Group 5 Pulmonary Hypertension Associated With T-Cell Large Granular Lymphocytic Leukemia: Hemodynamics and Treatment.

Group 5 pulmonary hypertension (PH) encompasses diverse diseases, with a few cases linking it to T-cell large granular lymphocytic (LGL) leukemia. We report a case of a 76-year-old woman, diagnosed with LGL leukemia and concomitant PH, treated with oral triple pulmonary arterial hypertension (PAH) therapy. She initially presented with dyspnea on exertion; evaluation revealed severe precapillary PH. Implementing cyclophosphamide for leukemia along with tadalafil and macitentan for PH led to sustained symptomatic and hemodynamic improvement for over 3 years. At that time, deterioration in PH prompted the addition of selexipag, resulting in sustained clinical improvement for an additional 5 years. This case exemplifies the potential for sustained benefits of PAH therapy in leukemia-associated PH and highlights the need for continued research on the mechanistic relationship between LGL leukemia and PH, with the hope of identifying new management strategies.

Single and combined toxicity of tadalafil (Cilais) and microplastic in Tilapia fish (Oreochromis niloticus).

The joint impact of tadalafil (Cilais) as a pharmaceutical residue and microplastics on fish is not well comprehended. The current study examined haematological, biochemical, and antioxidant parameters, along with immunohistochemical and histological indications in tilapia (Oreochromis niloticus) after being exposed to tadalafil, polyethylene microplastics (PE-MPs), and their mixtures for 15 days. The fish were distributed into 1st group control group (The fish was maintained in untreated water without any supplements); 2nd group exposed to 10 mg/L PE-MPs;3rd group exposed to 20 mg/l tadalafil (Cilais); 4th group exposed to 20 mg/l tadalafil (Cilais) + 10 mg/LPE-MPs (in triplicate). The levels of creatinine, uric acid, glucose, AST, ALT, and albumin in fish treated with tadalafil alone or in combination with PE-MPs were significantly higher than those in the control group. Fish exposed to PE-MPs, tadalafil, and tadalafil plus PE-MPs showed significantly lower levels of RBCs, Hb, Ht, neutrophils, and lymphocytes compared to the control group. Serum levels of total antioxidant capacity and reduced glutathione (GSH) were notably lowered in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations in comparison to the control group. Malondialdehyde (MDA) serum levels were notably elevated in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations compared to the control group. The most severe impact was observed in the tadalafil + PE-MPs combination group. Interleukin-6 (IL-6) levels were significantly increased in liver tissues following exposure to both tadalafil and microplastics compared to tissues exposed to only one substance or the control group. Changes in the gills, liver, and renal tissues were seen following exposure to PE-MPs, tadalafil, and tadalafil + PE-MPs combination in comparison to the control group of fish. Ultimately, the mixture of tadalafil and PE-MPs resulted in the most detrimental outcomes. Tadalafil and PE-MPs exhibited showed greater adverse effects, likely due to tadalafil being absorbed onto PE-MPs.

Benchtop NMR Coupled with Chemometrics: A Workflow for Unveiling Hidden Drug Ingredients in Honey-Based Supplements.

Recently, benchtop nuclear magnetic resonance (NMR) spectrometers utilizing permanent magnets have emerged as versatile tools with applications across various fields, including food and pharmaceuticals. Their efficacy is further enhanced when coupled with chemometric methods. This study presents an innovative approach to leveraging a compact benchtop NMR spectrometer coupled with chemometrics for screening honey-based food supplements adulterated with active pharmaceutical ingredients. Initially, fifty samples seized by French customs were analyzed using a 60 MHz benchtop spectrometer. The investigation unveiled the presence of tadalafil in 37 samples, sildenafil in 5 samples, and a combination of flibanserin with tadalafil in 1 sample. After conducting comprehensive qualitative and quantitative characterization of the samples, we propose a chemometric workflow to provide an efficient screening of honey samples using the NMR dataset. This pipeline, utilizing partial least squares discriminant analysis (PLS-DA) models, enables the classification of samples as either adulterated or non-adulterated, as well as the identification of the presence of tadalafil or sildenafil. Additionally, PLS regression models are employed to predict the quantitative content of these adulterants. Through blind analysis, this workflow allows for the detection and quantification of adulterants in these honey supplements.

Nucleotides as new co-formers in co-amorphous systems: Enhanced dissolution rate, water solubility and physical stability.

Developing co-amorphous systems is an attractive strategy to improve the dissolution rate of poorly water-soluble drugs. Various co-formers have been investigated. However, previous studies revealed that it is a challenge to develop satisfied acidic co-formers, e.g., acidic amino acids showed much poorer co-former properties than neutral and basic amino acids. Only a few acidic co-formers have been reported, such as aspartic acid, glutamic acid, and some other organic acids. Thus, this study aims to explore the possibility of adenosine monophosphate and adenosine diphosphate used as acidic co-formers. Mebendazole, celecoxib and tadalafil were used as the model drugs. The drug-co-former co-amorphous systems were prepared via ball milling and confirmed using XRPD. The dissolution study suggested that the solubility and dissolution rate of the drug-co-formers systems were increased significantly compared to the corresponding crystalline and amorphous drugs. The stability study revealed that using the two nucleotides as co-formers enhanced the physical stability of pure amorphous drugs. Molecular interactions were observed in MEB-co-former and TAD-co-former systems and positively affected the pharmaceutical performance of the investigated co-amorphous systems. In conclusion, the two nucleotides could be promising potential acidic co-formers for co-amorphous systems.

Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed-dose combination tablets versus the use of single-component tablets in healthy subjects.

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 (Cmax) 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 Cmax 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.

Phosphodiesterase 5A regulates the vomeronasal pump in mice.

The vomeronasal organ (VNO) is a specialized chemoreceptive structure in many vertebrates that detects chemical stimuli, mostly pheromones, which often elicit innate behaviors such as mating and aggression. Previous studies in rodents have demonstrated that chemical stimuli are actively transported to the VNO via a blood vessel-based pumping mechanism, and this pumping mechanism is necessary for vomeronasal stimulation in behaving animals. However, the molecular mechanisms that regulate the vomeronasal pump remain mostly unknown. In this study, we observed a high level of expression of phosphodiesterase 5A (PDE5A) in the vomeronasal blood vessel of mice. We provided evidence to support the potential role of PDE5A in vomeronasal pump regulation. Local application of PDE5A inhibitors-sildenafil or tadalafil-to the vomeronasal organ (VNO) reduced stimulus delivery into the VNO, decreased the pheromone-induced activity of vomeronasal sensory neurons, and attenuated male-male aggressive behaviors. PDE5A is well known to play a role in regulating blood vessel tone in several organs. Our study advances our understanding of the molecular regulation of the vomeronasal pump.

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

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.

The effect of combination treatment with low-intensity shockwave therapy and daily tadalafil on severe erectile dysfunction: a double-blind, randomized, sham-controlled clinical trial.

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.

Maternal tadalafil treatment does not increase uterine artery blood flow or oxygen delivery in the pregnant ewe.

Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .

Major adverse cardiovascular events related to phosphodiesterase 5 inhibitors: analysis of real-life data from Eudra-Vigilance database.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the standard medical treatment for erectile dysfunction. Aim of our study was to evaluate the rate of major adverse cardiovascular events (MACE) reported during PDE5i treatment based on Eudra-Vigilance (EV) reports. METHODS: EV database is the system for managing and analyzing data on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area. MACE are defined as non-fatal stroke, non-fatal myocardial infarction, non-fatal congestive heart failure, revascularization after aorto-coronary graft bypass and cardiovascular death. We recorded the number of MACE for sildenafil, tadalafil, vardenafil, avanafil per category and severity until 1st July 2023. Pooled Relative Risk (PRR) was used to compare data between drugs. RESULTS: Overall, 951 MACE events were reported. Most of them were observed in younger patients <65 years old (452/951 events, 48%). Overall, 377/8939 (4%) MACE events were observed for sildenafil, 221/5213 (4%) for tadalafil, 50/1029 (4%) for vardenafil and no events for avanafil. No significative differences were reported comparing sildenafil and tadalafil (PRR 0.71-0.99, IQR 0.61-1.35, P>0.05), neither sildenafil vs. vardenafil (PRR 0.68-0.79, IQR 0.43-1.55, P>0.05), neither tadalafil vs. vardenafil (PRR 0.77-0.95, IQR 0.64-1.30. P>0.05) even when compared for age. Comparison between different classes of age showed MACE were more frequent in patients younger than 65 years old taking sildenafil and tadalafil when compared to patients older than 85 years old (PRR 0.02-0.11. IQR 0.01-0.40. P<0.01) and when compared to patients in 65-85 class of age (PRR 0.02-0.12, IQR 0.01-0.95, P<0.01). CONCLUSIONS: Real life data is consistent with MACE related to PDE5i. PDE5is are infrequently (<5%) associated with MACE. However, risk seems higher in younger patients, particularly for sildenafil (452/951 events, 48%). Clinicians should consider these data when prescribing PDE5i especially in young patients.

Single-dose Tadalafil Reduces Opening Urethral Pressure: A Randomized, Double-blind, Placebo-controlled, Crossover Trial in Healthy Women.

INTRODUCTION AND HYPOTHESIS: Phosphodiesterase enzymes are widely distributed in female urogenital tissues. Yet, the understanding of their physiological roles and the impact of phosphodiesterase inhibitors on lower urinary tract symptoms in women remains limited. Current hypotheses are conflicting: one suggests that vasodilation might expand the periurethral vascular plexus, leading to increased urethral pressure, whereas the other proposes a relaxation of urethral musculature, resulting in decreased pressure. To further clarify this, we investigated the effect of tadalafil on the opening urethral pressure and voiding function in healthy women. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial involving 24 healthy women. Participants were randomly assigned to receive a single dose of tadalafil (40 mg) or placebo during their initial visit and then switched to the alternative treatment during their second visit. Opening urethral pressure was measured with urethral pressure reflectometry during both resting and squeezing conditions of the pelvic floor. Subsequently, voiding parameters were recorded. RESULTS: Compared with placebo, a single dose of tadalafil significantly reduced opening urethral pressure during both resting (-6.8 cmH20; 95% confidence interval [CI], -11.8 to -1.9; p = 0.009) and squeezing conditions (-8.8 cmH20; 95% CI, -14.6 to -3.1; p = 0.005). Voiding parameters did not show significant differences (average flow rate: -0.8 ml/s [95% CI, -2.0 to 0.4; p = 0.2]; maximum flow rate: -1.7 ml/s [95% CI, -4.8 to 1.5; p = 0.3]). CONCLUSIONS: A single dose of 40 mg tadalafil moderately reduced urethral pressure in healthy women, without affecting voiding parameters. The clinical implications of this are yet to be determined.

Evaluation of efficacy and safety profile of tadalafil 5 mg daily dose in the tablet form versus oral dispersible film in men with mild-to-moderate erectile dysfunction: a comparative placebo-controlled study.

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.

Medical Advancements in Benign Prostatic Hyperplasia Treatments.

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

Environmentally benign first derivative synchronous spectrofluorimetry for the analysis of two binary mixtures containing duloxetine with avanafil or tadalafil in spiked plasma samples.

Antidepressants can cause sexual dysfunction side effects, necessitating the co-administration of phosphodiesterase type 5 inhibitors. The simultaneous determination of these drugs in biological fluids is critical for therapeutic drug monitoring. For the first time, two binary mixtures containing duloxetine with either avanafil or tadalafil were estimated utilizing simple green spectrofluorimetric methods without the need for a previous separation step. The study was based on first derivative synchronous spectrofluorimetry in ethanol using a change in wavelength difference (∆λ) of 20 and 25 nm for the first and second combinations, respectively. Duloxetine and avanafil were estimated at 297.7 and 331 nm in their binary mixture, while duloxetine and tadalafil were determined at 290.3 and 297.7 nm, respectively. The linearity was achieved over the ranges of 0.1-1.5 µg mL-1 for both duloxetine and avanafil and 0.01-0.40 µg mL-1 for tadalafil, with limits of detection of 0.013, 0.022, and 0.004 µg mL-1 for duloxetine, avanafil, and tadalafil, respectively. Successful application of the developed approaches was accomplished for the estimation of the two mixtures in dosage forms as well as human plasma with excellent percentage recoveries (96-103.75% in plasma), which supports their suitability for use in quality control laboratories and pharmacokinetic studies. Moreover, the adopted approaches' greenness was evidenced by applying three tools.

Treatment preferences of patients with erectile dysfunction: a systematic review of randomized controlled trials.

INTRODUCTION: Patients' treatment preferences (PTP) depend on the complex interaction of numerous patient- and treatment-related factors; their assessment can guide therapy and promote compliance of patients with erectile dysfunction (ED). We aimed to systematically describe the literature evaluating the treatment preferences of patients with ED, published in the last 25 years. EVIDENCE ACQUISITION: A comprehensive bibliographic search of multiple databases was conducted in June, 2023. The literature search was limited to the articles published since 1998. Articles were deemed eligible if they described male patients with ED (P) undergoing treatment for this condition (I) compared with other treatments, placebo or sham therapy (C), and reported PTP (O). Only randomized controlled trials (RCTs) and post-hoc analyses of RCTs were selected (S). The data were presented in a narrative fashion. The risk of bias (RoB) was evaluated using the RoB 2 tool and the Mulhall-Montorsi model. EVIDENCE SYNTHESIS: A total 14 RCTs evaluating 6,841 patients and 4 post-hoc analyses of RCTs were included. All RCTs were considered to be at high RoB. No validated tool was used to investigate PTP. Sildenafil was the most frequently evaluated ED treatment (9 RCTs). Sildenafil was chosen over placebo by 78-100% of subjects and over ICI in 70% of patients due to its easier route of administration. No significant difference in patient preference was recorded between Sildenafil tablets and orodispersible (53% vs. 47%, P>0.05). Tadalafil was preferred over Sildenafil by 66-73% of patients (P<0.05), mainly because it allowed an erection long after taking the drug (55-67%). Tadalafil as-needed was chosen over Tadalafil 3 times/week by 57-59% of the patients (P<0.05). CONCLUSIONS: The available RCTs support the preference of ED patients for Sildenafil over ICI, Tadalafil over Sildenafil, and Tadalafil as-needed over Tadalafil 3 times/week. However, these findings should be considered at high RoB.

Placenta-anchored tadalafil liposomes rescues intrauterine growth restriction through continuous placental blood perfusion improvement.

Physiological or pathological hypoperfusion of the placenta is one of the main causes of intrauterine growth restriction (IUGR) which poses a significant risk to the health of the fetus and newborn. Tadalafil, a 5-type phosphodiesterase inhibitor, has previously been found to improve the symptoms of IUGR in various clinical studies. Unfortunately, its clinical utility is hindered by its limited water solubility, rapid metabolism, and lack of specific distribution in target tissues rendering tadalafil unable to maintain long-term placental perfusion. In this study, iRGD-modified tadalafil-loaded liposomes (iRGD-lipo@Tad) featuring a size of approximately 480 nm were designed to rectify the shortcomings of tadalafil. The prepared iRGD-lipo@Tad exhibited superior stability, sustained drug release capacity, and low cytotoxicity. The fluorescence study, tissue slice study, and drug biodistribution study together demonstrated the placenta-anchored ability of iRGD-modified liposomes. This was achieved by a dual approach consisting of the iRGD-mediated placenta-targeting effect and special particle size-mediated placenta resident effect. The pharmacokinetic study revealed a significant improvement in the in vivo process of tadalafil encapsulated by the iRGD-modified liposomes. In comparison to the tadalafil solution, the peak plasma concentration of iRGD-lipo@Tad was significantly increased, and the area under the curve was increased by about 7.88 times. In the pharmacodynamic study, iRGD-lipo@Tad achieved a continuous and efficient improvement of placental blood perfusion. This was achieved by decreasing the ratio of plasma soluble fms-like tyrosine kinase to placental growth factor and increasing the levels of cyclic guanosine monophosphate and nitric oxide. Consequently, iRGD-lipo@Tad resulted in a significant increase in embryo weight and a reduction in the miscarriage rate of N-Nitro-L-arginine methyl ester-induced IUGR pregnant mice without detectable toxicity. In summary, the nanotechnology-assisted therapy strategy presented here not only overcomes the limitations of tadalafil in the clinical treatment of IUGR but also offers new avenues to address the treatment of other placenta-originated diseases.

Evaluation of Potential Urologic Prescription Drug Savings With Mark Cuban Cost Plus Drug Company.

INTRODUCTION: Mark Cuban Cost Plus Drug Company (MCCPDC) launched in 2022 with a goal to decrease prescription drug costs. Thus far, research has focused on possible savings if Medicare purchased its annual volume of drugs at MCCPDC prices. The aim of this study is to analyze if MCCPDC can offer savings directly to urologic patients compared with other mail-order pharmacies, local pharmacies, and with patients using health insurance. METHODS: Twelve drugs used to treat urological diseases available on MCCPDC were analyzed. Pricing data of 30-tab and 90-tab prescriptions from MCCPDC, other mail-order pharmacies, and local in-person pharmacies near our zip code 40508 (Lexington, Kentucky) were compiled. To compare if MCCPDC could offer savings to patients using health insurance to fill their prescriptions, out-of-pocket drug costs for patients from the 2020 and 2021 Medical Expenditure Panel Survey and the 2021 Medicare Part D spending data were extracted. RESULTS: Greater savings at MCCPDC were found at 90-tab prescriptions, but overall variability in prices existed. When comparing without health insurance, 9 of 12 drugs at MCCPDC were cheaper at 90 tabs with solifenacin and tadalafil saving $20 and $12 per prescription. When considering patients using insurance, abiraterone, sildenafil, and tadalafil offered savings on out-of-pocket costs at 30- and 90-tab prescriptions. CONCLUSIONS: MCCPDC may offer cheaper prices for patients filling urologic medications, especially at 90-tab prescriptions. This study is the first to show patients could save money using MCCPDC and has implications for physician counseling when prescribing common urologic drugs.

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

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

Tadalafil versus tamsulosin as combination therapy with 5-alpha reductase inhibitors in benign prostatic hyperplasia, urinary and sexual outcomes.

PURPOSE: To compare the urological and sexual outcomes of using either tamsulosin/finateride or tadalafil/finasteride as combination therapies in patients with large prostate. PATIENTS AND METHODS: Selection criteria included prostate volume > 40 ml and IPSS > 7. Patients with severe erectile dysfunction (IIEF-erectile functions ≤ 10) were excluded. Patients were randomized into group I (tamsulosin/finasteride) and group II (tadalafil/finasteride). The primary endpoint was to define urinary and sexual function changes (IPSS, IPSS-quality of life, urinary flow rates and IIEF domains) within each group. The secondary endpoint was to compare the treatment induced changes between both groups. RESULTS: At 4th and 12th weeks, 131 and 127 patients were available in both groups, respectively. Both groups showed significant LUTS improvement (IPSS changes: - 4.9 ± 2.7 and - 4.3 ± 2.9 at 4th week and - 6.1 ± 3 and - 5.4 ± 2.8 points by the 12th week in both groups, respectively). Group I had better average flow rates at both follow-up visits. Meanwhile, maximum flow rates were comparable in both groups at 12th week (13.5 ± 3.9vs. 12.6 ± 3.7, p > 0.05). In group I, all IIEF domains were significantly lowered at both visits (p < 0.05). Group II showed significant increase in IIEF-erectile function scores (1.3 ± 1.1 and 1.8 ± 1.2 at the 4th and 12th weeks) with a transient significant reduction of IIEF-orgasm and sexual desire noted only by the 4th week (- 0.8 ± 0.4 and - 0.6 ± 0.4, respectively). CONCLUSION: Within three months, both combinations are comparably effective in improving BPH related LUTS. Tamsulosin/finasteride provided significantly better Qmax only at 4th week. Tadalafil/finasteride had the advantage of improving sexual performance over the other combination.

Novel drug therapy of acute hepatic failure induced in rats by a combination of tadalafil and Lepidium sativum.

BACKGROUND: Hepatocyte death and a systemic inflammatory response are the outcome of a complex chain of events mediated by numerous inflammatory cells and chemical mediators. The point of this study was to find out if tadalafil and/or Lepidium sativum (L. sativum) could help people who have been exposed to carbon tetrachloride (CCL4) and are experiencing acute moderate liver failure. This was especially true when the two were used together. METHOD AND MATERIALS: To cause mild liver failure 24 h before sacrifice, a single oral dosage of CCL4 (2.5 mL/kg b.w.) (50% in olive oil) was utilized. Furthermore, immunohistochemical expression of nuclear factor kappa B (NF-κB) as well as histological abnormalities were performed on liver tissue. RESULTS: The results showed that tadalafil and/or L. sativum, especially in combination, performed well to cure acute mild liver failure caused by CCL4. This was demonstrated by a decrease in NF-κB expression in the liver tissue and an improvement in organ damage markers observed in the blood and liver tissues. Furthermore, such therapy reduced interleukin1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the liver tissue. It's worth noting that the tested combination resulted in greater liver improvement. CONCLUSIONS: According to the findings, tadalafil and L. sativum, particularly in combination, have the ability to protect the liver from the negative effects of CCL4 exposure. Because of its capacity to improve liver function, restore redox equilibrium, and decrease inflammatory mediators, it is a prospective option for mitigating the negative effects of common environmental pollutants such as CCL4.