were ≥40 years with nocturia ≥2 and a prostate volume ≥20 mL. Patients were asked to complete a self-report questionnaire on the International Prostate Symptom Score (IPSS), the Nocturia Quality of Life questionnaire (N-QoL) and the International Index of Erectile Function 5 (IIEF5). Urinary frequency volume charts (FVCs) were also evaluated. These measures were evaluated at baseline, and after 4, 8, and 12 weeks of tadalafil administration (5 mg once daily). Results: Thirty-one patients with a mean age of 74 years, a mean prostate volume of 31 mL, and a mean prostate-specific antigen level of 2.8 ng/mL were included. Treatment with tadalafil significantly improved their nocturia after 4 weeks, and these improvements were maintained for the 12-week treatment period. Total N-QoL score in new patients and several N-QoL items (inadequate sleep at night and overall bother) in all patients improved significantly after tadalafil treatment. FVCs revealed a significant improvement in the number of hours of undisturbed sleep (HUS) after treatment with tadalafil. No serious adverse events were observed. Conclusions: This study indicates that tadalafil 5 mg once daily improves nocturia, nocturia-related QoL, and HUS in BPH patients with nocturia. These results suggest that tadalafil can offer a clinically meaningful treatment option for BPH patients with nocturia. [ABSTRACT FROM AUTHOR]

Aims: There have been few reports on whether long‐term oral phosphodiesterase 5 inhibitor administration can ameliorate bladder changes due to bladder outlet obstruction (BOO). Therefore, we clarified the chronological changes of the bladder using male BOO rats and evaluated the effects of tadalafil on these changes. Methods: Eight‐week‐old male Sprague‐Dawley rats were used. BOO was created by placing a polyethylene catheter around the urethra. Then, the rats were orally treated with a vehicle, or tadalafil 2 or 10 mg/kg until each evaluation period. Cystometric measurements were performed and the degree of fibrosis in the smooth muscle layer was evaluated at 2, 4, and 16 weeks. Results: In BOO rats, a significant increase in the number of non‐voiding contractions (NVCs) and a shortened intercontraction interval (ICI) were observed in the earlier phase (2 and 4 weeks) compared to Sham rats. In the chronic phase (16 weeks), markedly increased residual urine volume and an extended ICI were observed accompanied by enhanced smooth muscle fibrosis. These results indicated that the bladder in BOO rats represented the overactive phenotype in the earlier phase and changed into the underactive phenotype in the chronic phase. Even in Sham rats, an increased number of NVCs and enhanced fibrosis were observed with time. Tadalafil administration significantly prevented these bladder changes in both BOO and Sham rats. Conclusions: Long‐term oral administration of tadalafil can prevent functional and histological changes in the BOO rat bladder. This agent is also effective for the bladder functional change even in non‐obstructed rats. [ABSTRACT FROM AUTHOR]

Purpose: The prevalence of erectile dysfunction (ED) is higher in patients with lower urinary tract symptoms (LUTS). Phosphodiesterase 5 inhibitors (PDE5is) can improve both ED and LUTS and therefore is useful for these patients. Our aim of this study is to evaluate whether combination therapy of alpha blockers and PDE5i is more effective than alpha-blockers monotherapy for the treatment of LUTS. Materials and Methods: A systematic review and meta-analysis were undertaken to assess the difference between the combination therapy and alpha-blockers monotherapy by searching published randomized controlled trials from electronic databases PubMed, Embase, and the Cochrane Library up to April 2018. Results: A total of 13 randomized controlled studies with 1173 patients were included in our meta-analysis. Compared with alpha-blocker monotherapy, the combination therapy obtained a significantly better improvement in International Prostate Symptom Score (IPSS) (1.73, 95% confidence interval [CI]: 1.1–2.35), voiding subscore (0.99, 95% CI: 0.54–1.44), storage subscore (0.57, 95% CI: 0.03–1.1), peak flow rate (0.69 cc/s, 95% CI: 0.27–1.1), and erectile function (EF) symptom score. Meta-regression showed that baseline IPSS, baseline peak flow rate, baseline prostate volume, age, baseline EF symptom score, and dosage of PDE5is were not associated with the difference in IPSS improvement. Conclusion: A combination of alpha blockers and PDE5is has better therapeutic effects than alpha-blocker monotherapy on LUTS related to benign prostate hyperplasia. [ABSTRACT FROM AUTHOR]

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking.Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide.Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level.Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115. [ABSTRACT FROM AUTHOR]

– Tadalafil, a long-acting phosphodiesterase 5 (PDE5) inhibitor, alleviates preeclampsia (PE), and decreases the fetal and infant deaths associated with fetal growth restriction (FGR) in phase II clinical trial. Recently, we demonstrated that tadalafil alleviates FGR and hypertension in the dams with PE induced by l -NAME. –The aim of present study was to clarify the effect of tadalafil in another mouse model of PE, murine reduced uterine perfusion pressure (RUPP) model we have recently developed. –At 14.5 dpc we performed RUPP operation in mice to induce PE, administered the animals with tadalafil or vehicle in the drinking water daily from 15.5 dpc, and sacrificed them at 18.5 dpc for analyses. –Tadalafil improved maternal hypertension and glomerular endotheliosis in RUPP mice. Moreover, tadalafil prolonged pregnancy period, and improved survival and growth of the embryos. RUPP increased content of sFlt-1 protein in the placenta, and tadalafil corrected it back to control levels. – Tadalafil alleviates PE-like phenotype and FGR in RUPP murine model. RUPP model could help understand the mechanism of how tadalafil works on PE and FGR. • We used a novel mouse model of preeclampsia (PE), RUPP. • Tadalafil corrected maternal high blood pressure in RUPP PE. • Tadalafil ameliorated endothelial damage in RUPP PE. • Tadalafil prolonged pregnancy period in RUPP PE. • Tadalafil improved survival and growth of embryos in RUPP PE. [ABSTRACT FROM AUTHOR]

A retrospective chart review of 50 men with low testosterone levels treated for erectile dysfunction with testosterone therapy, phosphodiesterase-5 inhibitor, alone or both in combination, was conducted at a community urology practice. Clinically improved responses were found with combination therapy. [ABSTRACT FROM AUTHOR]

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microL of 5% formalin solution was applied to the hind-paw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

Abstract Background Previous studies suggested that phosphodiesterase 5 inhibitors (PDE5i) have a beneficial effect in patients with heart failure (HF), although the results were inconsistent. We performed a meta-analysis to evaluate the effect of PDE5i in HF patients, and investigated the relationship between PDE5i effects and pulmonary hemodynamics. Method We searched PubMed, EMBASE and the Cochrane Library for randomized controlled trials (RCTs) that compared PDE5i with placebo in HF with reduced ejection fraction (HFrEF) or HF with preserved EF (HFpEF). PDE5i effects were interpolated according to baseline pulmonary arterial pressure (PAP) or according to changes in PAP after PDE5i treatment. Results Thirteen RCTs enrolling 898 HF patients, and two sub-analysis studies with different study outcomes, were included in the meta-analysis. Among patients with HFrEF, PDE5i improved peak VO2 (mean difference [MD], 3.76 mL/min/kg; 95% confidence interval [CI], 3.27 to 4.25; P

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n = 200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p = 0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration., Competing Interests: Declaration of Competing Interest The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the U.S. Department of Health and Human Services; or Mezzion Pharma Co. Ltd., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In Alzheimer's disease pathology, inhibitors of nuclear factor kappa-β kinase subunit β (IKKB) and Tumor necrosis factor receptor 1 (TNFR1) signaling are linked to neuroinflammation-mediated cognitive decline. We explored the role of a phosphodiesterase 5 inhibitor (PDE5I) with dual antagonistic action on IKKB and TNFR1 to inhibit nuclear factor kappa B (NF-kB) and curb neuroinflammation. In the in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The top compound with dual antagonistic action on IKKB and TNFR1 was selected based on bonding and non-bonding interactions. Further, induced fit docking (IFD), molecular mechanics-generalized Born and surface area (MMGBSA), and molecular dynamic studies were carried out and evaluated. Lipopolysaccharide (LPS) administration caused a neuroinflammation-mediated cognitive decline in mice. Two doses of avanafil were administered for 28 days while LPS was administered for 10 days. Morris water maze (MWM) along with the passive avoidance test (PAT) were carried out. Concurrently brain levels of inflammatory markers, oxidative parameters, amyloid beta (Aβ), IKKB and NF-kB levels were estimated. Avanafil produced good IKKB and TNFR1 binding ability. It interacted with crucial inhibitory amino acids of IKKB and TNFR1. MD analysis predicted good stability of avanafil with TNFR1 and IKKB. Avanafil 6 mg/kg could significantly improve performance in MWM, PAT and oxidative parameters and reduce Aβ levels and inflammatory markers. As compared to avanafil 3 mg/kg, 6 mg/kg dose was found to exert better efficacy against elevated Aβ , neuroinflammatory cytokines and oxidative markers while improving behavioural parameters.Communicated by Ramaswamy H. Sarma.

Objective: The present study assesses whether phosphodiesterase type 5 (PDE-5) inhibitor or carnitine exert nephroprotective effects against clinical contrast-induced nephropathy (CIN). Materials and Methods: The present study consisted of three groups of CKD patients. The first group was control group, who were treated with N-acetyl-L-cysteine 1 day before and on the day of radiocontrast administration. The second one was carnitine group, where the patients were infused with carnitine over 10 min 2 h prior to the radiocontrast administration and 24 h post CT. The third one was PDE-5 inhibitor group, where patients were given tadalafil 2 h prior to the administration of the radiocontrast and in the subsequent day. Urine and blood samples were collected before and at the following time sequence: 2, 6, 12, 24, 48, and 120 h after the contrast administration, for creatinine and NGAL determination. Results: Pretreated with N-acetyl-L-cysteine prior to administration of contrast media (CM) to CKD patients caused a significant increase in urinary but not of plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum creatinine (SCr). In contrast, pretreatment with carnitine prevented the increase in urinary NGAL and reduced SCr below basal levels. Similarly, tadalafil administration diminished the elevation of CM-induced urinary NGAL. Conclusions: These results indicate that carnitine and PDE-5 inhibitors may comprise potential therapeutic maneuvers for CIN. [ABSTRACT FROM AUTHOR]

The purpose of this study was the development and validation of an LC-MS/MS method, for the determination of tadalafil from human plasma. The sample workup involved a simple protein precipitation procedure. A core/shell type analytical column (50×2,1 mm, 2.6 Å) was used with C18 stationary phase. The mobile phase consisting of 30% acetonitril and 70% water provided good peak shape, accuracy and precision (stable ionization). The mass spectrometer was operated in positive electrospray ionization mode for analyte and internal standard. The following parameters were evaluated for validation purpose: selectivity, sensitivity, matrix effect, anticoagulant effect, linearity, precision and accuracy, recovery, short and long term analyte/IS stability in solvent/matrix and carryover. The validated calibration range was 22.2-1111.3 ng/ml. The correlation coefficient R2 was at least 0.9995 in all validation batches. The validated method has been successfully used for the evaluation of bioequivalence of generic tadalafil 20 mg formulations. [ABSTRACT FROM AUTHOR]

Purpose: Recently, controversy exists regarding the oncologic outcomes associated with the use of phosphodiesterase 5 inhibitor (PDE5i). Therefore, we attempted to verify the effect of PDE5i on biochemical recurrence (BCR) following radical prostatectomy (RP) in patients with prostate cancer (PCa). Materials and Methods: From January 2011 to May 2016, 351 patients who had undergone bilateral neurovascular bundle saving and who were confirmed as having pT2N0M0 disease were included in the present study. We divided these patients into three groups: no PDE5i use, PDE5i use on demand , and PDE5i use for rehabilitation. We retrospectively analyzed the effect of PDE5i on BCR of PCa. Mean follow-up period was 34.4 months and mesurement of outcome was whether the patients developed BCR during regular follow-up. Results: 25 (7.1%) patients showed BCR and univariate analysis found no significant differences in BCR between the three groups (5 (6.9%) in no PDE5i use, 8 (9.5%) in PDE5i use on demand, 12 (6.2%) in PDE5i use for rehabilitation). Multivariable analyses showed that treatment type was not a significant factor for BCR between the groups with no PDE5i use and PDE5i use (HR = 1.34 [0.49–3.70]; P = .573) and between the groups with on demand and rehabilitation use (HR = 1.37 [0.35–5.37]; P = .646). Kaplan-Meier survival curves show that there were no significant differences in PSA recurrence-free survival in three groups (P > .05). Conclusion: Use of PDE5is was not associated with any adverse effects on BCR after RP in patients with PCa. [ABSTRACT FROM AUTHOR]

Although numerous reports have shown that α 1 -adrenoceptor (α 1 -AR) antagonists, which are used to treat benign prostatic hyperplasia (BPH), can cause ejaculatory disorders, few studies have investigated whether the phosphodiesterase 5 (PDE5) inhibitor tadalafil has such adverse effects. In this study, we compared the effects of tadalafil and α 1 -AR antagonists on seminal emission and their mechanisms of action. To evaluate in normal rats the possible effects of tadalafil on spontaneous seminal emission (SSE) and seminal contraction evoked by hypogastric nerve stimulation. Male Sprague-Dawley rats were used. To assess SSE, plastic corsets were fitted around the thorax and upper abdomen of male Sprague–Dawley rats to prevent genital autogrooming. Rats were treated orally with tadalafil or an α 1 -AR antagonist (silodosin, naftopidil, or tamsulosin) for 3 days and housed in wire-bottomed cages. Ejaculatory plugs dropped on the bottoms of the cages were counted and weighed. To assess the intraluminal pressure of seminal vesicles, the hypogastric nerve of urethane-anesthetized rats was isolated and electrically stimulated. After stabilization of seminal vesicle contraction, the rats were intravenously administered test drugs. The expression of PDE5, endothelial nitric oxide synthetase (eNOS), and neuronal NOS (nNOS) in the seminal vesicle and vas deferens were measured by reverse-transcription polymerase chain reaction. The number and weight of the ejaculatory plugs produced by corset-fitted rats and the intraluminal pressure of the seminal vesicle were evaluated. Tadalafil did not affect the number or weight of the ejaculatory plugs of corset-fitted rats, whereas all α 1 -AR antagonists decreased both in a dose-dependent manner. The α 1 -AR antagonists, but not tadalafil, inhibited the seminal vesicle contraction evoked by electrical stimulation of the hypogastric nerve. The seminal vesicle and vas deferens expressed higher levels of PDE5 and eNOS mRNA and lower levels of nNOS mRNA relative to the urethra. Tadalafil can be a treatment option in cases where there is concern about negative effects on seminal emission. We demonstrated different effects of tadalafil and 3 α 1 -AR antagonists on rat SSE and their mechanisms of action by measuring seminal vesicle contractility in vivo. A limitation is that we used normal rats, not BPH model rats, and so our results might not apply to human BPH patients. Tadalafil did not inhibit spontaneous seminal emission or electrical field stimulation–induced seminal vesicle contraction in normal rats. The NO–cyclic guanosine monophosphate pathway is unlikely to be involved in the inhibition of seminal vesicle contraction in normal rats. Yoshinaga R, Fukui T, Yoshifuji M, et al. Comparison of the Effects of Tadalafil and α 1 -Adrenoceptor Antagonists on Spontaneous Seminal Emission and Electrical Field Stimulation-Induced Seminal Vesicle Contraction in Rats. J Sex Med 2019;16:680–690. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with diabetes mellitus frequently experience erectile dysfunction. This systematic review and meta-analysis were conducted to find efficacy and tolerability of phosphodiesterase 5 (PDE5) inhibitors in patients with diabetes mellitus experiencing erectile dysfunction. Methodology: Electronic searches were carried out to identify English language peer-reviewed randomized controlled trials (RCTs), which reported clinical efficacy of any PDE5 inhibitor in patients with diabetes mellitus having erectile dysfunction. Effect sizes were computed using Cohen′s d, and I 2-test was used to assess heterogeneity. Pooled mean effect sizes were computed using random-effects model. Number needed to treat (NNT), and the adverse event rates were computed. Results: The systematic review included a total of 17 studies yielding 25 comparisons. Three studies were open RCTs while others were double-blind RCTs. The pooled mean effect size of any PDE5 inhibitor over placebo was 0.926 (95% confidence intervals [CI]: 0.864-0.987; I 2 =26.3). The pooled mean effect size for sildenafil was 1.198 (CI: 1.039-1.357; I 2 =), for tadalafil was 0.910 (CI: 0.838-0.981; I 2 =33.6), and for vardenafil was 0.678 (CI: 0.627-0.729; I 2 =). In pooled analysis, the NNT for sildenafil, tadalafil, vardenafil and any PDE5 inhibitor was 2.4, 2.6, 4.1 and 3.0 respectively. The most common side effects were headache, flushing, and nasal congestion. Conclusions: PDE5 inhibitors are effective and safe medications for the treatment of sexual dysfunction in patients with diabetes mellitus experiencing erectile dysfunction.

Background: Extract of the wild orchid, Eulophia macrobulbon (EM) inhibits phosphodiesterase5 (PDE5) suggesting it could preferentially dilate the pulmonary vasculature.Purpose and Study Design: To pharmacologically characterize the vascular actions of EM ethanolic extract and its active compound, 1-(4'-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol using isolated pulmonary arteries (PA) from rats having pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). PA were fixed and prepared for histology.Results: EM extract relaxed PA (EC50 = 0.17  mg/ml, Emax ∼ 94%) but less so for aorta (EC50 = 0.51 mg/ml, Emax ∼ 62%), suggesting some selectivity towards the pulmonary circulation. PA vasorelaxation was reduced by endothelial removal or NG-nitro-L-arginine methyl ester, but unaffected by indomethacin, apamin +charybdotoxin, 4-aminopyridine, glibenclamide, iberiotoxin, or 1H - [1,2,4]oxadiazolo[4,3-a]quinoxalin -1- one. Sodium nitroprusside-induced relaxation was enhanced by EM extract, probably via PDE5 inhibition. EM extract reduced contractions evoked by extracellular Ca2+application, and inhibited intracellular Ca2+release activated by phenylephrine. The phenanthrene relaxed PA independently of the endothelium. MCT thickened walls and decreased lumens of PA, and hypertrophied right ventricular myocytes, effects ameliorated by 3 weeks of oral sildenafil (20  mg/kg) or EM extract (15, 450 or 1000  mg/kg).Conclusion: PAH is improved by EM extract acting through PA relaxation mediated through endothelial NO, reduced Ca2+-mobilization, and reduced PA wall thickness and right ventricular hypertrophy. [ABSTRACT FROM AUTHOR]