Phosphodiesterase Type Research Articles

Proceedings of PRINCETON IV: PDE5 inhibitors and cardiac health symposium.

Prior consensus meetings have addressed the relationship between phosphodiesterase type 5 (PDE5) inhibition and cardiac health. Given significant accumulation of new data in the past decade, a fourth consensus conference on this topic was convened in Pasadena, California, on March 10 and 11, 2023. Our meeting aimed to update existing knowledge, assess current guidelines, and make recommendations for future research and practice in this area. An expert panel reviewed existing research and clinical practice guidelines. Key findings and clinical recommendations are the following: First, erectile dysfunction (ED) is a risk marker and enhancer for cardiovascular (CV) disease. For men with ED and intermediate levels of CV risk, coronary artery calcium (CAC) computed tomography should be considered in addition to previous management algorithms. Second, sexual activity is generally safe for men with ED, although stress testing should still be considered for men with reduced exercise tolerance or ischemia. Third, the safety of PDE5 inhibitor use with concomitant medications was reviewed in depth, particularly concomitant use with nitrates or alpha-blockers. With rare exceptions, PDE5 inhibitors can be safely used in men being treated for hypertension, lower urinary tract symptoms and other common male disorders. Fourth, for men unresponsive to oral therapy or with absolute contraindications for PDE5 inhibitor administration, multiple treatment options can be selected. These were reviewed in depth with clinical recommendations. Fifth, evidence from retrospective studies points strongly toward cardioprotective effects of chronic PDE5-inhibitor use in men. Decreased rates of adverse cardiac outcomes in men taking PDE-5 inhibitors has been consistently reported from multiple studies. Sixth, recommendations were made regarding over-the-counter access and potential risks of dietary supplement adulteration. Seventh, although limited data exist in women, PDE5 inhibitors are generally safe and are being tested for use in multiple new indications. Studies support the overall cardiovascular safety of the PDE5 inhibitors. New indications and applications were reviewed in depth.

Patient out-of-pocket costs for guideline-recommended treatments for erectile dysfunction: a medicare cost modeling analysis.

Patient out-of-pocket (OOP) cost represents an access barrier to erectile dysfunction (ED) treatment. We determined OOP cost for men with ED covered by Fee-for-Service Medicare. Coverage policies were obtained from the Medicare Coverage Database for treatments recommended by the 2018 American Urological Association (AUA) guidelines. OOP cost was retrieved from the 2023 Centers for Medicare & Medicaid Services Final Rule. OOP cost for treatments without Medicare coverage were extracted from GoodRx® or literature and inflated to 2022 dollars. Annual prescription costs were calculated using the published estimate of 52.2 yearly instances of sexual intercourse. Medicare has coverage for inflatable penile prostheses (IPP; strong recommendation), non-coverage for vacuum erection devices (VED; moderate recommendation) and phosphodiesterase type-5 inhibitors (PDE5i; strong recommendation), and no policies for intracavernosal injections (ICI; moderate recommendation), intraurethral alprostadil (IA; conditional recommendation), or low-intensity extracorporeal shock wave therapy (ESWT; conditional recommendation). Annual IA prescription is most costly ($4022), followed by ICI prescription ($3947), one ESWT course ($3445), IPP ($1600), PDE5i prescription ($696), and one VED ($213). PDE5i and IPP, both strongly recommended by AUA guidelines, are associated with lower OOP cost. Better understanding of patient financial burden may inform healthcare decision-making.

Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. Superiority, double-blind randomised controlled trial. A total of 20 UK fetal medicine units. Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

Two new limonoid glycosides from the seeds of Citrus Limon and their PDE4D inhibitory activities

Two new limonoid glycosides, named limonosides A (1) and B (2), along with four known limonoids (3–6) were obtained from the seeds of Citrus limon. Their structures were deduced based on extensive spectroscopic analysis. Limonoside A (1) and nomilin (4) were found to possess moderate phosphodiesterase type 4D (PDE4D) inhibitory effect with values of 89.8 ± 2.4% and 98.9 ± 3.0% at 10 μM, respectively.

Isoliquiritigenin: a potential drug candidate for the management of erectile dysfunction.

This study aimed to assess the erectogenic properties of isoliquiritigenin taking sildenafil (SDF) as the standard. The binding affinity of isoliquiritigenin (ISL) with the erectile marker proteins (endothelial nitric oxide synthase [eNOS] and enzyme phosphodiesterase type 5 [PDE5]) was investigated using Autodock Vina, which was validated using molecular dynamics simulation. Furthermore, the effect of ISL on the eNOS and PDE5 messenger ribonucleic acid (mRNA) expression and the sexual behavior of mice was investigated, along with the assessment of the pharmacokinetics of ISL. The results revealed that the binding affinity of ISL-eNOS/PDE5 and SDF-eNOS/PDE5 was in the range of -7.5 to -8.6 kcal/mol. The ISL-eNOS/PDE5 complexes remained stable throughout the 100 ns simulation period. Root mean square deviation, Rg, SASA, hydrogen, and hydrophobic interactions were similar between ISL-eNOS/PDE5 and SDF-eNOS/PDE5. Analysis of mRNA expressions in paroxetine (PRX)-induced ED mice showed that the co-administration of PRX with ISL reduced PDE5 and increased eNOS mRNA expression, similar to the co-administered group (PRX+SDF). The sexual behavior study revealed that the results of PRX+ISL were better than those of the PRX+SDF group. Pharmacokinetic evaluation further demonstrated that ISL possesses drug-like properties. The results showed that ISL is equally potent as SDF in terms of binding affinity, specific pharmacological properties, and modulating sexual behavior.

Pharmacokinetics and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers.

Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4mL) were collected from each subject 25 times spanning predose (0hour) to 24hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1ng/mL, the area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3ng•h/mL, and AUC from time 0 to infinity was 87.1ng•h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.

Antithrombotic therapy for durable left ventricular assist devices: protocol for a living systematic review with indirect comparison/network meta-analysis

BackgroundLeft ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage heart failure. Compared with the best medical therapy, LVADs improve survival and enhance functional...

Analysis of phosphodiesterase type 5 inhibitors and analogues as adulterants in herbal dietary food supplements in Saudi market using green UPLC-MS/MS method: Assessment of the greenness and whiteness profiles

Herbal dietary supplements are popular alternatives to oral phosphodiesterase type 5 inhibitors (PDE5Is) for treating Erectile Dysfunction (ED), yet concerns arise regarding their adulteration with undeclared synthetic PDE5Is or analogues, posing health risks. The aim of this study was to develop and validate a green UPLC-MS/MS method for sensitive and rapid detection of PDE5Is and analogues in sexual enhancement herbal dietary supplements marketed in Saudi Arabia. Method validation revealed good linearity with determination coefficients (r2) ≥ 0.9990, and LODs and LOQs in the range of 0.4 – 32 ng g−1 and 1––96 ng g−1, respectively. The accuracy ranged from 80.8 % to 103.4 % while inter-day precision was ≤ 8.6 % and intra-day precision was ≤ 8.4 %. The method was successfully utilized to analyze 32 herbal dietary supplements. The results revealed that 18 samples (56.3 %) tested positive for at least one of the target analytes. Sildenafil emerged as the most frequently detected analyte, found in 15 samples (20.1 µg g−1 to 37,492 µg g−1). Tadalafil was detected in 7 samples, with concentrations ranging from 4.46 µg g−1 to 19,986 µg g−1. Yohimbine was detected in only 4 samples, while icariin was detected at lower concentrations in 3 samples. Furthermore, the method greenness and whiteness profiles were evaluated using four metrics including the Analytical Eco-Scale, Green Analytical Procedure Index (GAPI), Analytical GREEnness (AGREE) metric, and Red-Green-Blue 12 (RGB 12) metric.This study provides foundational data on the adulteration of dietary supplements in Saudi Arabia and offers insights for future interventions to promote consumer safety and awareness regarding herbal dietary supplement consumption.

Phosphodiesterase-5 inhibitors use and the risk of alzheimer's disease: a systematic review and meta-analysis

BackgroundThe management of Alzheimer's disease (AD) poses considerable challenges, necessitating the pursuit of innovative therapeutic approaches. Recent research has spotlighted the promising role of phosphodiesterase type 5 inhibitors (PDE5Is) in reducing the prevalence of AD, utilizing their vasodilatory properties to suggest a potential neuroprotective effect. This meta-analysis and systematic review aims to assess the relationship between the use of PDE5Is and the risk of AD.MethodsA detailed examination was carried out across several electronic databases till March 2024, including PubMed, Web of Science, Scopus, CENTRAL, and Embase. The focus was on identifying studies that compare the occurrence of AD among PDE5I users vs non-users. Through a random-effects model, pooled hazard ratios (HRs) were calculated, in alignment with guidelines from the Cochrane Handbook for Systematic Reviews and Meta-Analysis and the PRISMA standards.ResultsThis analysis included six studies, cumulating a participant count of 8,337,313, involving individuals treated with sildenafil, tadalafil, and vardenafil, against a control group undergoing other or no treatments. The cumulative HR for AD risk among PDE5I users versus the control group was 0.53 (95% CI: 0.32–0.86, p = 0.008), signaling a markedly reduced likelihood of AD development in the PDE5I group. Particularly, sildenafil usage showed a significant risk reduction (HR: 0.46, 95% CI: 0.31–0.70, p < 0.001), while findings for tadalafil and vardenafil were not significant. Test of subgroup differences found no difference between male and female participants in the risk of AD.ConclusionsOur findings suggest that the use of PDE5Is is associated with a reduced risk of AD, highlighting its potential as a protective agent against neurodegenerative diseases. Given the very low quality of evidence and the heterogeneity among the included studies, further high-quality research is warranted to confirm these findings and elucidate the underlying mechanisms. Register number PROSPERO 2024: CRD42024522197.

Effects of phosphodiesterase 5 inhibitor (viagra) on biochemical parameters of l-name-induced testicular toxicity in adult male wistar rats

Testicular toxicity is a growing concern in today's world, with various factors contributing to its prevalence. Nitric oxide (NO) imbalance, often induced by N (gamma)-nitro-L-arginine methyl ester (L-NAME), is a significant factor associated with testicular dysfunction. Sildenafil (Viagra), a phosphodiesterase type 5 inhibitor, has shown promise in improving testicular function by modulating NO levels. This study aimed to investigate the role of Sildenafil (Viagra) on biochemical parameters of L-NAME-induced testicular toxicity in Wistar rats. Twenty-four adult male Wistar rats were divided into four groups: Control (physiological saline-treated), L-Name (L-Name-induced testicular toxicity), PDE (Sildenafil-treated), and L-Name + Sildenafil (co-treatment) and subjected to a 56-day treatment regimen. At the end of the administration, the animals were sacrificed, tissues collected and biochemical and histological assessments were performed. Findings revealed that L-Name administration led to a significant decreased in nitric oxide levels, follicle stimulating hormone, luteinizing hormone, testosterone and increase in oxidative stress when compared to the control group. Furthermore, histological analysis demonstrated structural alterations in the testes of L-NAME-treated rats, indicative of testicular toxicity. Rats treated with Sildenafil showed a slight reversal of these adverse effects. Also, slight reversals of impaired spermatogenesis were evident in the co-treatment group. This study provides compelling evidence for the potential therapeutic role of sildenafil in ameliorating L-NAME-induced testicular toxicity in adult male Wistar rats.

Gene therapy with phosphodiesterases 2A and 4B ameliorates heart failure and arrhythmias by improving subcellular cAMP compartmentation.

Gene therapy with cardiac phosphodiesterases (PDEs), such as phosphodiesterase 4B (PDE4B), has recently been described to effectively prevent heart failure (HF) in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here, we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload-induced HF in mice by acting on and restoring altered cAMP compartmentation in distinct subcellular microdomains. HF was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3, or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis, and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentation in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts, and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human-induced pluripotent stem-derived cardiomyocytes with the A2254V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia. Our data indicate that gene therapy with phosphodiesterases can prevent HF including associated cardiac remodelling and arrhythmias by restoring altered cAMP compartmentation in functionally relevant subcellular microdomains.

Prescribing semaglutide for weight loss in non-diabetic, obese patients is associated with an increased risk of erectile dysfunction: a TriNetX database study.

Semaglutide was approved in June 2021 for weight loss in non-diabetic, obese patients. While package inserts include sexual dysfunction as a side effect, no study has assessed the degree of this risk. The objective of our study is to assess the risk of developing erectile dysfunction after semaglutide is prescribed for weight loss in obese, non-diabetic men. The TriNetX Research database was used to identify men without a diagnosis of diabetes ages 18 to 50 with BMI > 30 who were prescribed semaglutide after June 1st, 2021. Men were excluded if they had a prior erectile dysfunction diagnosis, any phosphodiesterase-5 inhibitors prescription, intracavernosal injections, penile prosthesis placement, history of testosterone deficiency, testosterone prescription, pelvic radiation, radical prostatectomy, pulmonary hypertension, or were deceased. We further restricted our cohort to non-diabetic, obese men by excluding men with a prior diabetes mellitus diagnosis, a hemoglobin A1c > 6.5%, or having ever received insulin or metformin. Men were then stratified into cohorts of those that did and did not receive a semaglutide prescription. The primary outcome was the risk of new ED diagnosis and/or new prescription of phosphodiesterase type 5 inhibitors at least one month after prescription of semaglutide. The secondary outcome was risk of testosterone deficiency diagnosis. Risk was reported using risk ratios with 95% confidence intervals (95% CI). 3,094 non-diabetic, obese men ages 18-50 who received a prescription of semaglutide were identified and subsequently matched to an equal number cohort of non-diabetic, obese men who never received a prescription of semaglutide. After matching, average age at index prescription for non-diabetic, obese men was 37.8 ± 7.8 and average BMI at index prescription was 38.6 ± 5.6. Non-diabetic men prescribed semaglutide were significantly more likely to develop erectile dysfunction and/or were prescribed phosphodiesterase type 5 inhibitors (1.47% vs 0.32%; RR: 4.5; 95% CI [2.3, 9.0]) and testosterone deficiency (1.53% vs 0.80%; RR: 1.9; 95% CI [1.2, 3.1]) when compared to the control cohort of non-diabetic men who never received a semaglutide prescription.

Effect of phosphodiesterase type 5 inhibitors on surgical outcome of ventricular septal defect and pulmonary hypertension patients

BackgroundChildren with ventricular septal defect (VSD) and large systemic-to-pulmonary shunts eventually develop pulmonary hypertension (PH). The perioperative management of patients with VSD and PH is quite troublesome and still debatable, especially in developing countries where the different management options and standardization of treatment is not available. Oral phosphodiesterase type 5 (PDE-5) inhibitors are good treatment options being widely available, cheap, easy administration and do not require extensive monitoring. The aim of our study was to evaluate the effect of the PDE-5 inhibitors when given orally, early preoperative and continued for 3 months postoperative on controlling postoperative PH with its effect on right ventricle (RV) functions. Fifty-one patients were randomly assigned to either sildenafil or tadalafil, 1 week before and continued for 3 months after corrective surgery. The control group received a placebo.ResultsThere was no significant difference in the improvement in the right ventricle systolic pressure (RVSP) between both groups, early in the postoperative period (P = 0.255) and in follow-up (P = 0.259). There was also no significant difference in the changes in mean pulmonary artery pressure (mPAP), postoperatively and on follow-up (P = 0.788 and 0.059, respectively). There was a drop in RV functions in both groups postoperatively which improved on follow-up; however, it was not significant between both groups. The length of intensive care unit (ICU) stay was similar between both groups (P = 0.143).ConclusionPerioperative administration of PDE-5 inhibitors does not have an impact on the clinical course as regards improvement in pulmonary artery (PA) pressure, ventricular functions and ICU stay.

In search of the molecular mechanisms of adaptation memory in rods: basic activity of phosphodiesterase

Retinal rods, the photoreceptors responsible for twilight vision, are capable of adapting to a wide range of light levels. The molecular mechanisms of light adaptation have been well studied, but an interesting question is what changes occur in the phototransduction cascade after the adaptive light stimuli are eliminated. Previously, we showed the phenomenon of adaptation memory in amphibian rods: after background illumination photoreceptor sensitivity to light remained reduced for several minutes, while the dark current recovered within 20—30 s. This suggests the existence of additional, as yet unknown, regulatory mechanisms of the phototransduction cascade that act after the adaptive effect of light. In search of specific mechanisms that could explain the effect of adaptation memory, we performed electrophysiological experiments on isolated frog rods to evaluate the basal activity of the effector enzyme of the phototransduction cascade, the phosphodiesterase type 6, in the dark and after saturating background illumination. It was found that the post-adaptation state of rods was characterized by increased basal phosphodiesterase activity, which gradually decreased to the dark level within tens of seconds after turning off the adaptive illumination. These results also suggest that the components of the phototransduction cascade may undergo some unstudied changes after light adaptation.

Differences in ocular adverse events associated with phosphodiesterase-5 inhibitors: a real-world pharmacovigilance study

ABSTRACT Objective Our study aims to characterize the ocular safety profiles of phosphodiesterase type 5 (PDE5) inhibitors and explore the differences among different PDE5 inhibitors. Methods We analyzed reports on ocular adverse events associated with sildenafil, vardenafil and tadalafil submitted to the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2023. Disproportionality analysis was conducted to evaluate reporting risk profiles. Results Among 61,211 reports qualifying for analysis, 5,127 involved sildenafil, 832 vardenafil, and 3,733 tadalafil. All PDE5 inhibitors showed increased reporting odds ratios (ROR) for ocular adverse events, with vardenafil highest (ROR 4.47) followed by sildenafil and tadalafil. Key ocular adverse events included cyanopsia, optic ischemic neuropathy, visual field defects, unilateral blindness and blindness. Sildenafil showed the highest disproportionality for cyanopsia (ROR 1148.11) while vardenafil and tadalafil showed the highest disproportionality for optic ischemic neuropathy. Time-to-onset analysis also revealed significant differences, with sildenafil having a later median time-to-onset compared to vardenafil and tadalafil. Conclusions This comprehensive pharmacovigilance study reveals distinct patterns of ocular adverse events associated with PDE5 inhibitors. These findings contribute to a better understanding of the safety profiles of PDE5 inhibitors and may guide healthcare professionals in clinical decision-making.

PULMONARY HYPERTENSION AND CONGENITAL HEART DISEASE: THE CLINIC BEYOND THE EVIDENCE

Abstract Eisenmenger syndrome (ES), first described by Victor Eisenmenger, was defined by Paul Wood in pathophysiologic terms as “pulmonary hypertension (PH) at systemic level, caused by a high pulmonary vascular resistance (PVR), with reversed or bidirectional shunt at aorto–pulmonary, ventricular, or atrial level.” It represents the most severe hemodynamic phenotype of pulmonary arterial hypertension (PAH) in association with congenital heart disease (CHD) and develops in the presence of large, unrepaired atrial or ventricular septal defects, arterial shunts, or complex forms of CHD. Although therapeutic management has rapidly advanced in recent years, these patients were not included in randomized controlled trials for specific pulmonary arterial hypertension drugs, except for bosentan. However, in clinical practice we apply treatment strategies combining drugs targeting multiple pathobiological pathways. The clinical case we describe is that of a 44–year–old patient, suffering from Down syndrome, with ES due to subaortic VSD and a a patency of Botallo duct, followed in our PH clinic of the "Ruggi D‘Aragona" University Hospital for about 9 years. The patient, on dual therapy with Macitentan 10 mg and Sildenafil 60 mg, was in the intermediate–high risk class, stationary. During the last two checks, there was a progressive worsening of the hemodynamic parameters, walking distance of only 100 meters, with SpO2 at baseline 90% and desaturation during the 6mwt. On cardiac color Doppler ultrasound evidence of TAPSE 18 mm, PAPS 100 mmHg, RAA 20 cm²; TAPSE/PAPS 0.18. The patient presented in WHO class 3. The only RCTs currently available concern the use of bosentan, but in clinical practice, initial monotherapy with an endothelin receptor antagonist or a phosphodiesterase type 5 inhibitor for symptomatic patients is proposed. Reassess and consider escalation to a double combination therapy in case of clinical worsening or inadequate clinical response. Consider uptitration with the addition of prostanoids when inadequate response and timely assess the eligibility for transplantation. For our patient therefore, in consideration of the impossibility of surgery, although there is little evidence on prospective observational studies based on cohorts of a few patients, we added selexipag 200 ug x 2/day to titrate therapy.This case opens the door to still unclear scenarios in which unfortunately the only weapon available remains the clinician‘s judgment and experience.

Conservative treatment of Peyronie's disease: a guide.

To review the literature on the topic, to suggest a common line of treatment applicable across a wide community of specialists, and to contribute in maintaining the high level of interest in this disease. A comprehensive and exhaustive review of the literature was performed, identifying hundreds of articles on the topic. Peyronie's disease is a condition that has been recognized, studied, and treated for centuries; despite this, if one excludes surgery in cases in which the deformity is stable, no clear treatment (or line of treatment) is available for complete relief of signs and symptoms. Treatment options were divided into local, oral, and injection therapy, and a wide variety of drugs, remedies, and options were identified. Low-intensity extracorporeal shock wave therapy, vacuum therapy, penile traction therapy, phosphodiesterase type 5 inhibitors, hyaluronic acid, and collagenase of Clostridium histolyticum may be recommended only in specific contexts. Further studies on individual options or potential combinations are required.

Beta-amyloid interacts with and activates the long-form phosphodiesterase PDE4D5 in neuronal cells to reduce cAMP availability.

Inhibition of the cyclic-AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta-amyloid (Aβ) plaques in a mouse model of AD but that Aβ directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aβ as it possesses a unique binding site. Intriguingly, exogenous addition of Aβ to cells overexpressing the PDE4D5 longform caused PDE4 activation and a decrease in cAMP. We suggest a novel mechanism where PDE4 longforms can be activated by Aβ, resulting in the attenuation of cAMP signalling to promote loss of cognitive function in AD.

Current treatment options for erectile dysfunction in kidney transplant recipients.

Erectile dysfunction (ED) and kidney dysfunction share common risk factors linked to conditions involving endothelial impairment, such as coronary artery disease, dyslipidemia, diabetes mellitus, hypertension, smoking, and obesity. Men with chronic kidney disease experience a high incidence and prevalence of ED. While a functional renal graft can alleviate the issue for some patients, a significant portion of recipients still experience ED (20%-50%). This narrative review describes the variety of current treatments modalities on ED in kidney transplant recipients (KTRs) and their clinical outcomes. MEDLINE, Web of Science, PubMed, and Google Scholar were used to find eligible articles pertaining to the treatment options of ED in KTRs. A total of 64 articles were evaluated. In KTRs, ED stems from a multifaceted etiology: anxiety, drug side effects, interference with penile vascularity, or the response of cavernosal muscle to neurotransmitters, along with changes in the endocrine milieu. A diverse range of treatments to restore erectile function has proven to be safe and effective for KTRs. Options include drug therapy, surgical interventions, intracavernosal injection therapies, vacuum erection devices, and extracorporeal shockwave therapy. The initial treatment approach may involve the use of a phosphodiesterase type 5 inhibitors at a low dosage, especially if testosterone-circulating levels align with the diagnosis of hypogonadism. The consideration of a combination therapy involving testosterone and phosphodiesterase type 5 inhibitors should be contemplated due to the associated beneficial effects. Extracorporeal shockwave therapy has shown positive short-term clinical and physiological effects on erectile function in patients who did not respond to first-line treatments, resulting in spontaneous erections sufficient for sexual penetration in 50% of cases. Penile implants should be considered as third-line options based on specific patient needs and compliance with clinical conditions.

Androgens and erectile dysfunction: from androgen deficiency to treatment.

Androgens play important roles in regulating the growth and development of the male reproductive system and maintaining libido and erectile function. The specific mechanisms by which androgen deficiency leads to erectile dysfunction (ED) are not yet fully understood. To understand the mechanisms and treatment of androgen deficiency-related ED. A literature search in the past 10years was conducted in PubMed and Google Scholar to determine the effects of androgen deficiency on erectile function and the treatment of androgen deficiency. Androgen deficiency can be caused by hypothalamic-pituitary lesions and injuries, testicular-related diseases and injuries, endocrine and metabolic disorders, the side effects of medication, and age. Androgen deficiency can lead to ED by inhibiting the NOS/NO/cGMP pathway (nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate) and altering the expression of ion channel proteins, as well as by inducing oxidative stress, death, and fibrosis in penile corpus cavernosum cells. Testosterone replacement therapy is effective at improving the serum testosterone levels and erectile function in patients with androgen deficiency. For patients who need to maintain a low androgenic state, erectile function can be improved by lifestyle changes, treatment with phosphodiesterase type 5 inhibitors, low-intensity extracorporeal shock wave therapy, and stem cell therapy. Androgen deficiency can affect the structure and function of the penile corpus cavernosum, leading to ED. Areas of further study include how androgen replacement therapy can improve erectile function and how to improve the maintenance of erectile function in patients with hypoandrogenic status.