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Objectives: To determine the optimum combination therapy of Silodosin-Tadalafil versus Silodosin-Vardenafil in terms of both tolerability and efficacy for the management of distal ureteric stones., Methods: This prospective, double blinded, randomized clinical trial included 140 patients with distal ureteric stones, randomized into two groups: Group I (n = 67) received Silodosin 8 mg once daily combined with Tadalafil 5 mg once daily, and Group II (n = 68) received Silodosin 8 mg once daily combined with Vardenafil 10 mg once daily. The primary outcome was the tolerability of the combination therapies, assessed through the incidence of adverse events. Secondary outcomes included stone expulsion rate, expulsion time, and the need for analgesics., Results: Both combination therapies demonstrated similar efficacy, with no significant differences in stone expulsion rate (70.1% vs. 67.6%, P = 0.754), expulsion time (19 ± 3 days for both groups, P = 0.793), and analgesic requirements (P > 0.05). However, the Silodosin-Tadalafil combination showed a significantly lower occurrence of adverse events, with notable differences in headache (23.9% vs. 57.4%, P < 0.001), dizziness (32.8% vs. 60.3%, P = 0.001), and gastrointestinal upset (9% vs. 66.2%, P < 0.001), and other adverse effects. The overall occurrence of any adverse event was significantly lower in the Silodosin-Tadalafil group (88.1% vs. 98.5%, P = 0.017)., Conclusions: Both Silodosin-Tadalafil and Silodosin-Vardenafil therapies are effective in managing distal ureteric stones. However, the Silodosin-Tadalafil combination is associated with a significantly lower incidence of adverse events, making it a more tolerable option for patients., Competing Interests: Declarations. Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethics approval: The study was approved by the Research Ethics Committee, Faculty of Medicine, Benha University, Egypt (Approval code: RC 24-2-2023). Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The failure of achieving a penile erection for satisfactory sexual intercourse is known as erectile dysfunction (ED). The primary mediator for penile erection is nitric oxide (NO). ED is often associated with endothelial/nitrergic dysfunction characterized by a reduction of the bioavailability of NO. Phosphodiesterase-5 inhibitors (PDE-5Is) clinical efficacy in the treatment of ED depends on the integrity of the NO-sGC-PKG pathway. In the present study, we probed the effect of sodium nitroprusside incorporated into mesoporous silica nanoparticles (MPSi-NP), which traps cyanide and slowly releases NO. MPSi-NP induced a maximal relaxation of 92.8 ± 5.2% in rabbit corpora cavernosa (RbCC), blunted by a soluble guanylate cyclase (sGC) inhibitor and blockers of calcium-dependent potassium channels. MPSi-NP abolished spontaneous contractions of human corpora cavernosa (HCC) strips. In addition, MPSi-NP induced maximal relaxation of phenylephrine precontracted HCC by 118.6 ± 3.6%, and in comparison, tadalafil induced a maximal relaxation of HCC by 98.3 ± 1.2%. Similarly, the sGC inhibitor blocked the MPSi-NP relaxation. MPSi-NP potentiated the relaxation induced by tadalafil. MPSi-NP increased cGMP levels in HCC strips by 2.6-fold and increased by 3.5-fold the phosphorylation level of the VASP protein, which is a downstream target to PKG. MPSi-NP effectively relaxes RbCC and HCC by activating the sGC-PKG pathway and potentiates the tadalafil response. MPSi-NP could be helpful in conditions where nitric oxide availability is decreased. A topical gel formulation of MPSi-NP could be used as a rescue therapy to treat true non-responders of PDE5Is drugs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Nilberto Robson Falcao do Nascimento reports financial support was provided by UNIVERSIDADE ESTADUAL DO CEARÁ. Luiz Gonzaga de Franca Lopes reports financial support was provided by Federal University of Ceara. Elisane Longhinotti reports financial support was provided by Federal University of Ceara. Eduardo Henrique Silva de Sousa reports financial support was provided by Federal University of Ceara. Elisane Longhinotti has patent #BR 102021018060-9 A(2) pending to none. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bariatric surgery introduces significant changes in the gastrointestinal tract, which may affect oral drug absorption/bioavailability. Here we investigate the phosphodiesterase-5 inhibitor (PDE5i) tadalafil for potentially impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in vitro in different pHs, and ex vivo in gastric content aspirated from patients pre/post-surgery. Dissolution was studied in conditions mimicking pre/post-surgery stomach. Finally, the experimental data were used in physiologically-based pharmacokinetic (PBPK) model (GastroPlus ® ) to simulate pre- vs. post-surgery tadalafil PK. Tadalafil demonstrated low and pH-independent solubility, both in vitro and ex vivo. Tadalafil release from all drug products and under all gastric conditions was incomplete, with particularly poor dissolution (2%) of the highest dose under post-bariatric conditions. PBPK simulations revealed altered tadalafil PK after gastric bypass-but not after sleeve gastrectomy-compared to unoperated individuals, with 44-48% decreased C max , 35-56% decreased AUC and 44% shorter T max . This mechanistic analysis suggests that tadalafil may be as effective after sleeve gastrectomy as before the procedure; meanwhile, results after gastric bypass raise concerns regarding the bioperformance of the drug. In addition, the drug's duration of action may be much shorter after gastric bypass. Thus, the effectiveness of tadalafil, widely regarded as the 'weekend pill', may be shorter than expected among gastric bypass patients., Competing Interests: Declarations Conflict of Interest None., (© 2024. The Author(s).)

Objectives: The purpose of this study is to investigate choroidal and retinal vascular features in patients taking PDE5is by measuring dynamic vascular alterations and neurostructural features of the retina before and after oral tadalafil administration., Methods: The current clinical research involved 22 patients treated with tadalafil 20 mg on alternate days (OAD) after nerve-sparing robotic radical prostatectomy (NS-RARP) for prostate cancer. Patients underwent SD-OCT to assess ganglion cell complex (GCC), retinal nerve fiber layer (RNFL), and subfoveal choroidal thickness (SFCT), as well as OCTA to assess superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC), foveal avascular zone (FAZ), and radial peripapillary capillary thickness (RPC). All patients were evaluated at baseline (t0), and 3 (t1) and 6 (t2) months after the use of oral tadalafil., Results: A statistically significant reduction in DCP and CC vessel density was found at t2 compared to baseline. According to the SFCT parameter, a statistically significant increase was observed from t0 to t1, and from t1 to t2. GCC parameter increased at t2 compared to baseline in a statistically significant way. No statistically significant differences were recorded between t0, t1 and t2 for the SCP, RPC, FAZ area, RNFL parameter., Conclusions: Retinal and optic disc toxicity may be detected using modifications of capillary vessel density. Further studies are needed to detect the possible progression or regression of ocular or systemic vascular complications in long-term follow-up., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Aims: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities., Methods and Results: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups., Conclusions: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups., (© 2024 Actelion Pharmaceuticals Ltd. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Previous studies had shown that the neutrophils/lymphocytes (NLR) and platelets/lymphocytes (PLR) ratios could be used as markers of inflammatory load as well as prognostic factors in several medical conditions. The current study aimed to compare the effect of using daily tadalafil 5 mg/day versus daily sildenafil 25 mg/day in improving erectile function as well as their ability to reduce NLR and PLR., Methods: One hundred and four participants were recruited. Seventy-four randomized patients with erectile dysfunction were equally divided into 2 groups. Patients in group A used daily tadalafil 5 mg for 2 months while patients in group B used daily sildenafil 25 mg for 2 months. Patients were collected from June 2022 to June 2023. Thirty healthy individuals served as controls. All patients and controls were evaluated using the validated Arabic version of the international index of erectile function (ArIIEF-5) at baseline and after 2 months of medical treatment. Five cc of venous blood sample was obtained before and after 2 months of medical treatment to compare the effect of phosphodiesterase type 5 inhibitors (PDE-5Is) intake for erectile dysfunction on PLR and NLR before and after treatment., Results: The current study showed that there were no statistically significant differences between the cases and the controls apart from the ArIIEF-5 scores. Moreover, there was no significant difference between patients in group A and those in group B regarding PLR and NLR post administration of PDE-5Is. Interestingly, patients in group A demonstrated a highly significant difference between the ArIIEF-5 scores as well as the PLR and the NLR before and 2 months after administration of daily tadalafil 5 mg. On the other hand, patients in group B who were administrated daily sildenafil 25 mg for 2 months demonstrated only a highly significant difference between the ArIIEF-5 scores before and after administration. Meanwhile, patients in group B did not reveal any statistically significant difference in the PLR and the NLR before and 2 months after administration of sildenafil 25 mg. Further regression analysis after adjustment of different variables of the study showed a significant correlation between ArIIEF-5 and PLR in patients who received daily tadalafil 5 mg (r=0.430, p=0.004)., Conclusions: Tadalafil and sildenafil have similar clinical efficacy in treating erectile dysfunction. However, tadalafil is more effective in lowering PLR and NLR compared to sildenafil.

This study retrospectively examined the effects of low-intensity extracorporeal shockwave therapy and tadalafil on erectile dysfunction patients. 116 patients got low-intensity extracorporeal shockwave therapy twice weekly for 3 weeks, 5 mg of tadalafil daily for 3 weeks, and adjuvant therapy for 6 months. Group A (1 year), Group B (2 years), Group C (3 years), and Group D (4+ years) were treated patients' follow-up groups. The patients' International Index of Erectile Function-5 (IIEF-5) scores were gathered at the start of treatment via face-to-face interviews and at the end of follow-ups by telephone conversations. IIEF-5 scores and the minimal clinically significant differences were the main outcomes. Mean follow-up length, age, and IIEF-5 scores of the patients were 2 ± 1.16 years, 47.34 ± 12.65 years, and 12.09 ± 3.66 points, respectively. Compared to baseline, treatment increased the median IIEF-5 scores of patients in groups A, B, C, and D by 7 [3-12], 6 [0-8], 7 [1-9], and 6.5 [2.5-10] points, respectively (p = 0.001). 71%, 63%, 65.8%, and 65% of treated patients in groups A, B, C, and D met the minimal clinically significant differences criteria (n = 77). Mild disease patients were 9.14 times more likely to respond to treatment than severe illness patients (OR, 9.14; 95% CI, 1.28-65.46; P = 0.02). Low-intensity extracorporeal shockwave therapy and 5 mg of tadalafil can treat erectile dysfunction for up to 4 years with sustained outcomes. This treatment is optimal for mild illnesses., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: We aimed to compare the efficacy, safety, and compliance of tadalafil 5 mg daily dose in the tablet form versus oral dispersible film (ODF) in men with mild-to-moderate erectile dysfunction (ED)., Methods: One hundred thirty-five randomized patients were equally divided into three groups according to age where each group included forty-five patients. Within each group, 15 patients received oral tadalafil 5 mg, 15 patients received ODF tadalafil 5 mg and 15 patients received a placebo once daily for 1 month. All participants were assessed by the validated Arabic version of the international index of erectile function (ArIIEF-5) at baseline and after 1 month. Also, the efficacy of different forms of tadalafil 5 mg was assessed by responding affirmatively to a questionnaire., Results: Patients aged > 25 to < 40 years and 40-55 years and > 55 years showed a statistically significant improvement of ArIIEF-5 scores after tadalafil 5 mg tablet and ODF tadalafil 5 mg compared to placebo ODF (23 ± 1.4; 22.7 ± 0.9; 20 ± 0.9; 20.4 ± 1.3; 20.2 ± 1.2; 16.6 ± 1.2; 18.5 ± 1.7; 19.6 ± 1.4; 16.3 ± 1.4; p < 0.001, respectively). Three patients (> 25 to < 40 years) who received tadalafil 5 mg tablet showed muscle and back pain. Gastrointestinal (GIT) upset (eight patients) followed by headache (seven patients) were the main side effects reported in patients (40-55 years) who received tadalafil 5 mg tablet. While GIT upset was the main side effect reported in patients (> 55 years) who received tadalafil 5 mg tablet., Conclusion: ODF tadalafil 5 mg is an effective, tolerable, and safe formulation that can be used in patients with mild-to-moderate ED., (© 2024. The Author(s).)

Objectives: The study examined the impact of long term COVID-19 infection on the patients' erectile function and anxiety and depression in the same patients as well as the impact of daily tadalafil 5 mg supplementation on their erectile function., Methods: Recovered 114 men were evaluated by the validated Arabic version of the international index of erectile function (ArIIEF-5) and the Arabic versions of the patient health questionnaire-9 (PHQ-9) and the generalized anxiety disorder-7 (GAD-7) at time of presentation, at 3 months and at 6 months, respectively. Forty recovered patients who still complained of ED received tadalafil 5 mg daily for 2 months then were evaluated again at 3 and 6 months by penile duplex, the Arabic versions of the patient health questionnaire-9 (PHQ-9) and the generalized anxiety disorder-7 (GAD-7) at the same periods, respectively., Results: At the time of presentation, there was a positive correlation between the severity of COVID-19 infection, ArIIEF-5 and PHQ-9 ( r  = 0.249, p  = 0.008; r  = 0.241, p  = 0.010, respectively). Most of the patients showed normal penile duplex parameters. There were 40 ED patients at presentation, 5 ED patients at 3 months and 3 ED patients at 6 months, respectively., Conclusions: ED in COVID-19 patients who were not suffering from chronic illnesses before the affection, is primarily psychological and completely responsive to tadalafil., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Daily (once a day [OaD]) tadalafil intake is a valuable option for men favoring spontaneous over scheduled sexual intercourse., Aim: The study sought to assess the rate of and the clinical factors associated with spontaneous, medication-free erectile function (EF) recovery after discontinuation of tadalafil 5 mg OaD in a cohort of young men seeking first medical help for psychogenic erectile dysfunction (ED) as their primary complaint., Methods: Data from 96 consecutive patients <50 years of age seeking first medical help for ED and prescribed tadalafil 5 mg OaD were analyzed. Patients completed the International Index of Erectile Function (IIEF) and underwent baseline penile color Doppler ultrasound. Follow-up involved clinical assessments or phone interviews. Spontaneous medication-free EF recovery was defined as IIEF EF domain score >22 after tadalafil discontinuation, prompting cessation of follow-up. Descriptive statistics compared tadalafil OaD responders and nonresponders. Cox regression hazard models explored the association between baseline characteristics and EF recovery risk post-drug discontinuation. Kaplan-Meier analyses estimated EF recovery probability over time., Outcomes: The primary outcome was EF recovery after discontinuation of tadalafil 5 mg OaD., Results: Overall, median age was 39 (interquartile range [IQR], 32-45) years. Of all, 82 (85.4%) patients achieved EF recovery after tadalafil OaD discontinuation, while 14 (14.6%) patients were identified as nonresponders. Median tadalafil usage time (from beginning to discontinuation) was 3 (IQR, 2-11) months. The most common treatment-emergent adverse event was headache in 9 (9.4%) patients. Nonresponders were older (43 [IQR, 42-45] years vs 38 [IQR, 31-44] years; P = .03), had higher body mass index (25.5 [IQR, 23.4-29.9] kg/m2 vs 23.6 [IQR, 21.8-25.9] kg/m2; P = .04), and reported lower baseline IIEF EF domain scores (12 [IQR, 7-15] vs 15 [IQR, 10-22]; P = .02) than responders. Nonresponders and responders did not differ in terms of baseline ED severity, Charlson comorbidity index, smoking, alcohol consumption, regular physical exercise, and color Doppler ultrasound parameters. Upon Cox regression analysis, younger age (hazard ratio, 0.95; 95% confidence interval, 0.92-0.99; P = .01) was associated to EF recovery, after adjusting for baseline ED severity, body mass index, smoking, and Charlson comorbidity index ≥1. The Kaplan-Meier analysis displays the probability of EF recovery over time, indicating rates of 43%, 60%, and 72% at 3-, 6-, and 12-month follow-up intervals, respectively., Clinical Implications: Tadalafil 5 mg OaD is an effective short-term treatment for psychogenic ED, allowing its discontinuation after achieving a normal medication-free EF., Strengths and Limitations: The main limitations are the limited number of participants and the potential neglect of confounding factors., Conclusion: Almost 1 out of 2 young men with primary psychogenic ED who were prescribed with tadalafil 5 mg OaD recovered spontaneous medication-free EF after 3 months of treatment. Overall, the younger the patient was, the higher the chance there was of spontaneous EF recovery after drug discontinuation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Objectives: We aimed to evaluate the effect of daily 5 mg tadalafil on the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) in patients with erectile dysfunction (ED)., Patients and Methods: 30 subjects with ED were given tadalafil as well as 30 subjects with ED who were not receiving tadalafil were recruited. 30 healthy individuals served as controls., Results: Receiver operating characteristic curve (ROC) showed that the best cut off point of pre-treatment and post treatment NLR in the ED treatment group was found <1.51, <1.51, sensitivity of 68.3%, 58.3%, specificity of 53.3%, 53.3%, lower bound of 0.558, 0.517, upper bound of 0.789, 0.757, total accuracy of 67.4%, 63.7% and p 0.003, 0.0025, respectively. Additionally, the best cut off point of pre-treatment and post treatment PLR in the ED treatment group was found <5.89, <5.99, sensitivity of 65%, 63.3%, specificity of 63.3%, 53.3%, lower bound of 0.515, 0.435, upper bound of 0.755, 0.687, total accuracy of 63.5%, 56.1% and p 0.027, 0.341, respectively., Conclusion: Daily 5 mg Tadalafil supplementation significantly improves erectile function through decreasing these markers as well as depression and anxiety., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The objective is to evaluate the efficacy of coadministration of garlic (as a hydrogen sulfide [H2S] donor) and tadalafil for patients with ED using a placebo-controlled, prospective, randomized, two-arm pilot study in patients responding poorly to tadalafil alone., Materials and Methods: The patients with complaints of ED (with normal penile Doppler) who failed to maintain sustained improvement in erectile function with tadalafil were recruited after excluding those with comorbidities. The study sample was randomized into two groups. Group A received garlic 5 g twice a day orally and Group B received a placebo twice daily orally for 4 weeks. Both groups continued tadalafil 5 mg in the night for 4 weeks. Their erectile function was assessed at the beginning and at the end of 4 weeks using the International Index of Erectile Function (IIEF-EF), erectile function domain and compared. A value of P ≤ 0.05 was considered statistically significant., Results: Nineteen patients in Group A (mean age 37.5 ± 10.6 years) and 16 patients in Group B (mean age 39.6 ± 9.6 years) participated in the pilot study conducted from May 2022 to August 2022. The participants treated with garlic (as an H2S donor) as a coadministrant had statistically significant improvement in IIEF-EF score (P ≤ 0.0001) at the end of 4 weeks compared to placebo., Conclusions: Garlic (as an H2S donor) as adjunctive therapy was beneficial in our study participants responding poorly to tadalafil alone., (Copyright © 2024 Copyright: © 2024 Indian Journal of Pharmacology.)

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.

Background: The aim of this study was to investigate the efficacy, safety, and outcomes of the combination of low ıntensity external shock wave therapy (Li-ESWT) and platelet-rich plasma (PRP) therapy in acute phase Peyronie's disease (PD)., Methods: The datas of patients admitted with acute phase Peyronie's between January 2014 and January 2022 were reviewed retrospectively. In total, we included total 159 patients who used combination of vitamin E 600 mg/day plus colchicine 1.5 mg/day plus oral daily 5 mg tadalafil (N.=77) in group 1 and received Li-ESWT+PRP combination therapy plus oral daily 5 mg tadalafil (N.=82) in group 2. We noted characteristics of fibrous plaques, pain status, penile curvature degree, and erectile function parameters. All patients were visited at the 3 rd and 12 th months after the treatment., Results: Preoperative demographic characteristics were similar in the two groups. There was a statistically significant improvement in the mean plaque size, penile curvature degree, IIEF-5 and VAS scores in the intervention group after the treatment. Ecchymosis and hematoma were not observed at the injection site and Li-ESWT application areas in the intervention group. No local or systemic drug reactions were noted in either group., Conclusions: Combination of Li-ESWT and PRP are highly effective and safety to early treatment in the acute phase PD.

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (C max ) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of C max and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated., (© 2024 Actelion Pharmaceuticals Ltd. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Patients with severe erectile dysfunction (ED) remain the most challenging group in terms of available noninvasive treatment modalities., Aim: The study sought to assess the role of combination therapy with low-intensity shockwave therapy (LiST) and daily tadalafil 5 mg in a highly select group of patients with severe vasculogenic ED through a double-blind, randomized trial., Methods: Forty-eight sexually active men were randomly assigned to 12 sessions of LiST 3 times weekly and tadalafil 5 mg once daily (n = 34) or sham therapy and tadalafil (n = 17) for 4 weeks. Patients were assessed at 1 and 3 months after completion of treatment., Outcomes: Improvement of erectile function was evaluated through the International Index of Erectile Function-Erectile Function domain (IIEF-EF) or 6-item IIEF and the Sexual Encounter Profile (SEP) diary. The primary outcome was the difference between the groups in the IIEF-EF at 3 months after completion of treatment. Secondary outcomes comprised (1) the difference between the groups in the IIEF-EF at 1 month after completion of treatment, (2) the difference between the groups in the "yes" responses to question 3 of the SEP diary at 1 and 3 months, and (3) the treatment-related adverse events. The number of patients attaining a minimal clinically important difference in the IIEF-EF (improvement of at least 7 points) was also assessed., Results: After treatment, the absolute scores in the IIEF-EF were higher in patients receiving LiST and tadalafil vs sham therapy and tadalafil both at the 1-month (12.1 ± 2.4 vs 10.2 ± 1.7; P = .002) and at the 3-month (12.9 ± 2.1 vs 10.8 ± 1.8; P < .001) evaluation. Between the 2 groups, the proportion of "yes" responses to question 3 of the SEP diary was not statistically significant, whereas the number of patients attaining a minimal clinically important difference in the IIEF-EF was statistically significant only at the 3-month evaluation. No adverse events occurred., Clinical Implications: Application of LiST in patients with severe vasculogenic ED receiving daily dose tadalafil may further improve erectile function compared with tadalafil as a stand-alone treatment on the short term., Strengths and Limitations: Although we provided the first study in the field, severe vasculogenic ED was defined based on medical history and clinical examination and not based on penile ultrasound measures., Conclusion: The combination of 12 sessions LiST 3 times weekly and daily tadalafil for 4 weeks led to a 2-point difference in the IIEF-EF compared with sham therapy and daily tadalafil among patients with severe vasculogenic ED after 1 and 3 months from completion of treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The long-term safety and effectiveness of once-daily tadalafil is crucial, but limited data are available in Chinese patients with erectile dysfunction (ED). In this post-marketing, multicenter, randomized, open-label trial with 2-year follow-up, 635 ED cases were randomized to receive daily oral tadalafil 2.5 mg or 5 mg for 3 months, of whom 580 continued once-daily tadalafil 5 mg for 21 months. Treatment-emergent adverse events in the 12-month and 24-month period were similar, with the most common being viral upper respiratory tract infection, upper respiratory tract infection, and headache. Significant improvement from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) score was detected at month 12 (least squares mean [LSM] change: 7.9, 95% confidence interval [CI]: 7.5-8.4, P < 0.001) and was maintained to month 24 (LSM change: 8.6, 95% CI: 8.1-9.0, P < 0.001). The proportions of patients regaining normal erectile function (IIEF-EF score ≥26) were 43.7% and 48.0% at months 12 and 24, respectively. Global Assessment Questionnaire results showed improved erection function in 97.5% of patients and improved ability to engage in sexual activity in 95.9% of patients at month 12; these values were 96.1% and 95.0% at month 24, respectively. The quality of sexual life score based on the Sexual Life Quality Questionnaire (SLQQ) was increased by 52.2% at month 12 and by 55.3% at month 24 (both P < 0.001). The treatment satisfaction score determined by SLQQ (mean ± standard deviation) was 62.4 ± 21.0 at month 12 versus 65.9 ± 20.2 at month 24. Two-year daily application of tadalafil 5 mg in Chinese men with ED showed a favorable safety profile and durable improvement in sexual performance and satisfaction., (Copyright © 2024 Copyright: © The Author(s)(2024).)

Background: There is limited research into the efficacy and safety of tadalafil combined with tamsulosin for the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH), with or without erectile dysfunction (ED). Therefore, we aimed to investigate the efficacy and safety of combination therapy compared to that of monotherapy., Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, SinoMed, CNKI, WanFang Data Service Platform, and ClinicalTrials.gov to identify eligible studies. A total of 639 articles were retrieved, of which 12 were randomized controlled trials (RCTs) published as of February 2023 and included in this meta-analysis., Results: After screening 639 articles, 12 RCTs including 1,531 subjects were considered eligible for the meta-analysis. The results showed that the total International Prostate System Score (total IPSS), maximum flow rate (Qmax), and quality of life (QoL) in tadalafil combined with tamsulosin were significantly better than those in monotherapy. Compared with tadalafil monotherapy, combination therapy mainly improved IPSS voiding. As for postvoid residual urine (PVR), the combination therapy did not improve PVR compared to the tadalafil group, but significantly improved PVR compared to the tamsulosin group. For the International Index of Erectile Function (IIEF), the curative effect of the combined group was better than that of the tamsulosin group but not better than that of the tadalafil group. In terms of safety, the adverse reactions (AEs) in the combined treatment group were significantly higher than those in the monotherapy group. None of the 12 RCTs reported serious adverse events., Conclusions: Tadalafil combined with tamsulosin was more effective in the treatment of male LUTS/BPH, with or without ED, on the improvement of total IPSS, QoL, and Qmax. However, the benefits of combination therapy for ED remain unclear. However, combination therapy seemed to have a higher incidence of adverse reactions., (© 2023 S. Karger AG, Basel.)

Objective: To determine whether chronic phosphodiesterase-V (PDEV) inhibition with tadalafil will improve urinary sodium excretion, glomerular filtration rate (GFR), plasma cyclic guanosine 3', 5'-monophosphate (cGMP), and urinary cGMP excretion in response to volume expansion (VE) in patients with preclinical diastolic dysfunction (PDD) or stage B heart failure., Background: PDD is defined as abnormal diastolic function with normal systolic function, without clinical heart failure. PDD is predictive of development of heart failure and all-cause mortality. Impaired renal function and attenuated cGMP response to VE are hallmarks of PDD., Methods: A double-blind, placebo-controlled, proof-of-concept study was conducted to compare 12 weeks of tadalafil 20 mg daily (n = 14) vs placebo (n = 7). Subjects underwent 2 study visits 12 weeks apart. Renal, neurohormonal and echocardiographic assessments were performed before and after intravascular VE (normal saline 0.25 mL/kg/min for 1 hour)., Results: Baseline characteristics were similar. There was no increase in GFR, plasma cGMP or urinary cGMP excretion in response to VE in either group at visit 1. At visit 2, tadalafil did not result in significant change in GFR but increased plasma cGMP and urinary cGMP excretion at baseline. In response to VE, tadalafil resulted in increased urine flow, urinary sodium excretion, GFR (7.00 [-1.0, 26.3] vs -9.00 [-24.5, 2.0] mL/min/1.73m2; P = 0.02) and plasma cGMP (0.50 [-0.1, 0.7] vs -0.25 [-0.6, -0.1] pmol/mL; P = 0.02). It did not improve urinary cGMP excretion after VE., Conclusion: In PDD, chronic PDEV inhibition with tadalafil improved renal response to VE through increased urine flow, urinary sodium excretion, GFR, and plasma cGMP. Further studies are required to determine whether this enhanced renal response can mitigate progression to clinical heart failure., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Vascular complication is one of the causes of skin flap healing failure. Sildenafil and tadalafil, a type-5 phosphodiesterase inhibitor, can improve flap viability, however, the action mechanisms involved in this process are still unclear. To assess the effects of orally administered sildenafil and tadalafil on the healing kinetics and skin flap viability, sixty-two Wistar rats were divided into three groups: control (n = 22), sildenafil (n = 20), and tadalafil (n = 20). The solutions were administered orally (dose: 10 mg/kg) immediately after the surgical procedure and then every 24 h. At postoperative days 7 and 14, the skin flap samples were collected, submitted to histological processing and evaluated under optical microscopy. In experimental groups (sildenafil and tadalafil), we found an increased vascularization (p < 0.05) on the 7th and 14th day associated with the ulcer size decrease on the 14th day, although it was not significant. There was a higher influx of neutrophils and a decrease of mononuclear population on the 7th day (p < 0.05). On the 14th day, these differences were observed only in the tadalafil group (p < 0.05). This study suggested positive results with the use of sildenafil and tadalafil as adjuvant drugs in skin flap viability., (© 2021. The Author(s).)

Purpose: To investigate a therapeutic protocol for erectile dysfunction (ED) based on the combination of low-intensity extracorporeal shock wave therapy (Li-ESWT), tadalafil, and L-arginine., Materials and Methods: Recruited patients completed the International Index of Erectile Function erectile function domain (IIEF-EF) and the Erection Hardness Score (EHS) questionnaires at baseline and were randomly assigned in two groups: A (treatment group) and B (control group). Men in both groups received six weekly applications of Li-ESWT. Group A was prescribed adjuvant oral therapy with tadalafil 5 mg and L-arginine 2,500 mg. Follow-up visits were scheduled 1, 6, and 12 months after the last Li-ESWT application. At each follow-up visit, the IIEF-EF and EHS questionnaires were administered again. The main outcome measures were the changes from baseline to every follow-up visit in IIEF-EF and EHS scores., Results: The mean IIEF-EF score in group A was 16.0±4.0, 24.8±3.4, 23.3±4.6, and 21.6±5.5 at baseline, 1, 6, and 12 months of follow-up, respectively, whereas in group B the mean IIEF-EF score was 16.5±4.1, 22.7±4.2, 21.5±4.5, and 19.5±4.9, respectively. We reported an increase in the mean EHS score in group A from 2.07±0.72 at baseline to 3.39±0.59, 3.17±0.67, and 2.98±0.72 at 1, 6, and 12 months, respectively, and in group B from 2.12±0.80 at baseline to 3.07±0.78 and 2.95±0.76 at 1 and 6 months, respectively., Conclusions: Adjuvant daily therapy with L-arginine 2,500 mg and tadalafil 5 mg was safe and effective in increasing the efficacy and the duration of benefits of Li-ESWT., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2022.)

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