The relationship between the history of PDE5-inhibitors assumption and melanoma: a systematic review.

INTRODUCTION: Phosphodiesterase 5 inhibitors (PDE5-is) are used worldwide as first line therapy for erectile dysfunction (ED). Current literature reported data on the warning association between PDE5-is use and the development of cutaneous melanoma. However, these data are contrasting, thus we aim to summarise evidence regarding this association. CONTENT: A systematic review of all published articles related to the effects of PDE5-is in the development of cutaneous melanoma was performed. PubMed, EMBASE, and Cochrane library were queried for all the published studies indexed up to the 26th of May 2023. A combination of keywords related to PDE5-is and melanoma were used. Only original studies based on human subjects in the English language were included in the analysis. SUMMARY AND OUTLOOK: Of 505 articles identified, only eight original articles were considered for further analysis. Overall, five of the selected articles including 657,984 subjects agrees on an increased risk of developing melanoma in PDE5-is users. On the other hand, three original articles based on data regarding 360,915 subjects, disagree with the previous statement declaring any association between PDE5-i use and melanoma. Current literature still reports contrasting data regarding the association between PDE5-is assumption and increased risk of melanoma, but a possible association is described, bringing attention to higher risk melanoma category of patients. More clinical studies are needed to clarify the impact of PDE5-is in the development and progression of melanoma.

Vardenafil alleviates cigarette smoke-induced chronic obstructive pulmonary disease by activating autophagy via the AMPK/mTOR signalling pathway: an in vitro and in vivo study.

Chronic obstructive pulmonary disease (COPD) has always attracted global attention with its high prevalence, incidence rate, and mortality. Exposure to cigarette smoke is one of main causes of COPD. Therefore, it is still necessary to study its pathogenesis and find new therapeutic strategies for early COPD prevention and treatment. Vardenafil, a type 5 phosphodiesterase (PDE5) inhibitor, is known to have an efficient therapy in some cardiovascular, pulmonary, and vascular diseases, which is an important mechanism for COPD. However, it still loss relevant research on whether vardenafil is effective in COPD and its mechanism. In this study, the cigarette smoke inhalation was performed to establish cigarette smoke-induced COPD model using C57BL/6 mice and 16HBE cells were treated with cigarette smoke extract (CSE). Mice were treated with vardenafil for 30 d. Then condition of lung injury was evaluated using histological analysis. The content of cytokines and the number of inflammatory cells in lung tissues or bronchoalveolar lavage fluid were measured. Additionally, western blot analysis was employed to evaluate the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)-mediated autophagy in vitro. The results showed that vardenafil abolished CSE's effect by activating autophagy via the AMPK/mTOR signalling pathway in vitro. Vardenafil attenuated cigarette smoke-induced lung injury and inflammation response by activating autophagy via the AMPK/mTOR signalling pathway in vivo. These results provide valuable insights into the molecular mechanisms underlying vardenafil's beneficial effects in cigarette smoke-induced COPD treatment. In conclusion, vardenafil alleviates cigarette smoke-induced experimental COPD by activating autophagy via the AMPK/mTOR signalling pathway.

Analytical methods for the detection and characterization of unapproved phosphodiesterase type 5 inhibitors (PDE-5i) used in adulteration of dietary supplements- a review.

This article is an up-to-date review of 112 unapproved phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in sexual enhancement dietary supplements and other products from 2003 to July 2023. Seventy-five of these unapproved PDE-5i are analogues of sildenafil (67%), followed by 26 analogues of tadalafil (23%), 9 analogues of vardenafil (8%) and 2 other type of compounds (2%). The products have been formulated in various packaging, primarily in capsule, tablet, and powder forms. Common screening techniques allowing detection of such analogues include high performance or ultra-high performance liquid chromatography in tandem with ultra-violet detector (HPLC-UV or UPLC-UV) (50%) and thin-layer chromatography in tandem with ultra-violet detection (TLC-UV) (7%). Screening by mass spectrometry (MS) is relatively less common with the use of single-, triple-quadrupole or time-of-flight (TOF) mass spectrometers (9%). Meanwhile, the combined detection by UV-MS has been recorded at 10% usage. Screening by proton nuclear magnetic resonance spectroscopy (NMR) (11%) has also been applied. For compound characterization, i.e. structural elucidation, NMR spectroscopy has been preferred (100 out of 112 compounds), followed by high-resolution mass spectrometry (HRMS) (74 out of 112 compounds) and Fourier-transform infrared spectroscopy (FTIR) (44 out of 112 compounds). Over the past two decades, analytical technology has been evolving with enhanced sensitivity and resolution. Despite this, structural elucidation of the new emerging analogues in adulterated dietary supplements remains a challenge, especially when the analogues involve complex structural modification. Therefore, the above-mentioned techniques may not be adequate to characterize the analogues. Additional work involving chiroptical methods, two-dimensional (2D) NMR experiments and X-ray crystallography are likely to be required in the future.

Neuromodulatory effect of vardenafil on aluminium chloride/D-galactose induced Alzheimer's disease in rats: emphasis on amyloid-beta, p-tau, PI3K/Akt/p53 pathway, endoplasmic reticulum stress, and cellular senescence.

Dysregulation of protein homeostasis, proteostasis, is a distinctive hallmark of many neurodegenerative disorders and aging. Deleteriously, the accumulation of aberrant proteins in Alzheimer's disease (AD) is accompanied with a marked collapse in proteostasis network. The current study explored the potential therapeutic effect of vardenafil (VAR), a phosphodiesterase-5 inhibitor, in AlCl3/D-galactose (D-gal)-induced AD in rats and its possible underlying mechanisms. The impact of VAR treatment on neurobehavioral function, hippocampal tissue architecture, and the activity of the cholinergic system main enzymes were assessed utilizing VAR at doses of 0.3 mg/kg and 1 mg/kg. Additionally, the expression level of amyloid-beta and phosphorylated tau proteins in the hippocampus were figured out. Accordingly, VAR higher dose was selected to contemplate the possible underlying mechanisms. Intriguingly, VAR elevated the cyclic guanosine monophosphate level in the hippocampus and averted the repressed proteasome activity by AlCl3/D-gal; hence, VAR might alleviate the burden of toxic protein aggregates in AD. In addition, a substantial reduction in the activating transcription factor 6-mediated endoplasmic reticulum stress was demonstrated with VAR treatment. Notably, VAR counteracted the AlCl3/D-gal-induced depletion of nuclear factor erythroid 2-related factor 2 level. Moreover, the anti-senescence activity of VAR was demonstrated via its ability to restore the balance of the redox circuit. The modulation of phosphatidylinositol-3-kinase/protein kinase B/p53 pathway and the reduction of nuclear factor kappa B level, the key regulator of senescence-associated secretory phenotype mediators release, with VAR treatment were also elucidated. Altogether, these findings insinuate the possible therapeutic benefits of VAR in AD management.

Pharmacokinetics comparison of vardenafil as administered by an intranasal spray formulation vs a 10-mg oral tablet.

BACKGROUND: Oral vardenafil (VDF) tablet is an effective treatment for erectile dysfunction (ED), but intranasal administration with a suitable formulation can lead to a faster onset of action and offer more convenient planning for ED treatment. AIM: The primary purpose of the present pilot clinical study was to determine whether intranasal VDF with an alcohol-based formulation can result in more "user-friendly pharmacokinetics" as compared with oral tablet administration. METHODS: This single-dose randomized crossover study was conducted in 12 healthy young volunteers receiving VDF as a 10-mg oral tablet or 3.38-mg intranasal spray. Multiple blood concentrations were obtained, and VDF concentrations were determined with a liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters following each treatment were compared and adverse events assessed. OUTCOMES: Pharmacokinetic parameters were obtained: apparent elimination rate constant, elimination half-life, peak concentration, peak time, total area under the curve, and relative bioavailability. RESULTS: Although mean apparent elimination rate constant, elimination half-life, peak concentration, and total area under the curve were similar between intranasal and oral administration, the median peak time from intranasal was much shorter (10 vs 58 minutes, P < .001, Mann-Whitney U test). The variability of the pharmacokinetic parameters was also less with intranasal than oral administration. The relative bioavailability of intranasal to oral was 1.67. Intranasal VDF caused transient but tolerable local nasal reactions in 50% of subjects. Other adverse events (eg, headache) were similar between the treatments. The incidence of adverse events was, however, significantly less in the second treatment after initial exposure to VDF. No serious adverse events were noted. CLINICAL IMPLICATIONS: Intranasal VDF potentially offers a more timely and lower dose for the treatment of ED in patients who can tolerate the transient local adverse reactions. STRENGTHS AND LIMITATIONS: The strength of this study is its randomized crossover design. Because the study was conducted in 12 healthy young subjects, the results may not reflect those observed in elderly patients who may be likely taking VDF for ED. Nevertheless, the changes of pharmacokinetic parameters in the present study are likely a reflection of the differences between intranasal and oral administration of the formulations. CONCLUSION: Our study indicated that the present VDF formulation, when administered intranasally, can achieve a more rapid but similar plasma concentration with only about one-third dose when compared with the oral administration.

Phosphodiesterase 5 (PDE-5) inhibitors (sildenafil, tadalafil, and vardenafil) effects on esophageal motility: a systematic review.

BACKGROUND: Esophageal motility disorders are a group of disorders associated with dysfunctional swallowing resulting from impaired neuromuscular coordination. Phosphodiesterase 5 (PDE-5) inhibitors induce smooth relaxation and are proposed as a treatment option for esophageal motility disorders such as achalasia. METHODS: This study is conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched MEDLINE/ PubMed, Scopus, EMBASE, and Web of Science databases for esophageal outcomes of individuals treated with PDE5 inhibitors. A random effect meta-analysis was conducted. RESULTS: A total of 14 studies were included. They were conducted in different countries, with Korea and Italy having the highest number of articles. The main drug assessed was sildenafil. PDE-5 inhibitors resulted in a significant reduction in lower esophageal sphincter pressure (SMD - 1.69, 95% CI: -2.39 to -0.99) and the amplitude of contractions (SMD - 2.04, 95% CI: -2.97 to -1.11). Residual pressure was not significantly different between the placebo and sildenafil groups (SMD - 0.24, 95% CI: -1.20 to 0.72). Furthermore, a recent study reported contractile integral, stating that ingestion of sildenafil leads to a significant reduction in distal contractile integral and a significant increase in proximal contractile integral. CONCLUSION: PDE-5 inhibitors significantly reduce LES resting pressure and esophageal peristaltic vigor, decreasing esophageal body contractility and contraction reserve. Therefore, using these drugs in patients affected by esophageal motility disorders may potentially improve their condition regarding symptom relief and prevention of further associated complications. Future reports investigating larger sample size is necessary in order to establish definite evidence regarding the efficacy of these drugs.

Statins synergize with phosphodiesterase type 5 inhibitors but not with selective estrogen receptor modulators to prevent myofibroblast transformation in an in vitro model of Peyronie's disease.

BACKGROUND: Peyronie's disease (PD) is a fibrotic disorder characterized by plaque formation in the tunica albuginea (TA) of the penis, and we have previously shown that inhibition of transformation of TA-derived fibroblasts to myofibroblasts using a combination phosphodiesterase type 5 (PDE5) inhibitors and selective estrogen receptor modulators (SERMs) is effective in slowing the progression of early PD. AIM: The study sought to investigate whether combinations of statins with PDE5 inhibitors or SERMs would affect myofibroblast transformation in vitro. METHODS: Primary fibroblasts were isolated from TA of patients with PD and stimulated with transforming growth factor ß1 in the absence and presence of a range of concentrations of statins, PDE5 inhibitors, SERMs, and their combinations for 72 hours before quantifying α-smooth muscle actin using in-cell enzyme-linked immunosorbent assay. OUTCOMES: The prevention of transforming growth factor ß1-induced transformation of TA-derived fibroblasts to myofibroblasts was measured in vitro. RESULTS: Statins (simvastatin, lovastatin) inhibited myofibroblast transformation in a concentration-dependent manner with half maximal inhibitory concentration values of 0.77 ± 0.07 µM and 0.8 ± 0.13 µM, respectively. Simvastatin inhibited myofibroblast transformation in a synergistic fashion when combined with vardenafil (a PDE5 inhibitor; log alpha >0). Combination of tamoxifen (a SERM) and simvastatin did not show synergy (log alpha <0). When 3 drugs (simvastatin, vardenafil, and tamoxifen) were combined, the effect was not synergistic, but rather was additive. CLINICAL IMPLICATIONS: A combination of a statin with a PDE5 inhibitor might be useful in the clinic to slow the progression of the disease in patients with early PD; however, caution should be taken with such a combination because of the reported myopathy as a side effect. STRENGTHS AND LIMITATIONS: The use of primary human cells from patients with PD is a strength of this study. The mechanisms by which these drug classes exert synergy when used in combination was not investigated. CONCLUSION: This is the first demonstration of an antifibrotic synergy between statins and PDE5 inhibitors.

Changes in Left Ventricular Ejection Fraction and Oxidative Stress after Phosphodiesterase Type-5 Inhibitor Treatment in an Experimental Model of Retrograde Rat Perfusion.

Background and objectives: Taking into consideration the confirmed role of oxidative stress in ischemia/reperfusion injury and the insufficiency in knowledge regarding the phosphodiesterase 5 (PDE5)-mediated effects on the cardiovascular system, the aim of our study was to investigate the influence of two PDE5 inhibitors, tadalafil and vardenafil, with or without the addition of N(G)-nitro-L-arginine methyl ester (L-NAME), on oxidative stress markers, coronary flow and left ventricular function, both ex vivo and in vivo. Methods: This study included 74 male Wistar albino rats divided into two groups. In the first, 24 male Wistar rats were orally treated with tadalafil or vardenafil for four weeks in order to perform in vivo experiments. In the second, the hearts of 50 male Wistar albino were excised and perfused according to the Langendorff technique in order to perform ex vivo experiments. The hearts were perfused with tadalafil (10, 20, 50 and 200 nM), vardenafil (10, 20, 50 and 200 nM) and a combination of tadalafil/vardenafil and L-NAME (30 µM). The CF and oxidative stress markers, including nitrite bioaviability (NO2-), superoxide anion radical (O2-), and the index of lipid peroxidation, were measured in coronary effluent. Results: The L-arginin/NO system acts as the mediator in the tadalafil-induced effects on the cardiovascular system, while it seems that the vardenafil-induced increase in CF was not primarily induced by the NO system. Although tadalafil induced an increase in O2- in the two lowest doses, the general effects of both of the applied PDE5 inhibitors on oxidative stress were not significant. The ejection function was above 50% in both groups. Conclusions: Our results showed that both tadalafil and vardenafil improved the coronary perfusion of the myocardium and LV function by increasing the EF.

Adverse reactions of PDE5 inhibitors: An analysis of the World Health Organization pharmacovigilance database.

BACKGROUND: Despite their efficacy and general safety, rare but devastating adverse drug reactions have been associated with phosphodiesterase type 5 inhibitors. OBJECTIVES: To determine the safety profile of oral phosphodiesterase type 5 inhibitors with a particular focus on priapism and malignant melanoma. MATERIALS AND METHODS: In this case-non-case study, we queried the individual case safety reports for phosphodiesterase type 5 inhibitors within the World Health Organization global database of individual case safety reports (VigiBase) between 1983 and 2021. We included all individual case safety reports for sildenafil, tadalafil, vardenafil, and avanafil in men. For comparison, we also extracted the safety data from the Food and Drug Administration trials for these drugs. We assessed the safety profile of phosphodiesterase type 5 inhibitors by disproportionality analysis by measuring reporting odds ratio for their most commonly reported adverse drug reactions, once for all phosphodiesterase type 5 inhibitor reports and once for reports of oral phosphodiesterase type 5 inhibitor use in adult men (≥18 years old) with sexual dysfunction. RESULTS: A total of 94,713 individual case safety reports for phosphodiesterase type 5 inhibitors were extracted. A total of 31,827 individual case safety reports were identified relating to adult men taking oral sildenafil, tadalafil, vardenafil, or avanafil for sexual dysfunction. The most common adverse drug reactions included poor drug efficacy (42.5%), headache (10.4% vs. 8.5%-27.6% [Food and Drug Administration]), abnormal vision (8.4% vs. ≤4.6% [Food and Drug Administration]), flushing (5.2% vs. 5.1%-16.5% [Food and Drug Administration]), and dyspepsia (4.2% vs. 3.4%-11.1% [Food and Drug Administration]). Priapism showed significant signals for sildenafil (reporting odds ratio = 13.81, 95% confidence interval: 11.75-16.24), tadalafil (reporting odds ratio = 14.54, 95% confidence interval: 11.56-18.06), and vardenafil (reporting odds ratio = 14.12, 95% confidence interval: 8.36-22.35). Comparing with other medications in VigiBase, sildenafil (reporting odds ratio = 8.73, 95% confidence interval: 7.63-9.99) and tadalafil (reporting odds ratio = 4.25, 95% confidence interval: 3.19-5.55) had significantly higher reporting odds ratios for malignant melanoma. CONCLUSION: Phosphodiesterase type 5 inhibitors show significant signals correlating with priapism among a large international cohort. Further clinical study is needed to elucidate whether this is from proper or inappropriate use or other confounding conditions, as analysis of pharmacovigilance data does not allow for quantifying the clinical risk. Also, there appears to be a relationship between phosphodiesterase type 5 inhibitor use and malignant melanoma, which warrants additional study to better understand causation.

Intracellular cGMP increase is not involved in thyroid cancer cell death.

INTRODUCTION: Type 5 phosphodiesterase (PDE5) inhibitors (PDE5i) lead to intracellular cyclic-guanosine monophosphate (cGMP) increase and are used for clinical treatment of erectile dysfunction. Studies found that cGMP may up/downregulate the growth of certain endocrine tumor cells, suggesting that PDE5i could impact cancer risk. AIM: We evaluated if PDE5i may modulate thyroid cancer cell growth in vitro. MATERIALS AND METHODS: We used malignant (K1) and benign (Nthy-ori 3-1) thyroid cell lines, as well as the COS7 cells as a reference model. Cells were treated 0-24 h with the PDE5i vardenafil or the cGMP analog 8-br-cGMP (nM-µM range). cGMP levels and caspase 3 cleavage were evaluated by BRET, in cGMP or caspase 3 biosensor-expressing cells. Phosphorylation of the proliferation-associated extracellularly-regulated kinases 1 and 2 (ERK1/2) was evaluated by Western blotting, while nuclear fragmentation by DAPI staining. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Both vardenafil and 8-br-cGMP effectively induced dose-dependent cGMP BRET signals (p≤0.05) in all the cell lines. However, no differences in caspase 3 activation occurred comparing PDE5i-treated vs untreated cells, at all concentrations and time-points tested (p>0.05). These results match those obtained upon cell treatment with 8-br-cGMP, which failed in inducing caspase 3 cleavage in all the cell lines (p>0.05). Moreover, they reflect the lack of nuclear fragmentation. Interestingly, the modulation of intracellular cGMP levels with vardenafil or the analog did not impact cell viability of both malignant and benign thyroid tumor cell lines, nor the phosphorylation of ERK1/2 (p>0.05). CONCLUSIONS: This study demonstrates that increased cGMP levels are not linked to cell viability or death in K1 and Nthy-ori 3-1 cell lines, suggesting that PDE5i do not impact the growth of thyroid cancer cells. Since different results were previously published, further investigations are recommended to clarify the impact of PDE5i on thyroid cancer cells.

The POWER saga from 2007 to 2022: An example of a sexual enhancement dietary supplement tainted by different adulterants and still on the market.

Ten POWER dietary supplements, chronologically called tabs, pills then caps, and advertised as 100% natural aphrodisiacs, were analyzed by 1H NMR from 2007 to 2022. They were all tainted by PDE-5 inhibitors. Eight different adulterants were identified (sildenafil (1), sildenafil analogues (6), and vardenafil analogue (1)). Their amounts ranged from 15 to 145 mg/capsule. Four supplements contained at least 100 mg/capsule of PDE-5 inhibitor or analogue, the maximal recommended dose of sildenafil. The nature of the adulterant has changed over time, probably to evade its detection by regulatory agencies routine screening tests. Despite several warnings and/or seizures from several European food and/or health authorities, the dietary supplement POWER is still on sale on the Internet, thus demonstrating the impossibility of controlling this market. Faced with this situation, the consumer should be better informed by establishing at the European level a public database of tainted dietary supplements on the model of that of the US Food and Drug Administration. It should indicate the product name, its photo, the adulterant name, and be easily accessible to everyone.

Treating diabetes with combination of phosphodiesterase 5 inhibitors and hydroxychloroquine-a possible prevention strategy for COVID-19?

Type 2 diabetes (T2D) is one of the major risk factors for developing cardiovascular disease and the resultant devastating morbidity and mortality. The key features of T2D are hyperglycemia, hyperlipidemia, insulin resistance, and impaired insulin secretion. Patients with diabetes and myocardial infarction have worse prognosis than those without T2D. Moreover, obesity and T2D are recognized risk factors in developing severe form of COVID-19 with higher mortality rate. The current lines of drug therapy are insufficient to control T2D and its serious cardiovascular complications. Phosphodiesterase 5 (PDE5) is a cGMP specific enzyme, which is the target of erectile dysfunction drugs including sildenafil, vardenafil, and tadalafil. Cardioprotective effects of PDE5 inhibitors against ischemia/reperfusion (I/R) injury were reported in normal and diabetic animals. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug and its hyperglycemia-controlling effect in diabetic patients is also under investigation. This review provides our perspective of a potential use of combination therapy of PDE5 inhibitor with HCQ to reduce cardiovascular risk factors and myocardial I/R injury in T2D. We previously observed that diabetic mice treated with tadalafil and HCQ had significantly reduced fasting blood glucose and lipid levels, increased plasma insulin and insulin-like growth factor-1 levels, and improved insulin sensitivity, along with smaller myocardial infarct size following I/R. The combination treatment activated Akt/mTOR cellular survival pathway, which was likely responsible for the salutary effects. Therefore, pretreatment with PDE5 inhibitor and HCQ may be a potentially useful therapy not only for controlling T2D but also reducing the rate and severity of COVID-19 infection in the vulnerable population of diabetics.

PDE5 inhibitors: breaking new grounds in the treatment of COVID-19.

INTRODUCTION: Despite the ever-increasing occurrences of the coronavirus disease (COVID-19) cases around the world, very few medications have been validated in the clinical trials to combat COVID-19. Although several vaccines have been developed in the past quarter, the time elapsed between deployment and administration remains a major impediment. CONTENT: Repurposing of pre-approved drugs, such as phosphodiesterase 5 (PDE5) inhibitors, could be a game-changer while lessening the burden on the current healthcare system. Repurposing and developing phosphodiesterase 5 (PDE5) inhibitors could extrapolate their utility to combat the SARS-CoV-2 infection, and potentially aid in the management of the symptoms associated with its newer variants such as BF.7, BQ.1, BQ.1.1, XBB.1.5, and XBB.1.16. SUMMARY: Administration of PDE5 inhibitors via the oral and intravenous route demonstrates other potential off-label benefits, including anti-apoptotic, anti-inflammatory, antioxidant, and immunomodulatory effects, by intercepting several pathways. These effects can not only be of clinical importance in mild-to-moderate, but also moderate-to-severe SARS-CoV-2 infections. This article explores the various mechanisms by which PDE5 inhibitors alleviates the symptoms associated with COVID-19 as well as well as highlights recent studies and findings. OUTLOOK: These benefits of PDE5 inhibitors make it a potential drug in the physicians' armamentarium in alleviating symptoms associated with SARS-CoV-2 infection. However, adequate clinical studies must be instituted to eliminate any untoward adverse events.

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH. METHODS: This prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization-confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients' changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234. CONCLUSION: This is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04266197.

Screening and Determination of Synthetic PDE-5 Inhibitors in Adulterated Sexual Enhancement Supplements.

This paper reports an important investigation and quantification of adulteration of sexual enhancement supplements with prescription medicines available in United Arab Emirates (UAE): tadalafil, sildenafil and vardenafil. A total of 158 sexual enhancement supplements were collected and analyzed in the current study. The samples were screened using REVERSE-phase liquid chromatography tandem high-resolution mass spectrometry/mass spectrometry (RP-HPLC-MS/MS). Of all sexual enhancements, 12.7% (95% CI: 7.4-18) contained undeclared sildenafil, 3.8% (95% CI: 0.78-6.81) contained undeclared tadalafil and 1.9% (95% CI: 0.25-4.05) contained undeclared vardenafil. Of all sexual enhancement supplements, 13.9% (95% CI: 8.5-19.4) contained significant concentrations of sildenafil, tadalafil or vardenafil. While the study found relatively low levels of undeclared pharmaceutical ingredients in the sexual enhancement dietary supplements available on the UAE market, it is likely that patients with ED tend to consume multiple such supplements daily, thereby exposing themselves to highly elevated cumulative levels.

PDE5 inhibitors and male reproduction: Is there a place for PDE5 inhibitors in infertility clinics or andrology laboratories?

The objective of this review study is to evaluate the therapeutic role of PDE5 inhibitors (PDE5is) in the amelioration of oligoasthenospermia in infertile males. PDE5is have a beneficial influence on the secretory function of the Leydig and Sertoli cells, the biochemical environment within the seminiferous tubule, the contractility of the testicular tunica albuginea, and the prostatic secretory function. In several studies, the overall effect of sildenafil and vardenafil increased quantitative and qualitative sperm motility. Furthermore, some studies indicate that PDE5is influence positively the sperm capacity to undergo capacitation under biochemical conditions that are known to induce the sperm capacitation process. Additional research efforts are necessary in order to recommend unequivocally the usage of sildenafil, vardenafil, or avanafil for the alleviation of male infertility.

Prostaglandins as a Topical Therapy for Erectile Dysfunction: A Comprehensive Review.

INTRODUCTION: Erectile dysfunction (ED) is a substantial cause of dissatisfaction among many men. This discontentment has led to the emergence of various drug treatment options for this problem. OBJECTIVES: Unfortunately, due to various interactions, contraindications, and side effects, systemic therapies such as phosphodiesterase-5 inhibitors (including sildenafil, tadalafil, vardenafil, avanafil, etc.) are not welcomed in many patients. These problems have led researchers to look for other ways to reduce these complications. METHODS: This article holistically reviews the efficacy of topical prostaglandins and their role in treating ED. We sought to provide a comprehensive overview of recent findings on the current topic by using the extensive literature search to identify the latest scientific reports on the topic. RESULTS: In this regard, topical and transdermal treatments can be suitable alternatives. In diverse studies, prostaglandins, remarkably PGE1 (also known as alprostadil), have been suggested to be an acceptable candidate for topical treatment. CONCLUSION: Numerous formulations of PGE1 have been used to treat patients so far. Still, in general, with the evolution of classical formulation methods toward modern techniques (such as using nanocarriers and skin permeability enhancers), the probability of treatment success also increases. Hamzehnejadi M, Tavakoli MR, Homayoun F et al. Prostaglandins as a Topical Therapy for Erectile Dysfunction: A Comprehensive Review. Sex Med Rev 2022;10:764-781.

The PDE5 inhibitor, vardenafil, ameliorates progressive pathological changes in a focal segmental glomerulosclerosis mouse model.

AIMS: Phosphodiesterase 5 inhibitors (PDE5is) inhibit the hydrolysis of cyclic guanosine 5'-monophosphate in smooth muscle cells and are a widely known treatment for erectile dysfunction. Accumulating evidence also suggests that PDE5is exhibit potential benefits in cardiovascular and chronic kidney diseases. In this study, we examined the therapeutic effects of a PDE5i, vardenafil (VAR), in a focal segmental glomerulosclerosis (FSGS) mouse model. MATERIALS AND METHODS: FSGS was induced in BALB/c mice by the intravenous administration of Adriamycin (AD, 11 mg/kg of body weight). After 24 h, VAR (at 12.5 µg/ml) was given in drinking water ad libitum until the animals were sacrificed. At the end of the experiment, plasma and kidney samples were harvested to evaluate clinical parameters, histopathological changes, and alterations in transcriptome and protein expressions. KEY FINDINGS: In this study, VAR treatment attenuated the deterioration of proteinuria, renal dysfunction, and hypercholesterolemia in AD-induced FSGS. Treatment with VAR exhibited reductions in the severity of both glomerulosclerosis and tubulointerstitial injury in the histological analysis. In addition to relieving AD-induced podocyte loss, VAR also preserved endothelial cells in glomerular capillaries and ameliorated the accumulation of collagen fibers in the mesangial area and Bowman's capsule basement membrane. In addition, VAR showed an ability to suppress transforming growth factor-ß-induced fibroblast-to-myofibroblast transdifferentiation. SIGNIFICANCE: Our data suggest that VAR exhibited reno-therapeutic effects via attenuating podocyte loss, preserving the integrity of the glomerular vasculature, and ameliorating fibrotic changes. These findings suggest that PDE5is might be a promising treatment modality for nephrotic syndrome.

Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance.

Hepatocellular carcinoma (HCC) has emerged as one of the most common and lethal cancers worldwide and is caused due to contamination of diets with aflatoxin B1 and chronic viral hepatitis. Recent reports suggest that phosphodiesterase-5 inhibitor (PDE5i) exhibits anticancer properties against several forms of cancer but till now has not been evaluated against HCC. We aimed to evaluate the anticancer property of phosphodiesterase-5 inhibitors (PDE5i) tadalafil and sildenafil against aflatoxin B1 HCC. Rats of HCC group were fed with 5% alcohol via drinking water for 3 weeks, followed by administration of AFB1 (1 mg/kg/bw, i.p.) at an interval of two subsequent days. PDE5i (tadalafil and sildenafil, 10 mg/kg bw) was administered along with drinking water after 6 weeks of treatment with AFB1 for 2 weeks. In the present investigation, in HCC elevation in the level of SGOT, SGPT, ALP, and urea vis-à-vis activity of key glycolytic enzyme LDH and mRNA expression of c-myc, Akt, LDH-A, and PFKFB3 was noted. Similarly, the level of multidrug resistance protein (MDR) and breast cancer resistance protein (BCRP/ABCG2) was elevated along with increased expression of angiogenesis marker (HIF-1α, VEGF, and TGF-ß1) in HCC. Post-treatment with PDE5 inhibitor (tadalafil and sildenafil) downregulated and brought back the above parameters towards normal and out of two PDE5i (tadalafil and sildenafil), sildenafil effect was more potent as compared to tadalafil. Our findings demonstrate for the first time that PDE5 inhibitors tadalafil and sildenafil are able to prohibit the development and progression of aflatoxin B1 induced HCC.