ABSTRACT
Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFß1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFß1 suppression. Overall, TGFß1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process.
Subject(s)
Fibroblast Growth Factor 9 , Fibrosis , MicroRNAs , Phosphodiesterase 5 Inhibitors , Prostatic Hyperplasia , Tadalafil , Male , Prostatic Hyperplasia/metabolism , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Tadalafil/pharmacology , Phosphodiesterase 5 Inhibitors/pharmacology , Humans , Fibroblast Growth Factor 9/metabolism , Fibroblast Growth Factor 9/genetics , Prostate/drug effects , Prostate/metabolism , Myofibroblasts/metabolism , Myofibroblasts/drug effects , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/genetics , Cell Proliferation/drug effectsABSTRACT
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.
Subject(s)
Anti-Anxiety Agents , Antidepressive Agents , Brain-Gut Axis , Encephalomyelitis, Autoimmune, Experimental , Gastrointestinal Microbiome , Mice, Inbred C57BL , Phosphodiesterase 5 Inhibitors , Tadalafil , Animals , Tadalafil/pharmacology , Tadalafil/therapeutic use , Phosphodiesterase 5 Inhibitors/pharmacology , Phosphodiesterase 5 Inhibitors/therapeutic use , Mice , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Gastrointestinal Microbiome/drug effects , Brain-Gut Axis/drug effects , Brain-Gut Axis/physiology , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Female , Depression/drug therapy , Autoimmunity/drug effectsABSTRACT
OBJECTIVE: To assess the clinical effect and safety of comprehensive therapy of traditional Chinese medicine (TCM) in the treatment of erectile dysfunction (ED) with damp-heat stasis. METHODS: We selected 108 cases of ED with damp-heat stasis meeting the inclusion criteria and treated with tadalafil (the control group, n = 54) or tadalafil + comprehensive TCM therapy (the trial group, n = 54) in the First Affiliated Hospital of Henan University of Chinese Medicine in the same period. After 8 weeks of treatment, we recorded the patients' scores on IIEF-5, TCM syndrome, erectile quality (EQS), 9-Item Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Scale 7 (GAD-7). At 16 weeks of our study, we collected the efficacy parameters, safety indicators and adverse reactions by telephone follow-up and compared the data obtained between the two groups of patients. RESULTS: Totally, 103 of the patients completed the study, 51 in the control and 52 in the trial group. Compared with the baseline, the IIEF-5 and EQS scores were both markedly increased after 8 weeks of treatment in the trial group (12.35±3.00 vs 18.36±2.82, P< 0.05; 39.5 ï¼»30.25ï¼43ï¼½ vs 67.5 ï¼»54.5ï¼76.75ï¼½, P< 0.05) and the control (11.96±2.79 vs 15.88±3.86, P< 0.05; 38.0 ï¼»29ï¼42ï¼½ vs 56 ï¼»49ï¼64ï¼½, P< 0.05), even more significantly in the former than in the latter (P< 0.05); the TCM syndrome and GAD-7 scores were remarkably decreased in the trial (9.5 ï¼»8ï¼12ï¼½ vs 4.0 ï¼»2.25ï¼5ï¼½, P< 0.05; 5 ï¼»2.25ï¼6.75ï¼½ vs 2.5 ï¼»1ï¼4.75ï¼½, P< 0.05) and the control group (10.0 ï¼»8ï¼12ï¼½ vs 5.0 ï¼»3ï¼6ï¼½, P< 0.05; 5.0 ï¼»3ï¼6ï¼½ vs 4.0 ï¼»2ï¼5ï¼½, P< 0.05), even more significantly in the former than in the latter (P< 0.05), so were the PHQ-9 scores (P< 0.05), but with no statistically significant difference between the two groups (P > 0.05). The IIEF-5 scores of the two groups remained significantly higher than the baseline during the follow-up (P< 0.05), even higher in the trial than in the control group (17.04±2.60 vs 14.16±3.34, P< 0.05). No obvious abnormal safety indicators or adverse events were observed during the study. CONCLUSION: Comprehensive TCM therapy combined with tadalafil is superior to tadalafil alone in the treatment of ED with damp-heat stasis, and has a better long-term efficacy and a higher safety.
Subject(s)
Drugs, Chinese Herbal , Erectile Dysfunction , Medicine, Chinese Traditional , Tadalafil , Humans , Male , Erectile Dysfunction/drug therapy , Erectile Dysfunction/therapy , Medicine, Chinese Traditional/methods , Tadalafil/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Treatment Outcome , Surveys and Questionnaires , Middle AgedABSTRACT
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.
Subject(s)
Hypertension, Pulmonary , Leukemia, Large Granular Lymphocytic , Humans , Aged , Female , Leukemia, Large Granular Lymphocytic/complications , Leukemia, Large Granular Lymphocytic/diagnosis , Leukemia, Large Granular Lymphocytic/drug therapy , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/diagnosis , Hemodynamics/physiology , Tadalafil/therapeutic use , Cyclophosphamide/therapeutic use , Pyrimidines/therapeutic use , Sulfonamides/therapeutic useABSTRACT
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.
Subject(s)
Cichlids , Microplastics , Tadalafil , Water Pollutants, Chemical , Animals , Tadalafil/pharmacology , Cichlids/metabolism , Water Pollutants, Chemical/toxicity , Microplastics/toxicity , Antioxidants/metabolism , Tilapia/metabolism , Glutathione/metabolism , Glutathione/blood , Gills/drug effects , Gills/metabolism , Oxidative Stress/drug effectsABSTRACT
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.
Subject(s)
Erectile Dysfunction , Phosphodiesterase 5 Inhibitors , Tadalafil , Humans , Male , Tadalafil/therapeutic use , Tadalafil/administration & dosage , Erectile Dysfunction/drug therapy , Adult , Phosphodiesterase 5 Inhibitors/therapeutic use , Phosphodiesterase 5 Inhibitors/adverse effects , Phosphodiesterase 5 Inhibitors/administration & dosage , Penile Erection/drug effects , Recovery of Function , Middle Aged , Drug Administration ScheduleABSTRACT
BACKGROUND: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension. METHODS: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline. RESULTS: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P=0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P=0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group. CONCLUSIONS: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points. REGISTRATION: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.
Subject(s)
Heart Failure , Hypertension, Pulmonary , Phosphodiesterase 5 Inhibitors , Stroke Volume , Tadalafil , Humans , Tadalafil/therapeutic use , Heart Failure/drug therapy , Heart Failure/mortality , Heart Failure/physiopathology , Male , Female , Stroke Volume/drug effects , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/mortality , Hypertension, Pulmonary/physiopathology , Aged , Middle Aged , Double-Blind Method , Phosphodiesterase 5 Inhibitors/therapeutic use , Phosphodiesterase 5 Inhibitors/adverse effects , Treatment OutcomeABSTRACT
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.
Subject(s)
Area Under Curve , Cross-Over Studies , Drug Combinations , Food-Drug Interactions , Healthy Volunteers , Pyrimidines , Sulfonamides , Tablets , Tadalafil , Therapeutic Equivalency , Humans , Male , Adult , Pyrimidines/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/blood , Tadalafil/pharmacokinetics , Tadalafil/administration & dosage , Tadalafil/blood , Young Adult , Female , Sulfonamides/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/blood , Middle Aged , Administration, Oral , Fasting , AdolescentABSTRACT
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.
Subject(s)
Adverse Drug Reaction Reporting Systems , Databases, Factual , Eye Diseases , Pharmacovigilance , Phosphodiesterase 5 Inhibitors , Sildenafil Citrate , Tadalafil , Vardenafil Dihydrochloride , Humans , Phosphodiesterase 5 Inhibitors/adverse effects , Phosphodiesterase 5 Inhibitors/administration & dosage , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Tadalafil/adverse effects , Tadalafil/administration & dosage , Sildenafil Citrate/adverse effects , Sildenafil Citrate/administration & dosage , Male , Vardenafil Dihydrochloride/adverse effects , Vardenafil Dihydrochloride/administration & dosage , Eye Diseases/chemically induced , Eye Diseases/epidemiology , United States/epidemiology , Middle Aged , Aged , AdultABSTRACT
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.
Subject(s)
Celecoxib , Drug Stability , Nucleotides , Solubility , Water , Water/chemistry , Nucleotides/chemistry , Celecoxib/chemistry , Tadalafil/chemistry , Chemistry, Pharmaceutical/methods , Mebendazole/chemistry , Drug LiberationABSTRACT
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.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 5 , Vomeronasal Organ , Animals , Vomeronasal Organ/metabolism , Mice , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5/genetics , Male , Phosphodiesterase 5 Inhibitors/pharmacology , Tadalafil/pharmacology , Sildenafil Citrate/pharmacology , Pheromones/metabolism , Aggression/physiology , Female , Mice, Inbred C57BLABSTRACT
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.
Subject(s)
Dietary Supplements , Honey , Magnetic Resonance Spectroscopy , Honey/analysis , Dietary Supplements/analysis , Magnetic Resonance Spectroscopy/methods , Sildenafil Citrate/analysis , Workflow , Chemometrics/methods , Tadalafil/analysis , Least-Squares Analysis , Drug Contamination/prevention & control , Discriminant AnalysisABSTRACT
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 â¼15-75 min (TAD 1) and â¼75-135 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 Ì 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 ${D_{{{\mathrm{O}}_2}}}$ .
Subject(s)
Oxygen , Placenta , Placental Circulation , Tadalafil , Uterine Artery , Animals , Female , Tadalafil/pharmacology , Tadalafil/administration & dosage , Pregnancy , Sheep , Uterine Artery/drug effects , Placenta/drug effects , Placenta/blood supply , Placental Circulation/drug effects , Oxygen/blood , Regional Blood Flow/drug effects , Phosphodiesterase 5 Inhibitors/pharmacology , Phosphodiesterase 5 Inhibitors/administration & dosage , Magnetic Resonance Imaging , Fetus/blood supply , Fetus/drug effectsABSTRACT
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.
Subject(s)
Erectile Dysfunction , Phosphodiesterase 5 Inhibitors , Tadalafil , Humans , Male , Tadalafil/therapeutic use , Tadalafil/administration & dosage , Double-Blind Method , Middle Aged , Phosphodiesterase 5 Inhibitors/therapeutic use , Phosphodiesterase 5 Inhibitors/administration & dosage , Combined Modality Therapy , Erectile Dysfunction/drug therapy , Erectile Dysfunction/therapy , Extracorporeal Shockwave Therapy/methods , Treatment Outcome , Adult , Impotence, Vasculogenic/therapy , Impotence, Vasculogenic/drug therapy , Severity of Illness IndexABSTRACT
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.
Subject(s)
Erectile Dysfunction , Lymphocytes , Neutrophils , Phosphodiesterase 5 Inhibitors , Tadalafil , Humans , Male , Tadalafil/therapeutic use , Tadalafil/administration & dosage , Erectile Dysfunction/drug therapy , Prospective Studies , Middle Aged , Phosphodiesterase 5 Inhibitors/therapeutic use , Phosphodiesterase 5 Inhibitors/administration & dosage , Blood Platelets/drug effects , Adult , Platelet Count , Lymphocyte Count , Leukocyte CountABSTRACT
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.
Subject(s)
Anxiety , COVID-19 , Depression , Erectile Dysfunction , Tadalafil , Humans , Male , Tadalafil/therapeutic use , Tadalafil/administration & dosage , Erectile Dysfunction/drug therapy , COVID-19/complications , Middle Aged , Depression/drug therapy , Anxiety/drug therapy , Adult , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/therapeutic use , Time Factors , Penile Erection/drug effects , AgedABSTRACT
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.
Subject(s)
Erectile Dysfunction , Phosphodiesterase 5 Inhibitors , Tablets , Tadalafil , Humans , Tadalafil/administration & dosage , Male , Erectile Dysfunction/drug therapy , Middle Aged , Adult , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/adverse effects , Administration, Oral , Treatment Outcome , Severity of Illness Index , Double-Blind MethodABSTRACT
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.
Subject(s)
Erectile Dysfunction , Lower Urinary Tract Symptoms , Prostatic Hyperplasia , Male , Humans , Prostatic Hyperplasia/complications , Prostatic Hyperplasia/drug therapy , Drug Therapy, Combination , Erectile Dysfunction/drug therapy , Phosphodiesterase 5 Inhibitors/therapeutic use , Tadalafil/therapeutic use , Lower Urinary Tract Symptoms/etiology , Lower Urinary Tract Symptoms/complications , Adrenergic alpha-Antagonists/therapeutic use , Treatment OutcomeABSTRACT
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.
Subject(s)
Lower Urinary Tract Symptoms , Urethra , Female , Humans , Tadalafil/pharmacology , Tadalafil/therapeutic use , Cross-Over Studies , Urination , Lower Urinary Tract Symptoms/drug therapy , Double-Blind Method , Carbolines/pharmacology , Carbolines/therapeutic useABSTRACT
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.