Role of Aortic Stiffness in Predicting Response to Phosphodiesterase-5 Inhibitors in the Treatment of Erectile Dysfunction. / Papel da Rigidez Aórtica na Previsão da Resposta aos Inibidores da Fosfodiesterase-5 no Tratamento da Disfunção Erétil.

BACKGROUND: It is known that aortic stiffness (AS) increases in patients with erectile dysfunction (ED). Phosphodiesterase type-5 (PDE-5) enzyme inhibitors are used in the treatment of ED, and patients' responses to this treatment may vary. OBJECTIVES: We aimed to investigate the role of AS in predicting the response of patients planned to take PDE-5 enzyme inhibitors due to ED. METHODS: A total of 96 male patients with ED were included in the study. The International Index of Erectile Function (IIEF) questionnaire was used to evaluate the presence and severity of ED and the response to treatment. Transthoracic echocardiography was used to evaluate AS. RESULTS: There was a statistically significant difference between the aortic strain and aortic distensibility values of the study groups (p<0.001). The delta IIEF score had a high level of positive correlation with aortic strain (p<0.01, r=0.758) and a moderate level of positive correlation with aortic distensibility (p<0.01, r=0.574). CONCLUSION: We determined that in patients with ED, aortic strain and aortic distensibility measured non-invasively using transthoracic echocardiography are important parameters in predicting patients' response to PDE-5 inhibitor therapy.

FUNDAMENTO: Sabe-se que a rigidez aórtica (RA) aumenta em pacientes com disfunção erétil (DE). Os inibidores da enzima fosfodiesterase tipo 5 (PDE-5) são usados no tratamento da DE, e as respostas dos pacientes a esse tratamento podem variar. OBJETIVOS: Nosso objetivo foi investigar o papel da RA na previsão da resposta de pacientes planejados para tomar inibidores da enzima PDE-5 devido à DE. MÉTODOS: Um total de 96 pacientes do sexo masculino com DE foram incluídos no estudo. O questionário do Índice Internacional de Função Erétil (IIEF) foi utilizado para avaliar a presença e gravidade da DE e a resposta ao tratamento. A ecocardiografia transtorácica foi utilizada para avaliar RA. RESULTADOS: Houve diferença estatisticamente significativa entre os valores de deformação aórtica e distensibilidade aórtica dos grupos de estudo (p<0,001). O escore delta IIEF apresentou alto nível de correlação positiva com a deformação aórtica (p<0,01, r=0,758) e um nível moderado de correlação positiva com a distensibilidade aórtica (p<0,01, r=0,574). CONCLUSÃO: Determinamos que em pacientes com DE, a deformação aórtica e a distensibilidade aórtica medidas de forma não invasiva por meio de ecocardiografia transtorácica são parâmetros importantes na previsão da resposta dos pacientes à terapia com inibidores da PDE-5.

Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors- Towards Wound Healing.

Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed in vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.

Medical Advancements in Benign Prostatic Hyperplasia Treatments.

PURPOSE OF REVIEW: This review aims to identify and summarize the current literature on the most recent therapeutic agents and combination strategies for the medical management of lower urinary tract symptoms resulting from benign prostatic hyperplasia. RECENT FINDINGS: The latest advancements in BPH therapy have been in combination strategies. Alpha blockers continue to be the mainstay of treatment, but research is exploring the synergistic benefits of combining them with 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase-5 (PDE5) inhibitors, and beta-3 agonists. The alpha-blocker + 5-ARI combination remains ideal for enlarged, significantly reducing clinical progression risk compared to monotherapy. Alpha-blocker + PDE5 inhibitor combinations appear safe and potentially beneficial for men with concomitant erectile dysfunction; sildenafil might hold an edge over tadalafil based on limited data. Beta-3 agonists show synergistic effects with alpha blockers for residual storage symptoms, offering similar efficacy to anticholinergics but with a better side effect profile.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

Rapid screening and identification of targeted and non-targeted illegal added drugs in functional foods by MRSIT-HRMS based on NIST screening database.

The last few decades have witnessed the increasing consumption of functional foods, leading to the expansion of the worldwide market. However, the illegal addition drugs in functional foods remains incessant despite repeated prohibition, making it a key focus of strict crackdowns by regulatory authorities. Effective analytical tools and procedures are desperately needed to rapidly screen and identify illegally added drugs in a large number of samples, given the growing amount and diversity of these substances in functional foods. The MRSIT-HRMS (Multiple Sample Rapid Introduction combined with High Resolution Mass Spectrometry) without chromatographic separation, after direct sampling, utilizes NIST software (National Institute of Standards and Technology) matching with a home-built library to target identification and non-targeted screen of illegal additives. When applied to 50 batches of suspicious samples, the targeted method detected illegal added drugs in 41 batches of samples, while the non-targeted method screened a new phosphodiesterase-5 (PDE-5) inhibitor type structural derivative. The positive results obtained by the targeted method were consistent with LC-MS/MS (QQQ). The novel MRSIT-HRMS with a limit of quantification (LOD) of 1 µg/mL achieved 100 % correct identification for all 50 batches of actual samples, demonstrating its potential as a highly promising and powerful tool for fast screening of illegally added drugs in functional food, especially when compared to traditional LC-MS/MS methods. This is essential for ensuring drug safety and public health.

Association of sildenafil use with age-related macular degeneration: a retrospective cohort study.

OBJECTIVE: Despite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)-a major cause of global blindness-lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data. METHODS AND ANALYSIS: Using the UK's IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years. RESULTS: The primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes. CONCLUSION: The study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil's protective effect on AMD is likely insignificant.

Sildenafil delays bone remodeling of fractured femora in aged mice by reducing the number and activity of osteoclasts within the callus tissue.

The elderly exhibit a reduced healing capacity after fracture, which is often associated with delayed or failed bone healing. This is due to a plethora of factors, such as an impaired bone vascular system and delayed angiogenesis. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil exerts pro-angiogenic and pro-osteogenic effects. Hence, we herein investigated in aged mice whether sildenafil can improve fracture healing. For this purpose, 40 aged CD-1 mice (16-18 months) were daily treated with 5 mg/kg body weight sildenafil (n = 20) or vehicle (control, n = 20) by oral gavage. The callus tissue of their femora was analyzed at 2 and 5 weeks after fracture by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry as well as Western blotting. These analyses revealed a significantly increased bone volume and higher ratio of callus to femoral bone diameter in sildenafil-treated mice at 5 weeks after fracture when compared to controls. This was associated with a reduced number and activity of osteoclasts at 2 weeks after fracture, most likely caused by an increased expression of osteoprotegerin (OPG). Taken together, these findings indicate that sildenafil does not improve fracture healing in the elderly but delays the process of bone remodeling most likely by reducing the number and activity of osteoclasts within the callus tissue.

Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study.

BACKGROUND AND OBJECTIVES: Repurposing phosphodiesterase type 5 inhibitors (PDE5Is) as drugs for Alzheimer disease (AD) risk reduction has shown promise based on animal studies. However, evidence in humans remains inconclusive. Therefore, we conducted a cohort study to evaluate the association between PDE5I initiation compared with nonuse and the risk of developing AD in men with erectile dysfunction (ED). METHODS: Using electronic health records from IQVIA Medical Research Data UK (formerly known as the THIN database), we identified men aged ≥40 years with a new diagnosis of ED between 2000 and 2017. Individuals with a previous diagnosis of dementia, cognitive impairment, confusion, or prescription for dementia symptoms were excluded. The occurrence of incident AD was identified using diagnostic read codes. To minimize immortal-time bias, PDE5I initiation was treated as a time-varying exposure variable. Potential confounders were adjusted using inverse probability of treatment weighting based on propensity scores. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) with 95% CIs. A secondary analysis explored the association between AD and the cumulative number of PDE5I prescriptions. Sensitivity analyses included lag (delay) periods of 1 and 3 years after cohort entry to address the prodromal stage of AD. RESULTS: The study included 269,725 men, with 1,119 newly diagnosed with AD during a median follow-up of 5.1 (interquartile range 2.9-8.9) years. The adjusted HR in PDE5I initiators compared with nonuse was 0.82 (95% CI 0.72-0.93). The associated risk of AD decreased in individuals issued >20 prescriptions: HR 0.56 (95% CI 0.43-0.73) for 21-50 prescriptions and HR 0.65 (95% CI 0.49-0.87) for >50 prescriptions. Sensitivity analysis with a 1-year lag period supported the primary findings (HR 0.82, 95% CI 0.72-0.94), but the results differed with the inclusion of a 3-year lag period (HR 0.93, 95% CI 0.80-1.08). DISCUSSION: PDE5I initiation in men with ED was associated with a lower risk of AD, particularly in those most frequently issued prescriptions. The differences between primary and sensitivity analyses highlight the need to explore the optimal lag period. To enhance the generalizability of our findings, a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and AD.

Design, synthesis, and biological evaluation of some new 2-phenyl-3,6-pyridazinedione derivatives as PDE-5 inhibitors.

Various 2-phenyl-3,6-pyridazinedione derivatives 4a-j, 5a-c, 6a,b, 7a-c, 8, 9, 10a-d, and 11a-d, were effectivelysynthesized, and tested for their potential inhibition of phosphodiesterase enzyme at 10 µM. Then fourteen compounds exhibiting the highest inhibition 4b, 4d, 4e, 4g, 4h, 4i, 5a, 6a,b, 7c, 10a,b, 11a, and 11d were selected for screening their PDE-5 inhibition, where compounds 4b,g,h, and 11a revealed promising PDE-5 inhibition having IC50 values = 25, 53, 22, and 42 nM, respectively in comparison with Sildenafil (IC50 = 16 nM). Additionally, these four most active compounds were safe to normal fibroblast cell line WI-38. Moreover, 4f, 4h, 4j, 10d, and 11d had almost the same anti-proliferative effect against the aortic cell line as Sildenafil. Furthermore, molecular docking illustrated that the binding of the target compounds with the key amino acids in the binding site of PDE-5 (PDB 2H42) was like to that of the cocrystallized ligand Sildenafil. Additionally, molecular dynamics simulation for the most active compound 4h revealed high stability of the 4h -PDE5 complex explaining its promising activity as a PDE-5 inhibitor. Therefore, the 2-phenyl-3,6-pyridazinedione scaffold can be considered an important core for designing more promising PDE-5 inhibitors.

Inhibition of PDE-4 isoenzyme attenuates frequency and overall contractility of agonist-evoked ureteral phasic contractions.

The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 µM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 µM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 µM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 µM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.

Avanafil: A comprehensive drug profile.

Avanafil is an oral medication used to treat erectile dysfunction (ED). As a phosphodiesterase type 5 (PDE5) inhibitor, it functions by inhibiting the PDE5 enzyme, which ultimately results in increased levels of cyclic guanosine monophosphate (cGMP) and improved blood flow to the penis. Approved by the FDA in 2012, avanafil is recognised for its rapid onset of action, short half-life, and favourable side-effects profile. While it has been explored for other potential therapeutic applications, its current approved use is limited to ED and should be used as prescribed by a medical professional. This chapter provides a comprehensive review of avanafil, encompassing its nomenclature, physicochemical properties, methods of preparation, and identification. Various techniques for analysing avanafil, such as electrochemical analysis, spectrophotometric, spectrofluorimetric, and chromatographic techniques, are discussed. The pharmacology of avanafil, including its pharmacokinetics and pharmacodynamics, is also examined.

The association of tadalafil exposure with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction.

BACKGROUND: Tadalafil is a long-acting phosphodiesterase-5 inhibitor (PDE-5i) indicated for erectile dysfunction (ED). HYPOTHESIS: Our hypothesis was that tadalafil will reduce the risk of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction, coronary revascularization, unstable angina, heart failure, stroke) and all-cause death in men with ED. METHODS: A retrospective observational cohort study was conducted in a large US commercial insurance claims database in men with a diagnosis of ED without prior MACE within 1 year. The exposed group (n = 8156) had ≥1 claim for tadalafil; the unexposed group (n = 21 012) had no claims for any PDE-5i. RESULTS: Primary outcome was MACE; secondary outcome was all-cause death. Groups were matched for cardiovascular risk factors, including preventive therapy. Over a mean follow-up of 37 months for the exposed group and 29 months for the unexposed group, adjusted rates of MACE were 19% lower in men exposed to tadalafil versus those unexposed to any PDE-5i (hazard ratio [HR] = 0.81; 95% confidence intervals [CI] = 0.70-0.94; p = .007). Tadalafil exposure was associated with lower adjusted rates of coronary revascularization (HR = 0.69; 95% CI = 0.52-0.90; p = .006); unstable angina (HR = 0.55; 95% CI = 0.37-0.81; p = .003); and cardiovascular-related mortality (HR = 0.45; CI = 0.22-0.93; p = .032). Overall mortality rate was 44% lower in men exposed to tadalafil (HR = 0.56; CI = 0.43-0.74; p < .001). Men in the highest quartile of tadalafil exposure had the lowest rates of MACE (HR: 0.40; 95% CI: 0.28-0.58; p < .001) compared to lowest exposure quartile. CONCLUSION: In men with ED, exposure to tadalafil was associated with significant and clinically meaningful lower rates of MACE and overall mortality.

Do Phosphodiesterase Type 5 Inhibitors Increase the Risk of Biochemical Recurrence After Radical Prostatectomy?

PURPOSE: There have been conflicting studies on the association between phosphodiesterase type 5 inhibitor (PDE5i) use and biochemical recurrence (BCR) following radical prostatectomy (RP). Our aim was to determine whether PDE5i drug exposure after RP increases the risk of BCR in patients undergoing RP. MATERIALS AND METHODS: An institutional database of prostate cancer patients treated between January 2009 and December 2020 was reviewed. BCR was defined as 2 PSA measurements greater than 0.1 ng/mL. PDE5i exposure was defined using a 0 to 3 scale, with 0 representing never use, 1 sometimes use, 2 regularly use, and 3 routinely use. The risk of BCR with any PDE5i exposure, the quantity of exposure, and the duration of PDE5i exposure were assessed by multivariable Cox proportional hazards models. RESULTS: The sample size included 4630 patients to be analyzed, with 776 patients having BCR. The median follow-up for patients without BCR was 27 (IQR 12, 49) months. Eighty-nine percent reported taking a PDE5i at any time during the first 12 months after RP, and 60% reported doing so for 6 or more months during the year after RP. There was no evidence of an increase in the risk of BCR associated with any PDE5i use (HR 1.05, 95% CI 0.84, 1.31, P = .7) or duration of PDE5i use in the first year (HR 0.98 per 1 month duration, 95% CI 0.96, 1.00, P = .055). Baseline oncologic risk was lower in patients using PDE5i, but differences between groups were small, suggesting that residual confounding is unlikely to obscure any causal association with BCR. CONCLUSIONS: Prescription of PDE5i to men after RP can be based exclusively on quality of life considerations. Patients receiving PDE5is can be reassured that their use does not increase the risk of BCR.

Phosphodiesterase type 5 inhibitors do not prevent curvature progression but shorten pain duration in the active phase of Peyronie's Disease: A retrospective cohort study.

Treatment with Phosphodiesterase Type 5 inhibitors (PDE5is) has shown promise in managing Peyronie's disease (PD) during its active phase. In a retrospective cohort study of 133 PD patients, we compared daily PDE5i treatment (sildenafil 25 mg or tadalafil 5 mg) in Group 1 (n = 101) to no treatment in Group 2 (n = 32). The mean age ± SD was 58.5 ± 10, (range: 29-77) years in Group 1 and 59 ± 13.7 years (range: 23-80) in Group 2 (p = 0.5). Mean symptom onset-to-visit time was 10.6 ± 7.2 months (range: 1-37) in Group 1 and 11 ± 6.3 months (range 3-27) in Group 2 (p = 0.5). Mean penile curvature change was +0.87° (95% CI: -1.8, 3.5) in Group 1 and +5.72° (95% CI: 1.4, 10) in Group 2 (p = 0.07) between first and last observations. Group 1 experienced shorter mean pain duration (9.1 ± 4.7 months, range: 2.5-24) than Group 2 (12.2 ± 6.5 months, range: 5-28) (p = 0.04). When controlling for baseline curvature and symptom onset-to-visit time, there were no differences between groups (-4.7, 95% CI: -10, 0.6) (p = 0.08). In conclusion, continuous PDE5i treatment did not affect PD curvature progression but showed a promising effect on pain.

Application of terahertz Time-Domain spectroscopy and chemometrics-based whale optimization algorithm in PDE5 inhibitor detection.

Combating the illicit use of PDE5 inhibitor drugs is a focal point in forensic science research. In order to achieve rapid identification of such drugs, this study applies terahertz time-domain spectroscopy combined with chemometrics to establish a fast and accurate detection method for PDE5 inhibitors. The optimal detection method is determined by comparing the spectral performance of three optical parameters, namely absorption coefficient, refractive index, and dielectric constant. Linear discriminant models based on different spectral parameters, whale optimization algorithm optimized extreme learning machine models, and whale optimization algorithm optimized random forest models are established. The effectiveness and performance of principal component analysis and competitive adaptive reweighted sampling algorithm for spectral feature data selection are also investigated. The PDE5 inhibitor identification model based on the competitive adaptive reweighted sampling - whale optimization algorithm - random forest (CARS-WOA-RF) model achieves an accuracy of 98.61%, and the identification model for two concentrations of Sildenafil achieves 100% accuracy. The results demonstrate that terahertz time-domain spectroscopy combined with chemometrics can effectively detect various common types of PDE5 inhibitor drugs and different concentrations.

Risk of Death in Patients With Coronary Artery Disease Taking Nitrates and Phosphodiesterase-5 Inhibitors.

BACKGROUND: Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication. OBJECTIVES: The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication. METHODS: Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE). RESULTS: In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83). CONCLUSIONS: The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted.

Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload.

While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

A Cost Analysis of Phosphodiesterase Type 5 Inhibitors in the United States.

OBJECTIVE: To perform a cost analysis of generic and brand-name Phosphodiesterase Type 5 (PDE5) inhibitors at different dosages and pharmacies across the US. METHODS: Using an all-payer retail pharmacy-claims database, we analyzed prescription drug data for three generic and six brand-name oral PDE5 inhibitors at different dosages across US chain and independent pharmacies in 2019. RESULTS: We obtained cash price data from 60,186 pharmacies (35,976 chain and 24,210 independent). The nationwide mean cash price per unit (PPU) ranged from $8.6 ± 5.2 (sildenafil 20 mg at chain pharmacies) to $107.1 ± 71 (Adcirca 20 mg at independent pharmacies) equal to 1145.3% difference. Chain pharmacies provided significantly lower average prices for one brand-name and six generic PDE5 inhibitors. Tadalafil PPU was cheaper at higher quantities, however, PPU increased with quantity prescribed for sildenafil. Looking at the top 10 metropolitan statistical areas, the highest PPUs were observed for tadalafil (Cialis) 10 mg and sildenafil (Viagra) 50 mg in Atlanta ($67.4 ± 8.7) and Los Angeles ($50.3 ± 24.0), while New York ($9.7 ± 2.6) and Miami ($27.9 ± 16.4) had the lowest PPUs for tadalafil (Cialis) 5 mg and sildenafil (Viagra) 100 mg, respectively. CONCLUSION: A substantial variability in PDE5 inhibitor cash prices exists across manufacturer, dosage, quantity, pharmacy type, and location. In addition, the pricing does not necessarily correlate with the regional socioeconomic factors. This highlights the importance of provider awareness and patient counseling on drug price including potentially assisting patients in identifying opportunities for cost savings.