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Urology Journal Jul 2023To compare the efficacy and adverse events of sildenafil monotherapy for benign prostatic hyperplasia (BPH) with its FDA-approved counterpart, tadalafil.
PURPOSE
To compare the efficacy and adverse events of sildenafil monotherapy for benign prostatic hyperplasia (BPH) with its FDA-approved counterpart, tadalafil.
MATERIALS AND METHODS
In this single-arm self-controlled clinical trial, 33 patients were enrolled. All patients underwent a 6-week treatment with sildenafil, followed by a 4-week washout period and finally a 6-week treatment with tadalafil. Patients were examined on each appointment and post-void residual (PVR) urine, International Prostate Symptom Score (IPSS) and Quality of life index (IPSS-QoL index) were recorded subsequently. Efficacy of each drug regimen was then evaluated by comparing these outcome parameters.
RESULTS
Both sildenafil and tadalafil were shown to improve PVR (both p < .001), IPSS (both p < .001) and IPSS- QoL index (both p < .001) significantly. Sildenafil was more effective than tadalafil in reducing PVR (mean difference (95%CI) = 9.91% (4.11, 15.72), p < .001) and ameliorating IPSS-QoL index (mean difference (95%CI) = 19.3% (4.47, 34.41), p = .027). Moreover, although not significant, sildenafil reduced IPSS more than tadalafil (mean difference (95%CI) = 3.33% (-0.22, 6.87), p = .065). Concurrent erectile dysfunction did not affect responsiveness to therapy with either sildenafil or tadalafil but age was inversely related to post-treatment IPSS in both sildenafil (B = 0.21 (0.04, 0.37), p = .015) and tadalafil (B = 0.14 (0.02, 0.26), p = .021) regimens with a more prominent role in responsiveness to sildenafil (β = 0.31) compared to tadalafil (β = 0.19).
CONCLUSION
Considering the significantly better improvement of PVR and IPSS-Qol index with sildenafil, this drug can be nominated as a suitable alternative for tadalafil as a BPH treatment, especially in younger patients who don't have any contraindications.
Topics: Humans; Male; Erectile Dysfunction; Lower Urinary Tract Symptoms; Phosphodiesterase 5 Inhibitors; Prostatic Hyperplasia; Quality of Life; Sildenafil Citrate; Tadalafil; Treatment Outcome; Urinary Retention
PubMed: 37245088
DOI: 10.22037/uj.v20i.7593 -
Journal of the American College of... Jan 2024Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial... (Randomized Controlled Trial)
Randomized Controlled Trial
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).
Topics: Humans; Pulmonary Arterial Hypertension; Tadalafil; Combined Modality Therapy; Phosphodiesterase 5 Inhibitors; Endothelin Receptor Antagonists; Tablets; Pyrimidines; Sulfonamides
PubMed: 38267108
DOI: 10.1016/j.jacc.2023.10.045 -
International Journal of Molecular... Dec 2023The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play... (Review)
Review
The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.
Topics: Humans; Pulmonary Arterial Hypertension; Nitric Oxide; Familial Primary Pulmonary Hypertension; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Soluble Guanylyl Cyclase
PubMed: 38203205
DOI: 10.3390/ijms25010036 -
Alzheimer's & Dementia (New York, N. Y.) 2023Alzheimer's disease and related dementias (ADRD) remain a major health-care challenge with few licensed medications. Repurposing existing drugs may afford prevention and...
UNLABELLED
Alzheimer's disease and related dementias (ADRD) remain a major health-care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase-5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration-approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real-world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half-life, and off-target effects.
HIGHLIGHTS
Potent phosphodiesterase-5 (PDE5) inhibitors are in clinical use as vasodilators.In animals PDE5 inhibitors enhance synaptic function and cognitive ability.In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease.Licensed PDE5 inhibitors have potential for repurposing in dementia.Prospective clinical trials of PDE5 inhibitors are warranted.
PubMed: 37766832
DOI: 10.1002/trc2.12412 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1)... (Review)
Review
Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.
PubMed: 37765060
DOI: 10.3390/ph16091252 -
International Journal of Molecular... Oct 2023Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many... (Review)
Review
Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.
Topics: Humans; Mice; Rats; Animals; Pulmonary Arterial Hypertension; Ventricular Function, Right; Pulmonary Artery; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Disease Models, Animal
PubMed: 37958522
DOI: 10.3390/ijms242115539 -
Journal of Personalized Medicine Oct 2023Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and...
Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC), maximum plasma concentration (C), and time to reach C (t) compared to fasting volunteers; male volunteers also showed higher AUC and C compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC, C and t compared to fasting individuals. Variants in , , , , and were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as or , on tadalafil and finasteride pharmacokinetics.
PubMed: 38003881
DOI: 10.3390/jpm13111566 -
Cureus Dec 2023Benign Prostatic Hyperplasia (BPH) is a prevalent condition that affects aging men, leading to the development of lower urinary tract symptoms (LUTS) and potentially... (Review)
Review
Benign Prostatic Hyperplasia (BPH) is a prevalent condition that affects aging men, leading to the development of lower urinary tract symptoms (LUTS) and potentially severe complications such as complete obstruction. The management of BPH typically involves the use of medications from different classes, including alpha-1 antagonists, 5-alpha reductase inhibitors, and anticholinergics. Combination therapy utilizing drugs from different classes can also effectively manage the BPH-LUTS complex. Recent research has revealed that phosphodiesterase 5 (PDE5) inhibitors, including Tadalafil and Sildenafil, are highly effective in treating LUTS associated with BPH. Tadalafil as a monotherapy has recently been shown to significantly improve LUTS in BPH patients. Additionally, the use of herbal remedies as a treatment option for BPH has also been widely debated. Previous research suggests that saw palmetto can reduce BPH symptoms through several proposed mechanisms, but recent trials have found inconsistencies in its efficacy. In this literature review, we conducted an extensive PubMed database search to provide current and comprehensive insights into BPH treatment options. This review comprehensively evaluates available treatments for managing BPH, highlighting the effectiveness of different classes of medications and combination therapies in managing associated symptoms. The present investigation also discusses recent research on the efficacy of PDE5 inhibitors in treating LUTS associated with BPH and the uncertain efficacy of herbal remedies. The insights provided by this study can guide healthcare professionals in making informed decisions about managing BPH, ultimately improving patient outcomes.
PubMed: 38288222
DOI: 10.7759/cureus.51314