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Frontiers in Pharmacology 2022The potential role of tadalafil, a PDE5 inhibitor, in anticancer activity and prolonged survival has been proposed. However, the systematic effects of tadalafil in...
The potential role of tadalafil, a PDE5 inhibitor, in anticancer activity and prolonged survival has been proposed. However, the systematic effects of tadalafil in colorectal cancer were not fully understood. In this study, we assessed the anti-tumor activity of tadalafil in human colorectal cancer cells. A systematic perspective of the tadalafil-induced anti-tumor mechanism was provided by the integration of transcriptomics and metabolomics. We found that differentially expressed genes (DEGs) were mainly involved in microRNAs in cancer, purine metabolism, glycosphingolipid biosynthesis, arginine biosynthesis, and amino acid metabolism. Amino acid metabolism, especially alanine, aspartate, and glutamate metabolism was the most of the differentially accumulated metabolites (DAMs) through the analysis of metabolomics. The conjoint analysis of DEGs and DAMs presented that they were also mainly involved in alanine, aspartate, and glutamate metabolism. Amino acid metabolism-related genes, , were significantly decreased after tadalafil treatment. In particular, the disturbance of alanine, aspartate, and glutamate metabolism may be the explanation for the major mechanism resulting from tadalafil anti-tumor activity.
PubMed: 35694253
DOI: 10.3389/fphar.2022.793499 -
Turkish Journal of Urology Dec 2017To evaluate the safety and efficacy of silodosin and tadalafil in ease of negotiation of large size ureteroscope (8/9.8 Fr) in the management of ureteral stone.
OBJECTIVE
To evaluate the safety and efficacy of silodosin and tadalafil in ease of negotiation of large size ureteroscope (8/9.8 Fr) in the management of ureteral stone.
MATERIAL AND METHODS
Between June 2015 and May 2016, 86 patients presented with ureteral stone of size 6-15 mm were on consent randomly assigned to 1 of 3 outpatient treatment arms: silodosin (Group A), tadalafil (Group B), and placebo (Group C). After two weeks of therapy 67 patients underwent ureteroscopy, and ureteral orifice configuration, ureteroscopic negotiation, ureteral dilatation, operating time, procedural complication and drug related side effects were noted in each group.
RESULTS
Ureteral negotiation was significantly better in Groups A (73.9%) and B (69.6%) as compared to Group C (38.1%) (p<0.01). Statistically significant difference was noted in the requirement for dilatation in Group C (71.4%) as compared to Groups A (26.1%) and B (39.1%) (p<0.01). Ureteral orifice was found to be more dilated in Groups A (69.6%) and B (60.9%) as compared to Group C (28.6%). Mean operating time was statistically lower in Groups A (35.2 min) and B (34.91 min) as compared to Group C (41.14 min) (p<0.01).
CONCLUSION
Both silodosin and tadalafil not only relax ureteral smooth muscle but also help in forward propagation of large size ureteroscope (8/9.8 Fr) without any significant risk of adverse events.
PubMed: 29201512
DOI: 10.5152/tud.2017.83548 -
PloS One 2023Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have...
A case-control study of phosphodiesterase-5 inhibitor use and Alzheimer's disease and related dementias among male and female patients aged 65 years and older supporting the need for a phase III clinical trial.
BACKGROUND
Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions.
METHODS
We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old.
RESULTS
Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension.
CONCLUSIONS
Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.
Topics: Aged; Female; Humans; Male; Alzheimer Disease; Case-Control Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin Receptor Antagonists; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil
PubMed: 37851623
DOI: 10.1371/journal.pone.0292863 -
Medicina (Kaunas, Lithuania) Oct 2019Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine...
Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine the ideal dosage to promote uterine blood flow. Materials and Methods: We recruited five pregnant women with FGR or preeclampsia before administration of tadalafil, all of which were administered tadalafil (20 mg/day, once-daily dosing). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration, and uterine blood flow was measured before tadalafil administration and 2-4 and 20-24 h after. We then analyzed the correlation between tadalafil blood concentration and uterine artery blood flow. The blood concentration of tadalafil correlated with uterine artery blood flow in pregnant women. The blood concentration of tadalafil and uterine artery blood flow decreased 5 h after administration of tadalafil. The blood concentration of tadalafil and uterine artery blood flow fluctuate in parallel, the latter was decreased by reduced blood concentration. Thus, a study of tadalafil administered twice a day in pregnant women will be needed to stabilize uterine artery blood flow.
Topics: Adult; Blood Circulation; Drug Administration Schedule; Female; Fetal Growth Retardation; Humans; Pre-Eclampsia; Pregnancy; Tadalafil; Ultrasonography, Doppler; Ultrasonography, Prenatal; Uterine Artery; Uterus; Vasodilator Agents; Young Adult
PubMed: 31640235
DOI: 10.3390/medicina55100708 -
Drug Design, Development and Therapy 2022The combined administration of tadalafil, a phosphodiesterase-5 inhibitor, and amlodipine, a calcium channel blocker, can be a promising therapeutic option for... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The combined administration of tadalafil, a phosphodiesterase-5 inhibitor, and amlodipine, a calcium channel blocker, can be a promising therapeutic option for hypertension patients with erectile dysfunction. This study aimed to examine the pharmacokinetic drug interaction between tadalafil and amlodipine and the tolerability of their combined administration in healthy male subjects.
SUBJECTS AND METHODS
Healthy volunteers (N = 24) were randomly assigned to one of the six sequences that consisted of three treatments: tadalafil (5 mg) alone, amlodipine (10 mg) alone, and tadalafil plus amlodipine. The study drugs were administered orally for 9 d, and the collected serial blood samples were analyzed up to 72 h after the last dosing. Pharmacokinetic parameters were calculated using non-compartmental analysis.
RESULTS
For tadalafil, geometric mean ratios (GMRs) (90% confidence interval (CI)) of the combined therapy over the monotherapy were 1.57 (1.46-1.68) for AUC and 1.34 (1.24-1.45) for C. For amlodipine, the GMRs (90% CI) of AUC and C were 0.93 (0.90-0.97) and 0.95 (0.91-0.99), respectively. The severity of all observed adverse events (AEs) related to the study drugs was mild, and the frequency of AEs of the combined administration was not significantly different from the monotherapy.
CONCLUSION
A substantial pharmacokinetic drug interaction between tadalafil and amlodipine was observed with respect to the concentration of tadalafil when administered concomitantly. However, the dose range of the combined administration of tadalafil and amlodipine in the present study was well tolerated by the subjects.
Topics: Administration, Oral; Amlodipine; Area Under Curve; Cross-Over Studies; Drug Interactions; Healthy Volunteers; Humans; Male; Tadalafil
PubMed: 35221673
DOI: 10.2147/DDDT.S348897 -
Frontiers in Endocrinology 2022This study aimed to evaluate two modes of Rigiscan for predicting tadalafil response, and to identify which Rigiscan variables are the most efficient at making these...
Selecting an Individualized Treatment Approach: The Predictive Value of Erotic Stimulation and Nocturnal Erections for Efficacy of Tadalafil and Cure in Patients With Erectile Dysfunction.
PURPOSE
This study aimed to evaluate two modes of Rigiscan for predicting tadalafil response, and to identify which Rigiscan variables are the most efficient at making these predictions.
METHODS
All patients received at least two rounds of nocturnal penile tumescence and rigidity (NPTR) testing and/or audiovisual sexual stimulation (AVSS), then completed the International Index of Erectile Function-5 (IIEF-5) questionnaire, followed by oral 5 mg tadalafil daily for 4 weeks. After a 4-week washout period, all respondents underwent an the IIEF-5 questionnaire again. ED patients were then categorized into tadalafil responders and tadalafil non-responders, who were then further divided into cured patients and uncured patients.
RESULTS
When predicting tadalafil responders, the area under the curve (AUC) of NPTR was superior to that of AVSS (0.68~0.84 VS 0.69~0.73), and the predicted optimal cut-off values were DOEE60≥17.75 min in NPTR, compared to other parameters regardless of AVSS or NPTR (P<0.05). When predicting which patients would be cured, the AUC of AVSS was superior to NPTR parameters (0.77~0.81 vs 0.61~0.76), and the determined best diagnostic cut-off values were DOEE≥4.125min in AVSS, compared to other parameters regardless of AVSS or NPTR (P < 0.05).
CONCLUSION
Rigiscan was able to predict the efficacy of daily tadalafil accurately and efficiently. Its diagnostic value was at maximum when DOEE60 ≥17.75 min of NPTR in tadalafil responders and DOEE ≥ 4.125 min of AVSS in cured patients.
Topics: Erectile Dysfunction; Humans; Male; Penile Erection; Tadalafil
PubMed: 35846318
DOI: 10.3389/fendo.2022.915025 -
International Journal of Molecular... Jan 2022Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no...
Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no effective intrauterine treatment method has been established. This study aimed to use tadalafil, a phosphodiesterase 5 inhibitor (PDE5) inhibitor, as a novel intrauterine treatment and conducted several basic and clinical studies. The study investigated the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR on 13 days post coitum (d.p.c.) but recovered to the same level as that of the control on 17 d.p.c. following tadalafil treatment. The results were similar for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) protein, which act downstream in the mTOR signaling pathway. We demonstrate that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and thus would be helpful for future clinical studies on FGR.
Topics: Animals; Female; Fetal Growth Retardation; Mice; NG-Nitroarginine Methyl Ester; Placenta; Pre-Eclampsia; Pregnancy; Signal Transduction; TOR Serine-Threonine Kinases; Tadalafil
PubMed: 35163395
DOI: 10.3390/ijms23031474 -
Journal of Pharmacological Sciences Jun 2022Podocyte injury is responsible for nephrotic syndrome. Previously, we found that tadalafil, a phosphodiesterase 5 inhibitor, might have protective effects on podocytes....
Podocyte injury is responsible for nephrotic syndrome. Previously, we found that tadalafil, a phosphodiesterase 5 inhibitor, might have protective effects on podocytes. Here, we investigated the effects of tadalafil in a nephrotic syndrome model and human podocyte cells. We divided adriamycin (ADR)-induced nephrotic syndrome model rats into the following groups: control + vehicle, control + tadalafil, ADR + vehicle, and ADR + tadalafil. The tadalafil-treated groups were orally administered 10 mg/kg tadalafil for 2 weeks. Renal parameters were measured. Immunohistology and immunofluorescence assays of glomerular injury were performed. Human primary podocytes were treated with or without tadalafil, and ADR. Cell viability and permeability assays were performed. ADR + vehicle exhibited severe proteinuria compared with control + vehicle and control + tadalafil. ADR + tadalafil attenuated proteinuria compared with ADR + vehicle. Wilms' tumor 1 (WT1) immunostaining revealed that the number of WT1-positive cells was decreased by ADR; however, this decrease was prevented by ADR + tadalafil. In human podocytes, tadalafil increased the viability of ADR-treated cells, which was abrogated by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Moreover, tadalafil prevented albumin permeability in ADR-treated cells. ADR treatment alone increased the permeability of albumin compared with the control. Tadalafil might inhibit kidney injury progression by preventing damage to podocytes and dysfunction of the glomerular filtration barrier.
Topics: Albumins; Animals; Doxorubicin; Female; Humans; Male; Nephrotic Syndrome; Podocytes; Proteinuria; Rats; Tadalafil
PubMed: 35512855
DOI: 10.1016/j.jphs.2022.03.003 -
European Journal of Pharmacology Dec 2023Recent studies suggest that lower urinary tract dysfunction may arise due to changes in local perfusion. Phosphodiesterase-5 inhibitors can improve urinary bladder blood...
Recent studies suggest that lower urinary tract dysfunction may arise due to changes in local perfusion. Phosphodiesterase-5 inhibitors can improve urinary bladder blood flow, although the local mechanisms have not been fully elucidated. The aim was to pharmacologically characterise the vascular supply to the bladder and determine the mechanisms underlying the effects of the phosphodiesterase-5 inhibitors tadalafil and sildenafil. Responses of isolated rings of porcine superior vesical arteries to electrical field stimulation (EFS) were measured in the absence and presence of inhibitors of key neurotransmitter systems. Vasodilation responses to nitric oxide (NO) donors were also recorded, and the effects of phosphodiesterase-5 inhibitors on all responses determined. EFS caused biphasic responses with an initial vasoconstriction and a slower developing vasodilation. Vasoconstriction was mediated by ATP (55%) and noradrenaline (45%) release, whilst vasodilation was reduced by L-NNA (100 μM) (80%) and propranolol (1 μM) (20%). The nitrergic component was inhibited (81%) by L-NPA, a selective inhibitor of neuronal nitric oxide synthase (nNOS). Endothelial removal did not affect vasodilation. Tadalafil and sildenafil depressed noradrenaline-evoked vasoconstriction (by 26.8% and 35.5% respectively, P < 0.01), enhanced vasodilation to EFS (by 27.8% and 51.8% respectively, p < 0.01) and enhanced responses to NO donors nitroprusside, SIN-1, and SNAP, increasing pIC values (P < 0.01), without affecting maximal responses. In conclusion, neuronal NOS has a predominant role in regulating vascular tone of the porcine superior vesical artery and potentiation of nNO-mediated vasodilation is the primary mechanism underlying effects of phosphodiesterase-5 inhibitors in the bladder vasculature.
Topics: Animals; Swine; Sildenafil Citrate; Tadalafil; Phosphodiesterase 5 Inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 5; Urinary Bladder; Vasodilation; Norepinephrine; Nitric Oxide
PubMed: 37925131
DOI: 10.1016/j.ejphar.2023.176152 -
International Journal of Molecular... Apr 2022Breast cancer seriously endangers women's health worldwide. Protein arginine methyltransferase 5 (PRMT5) is highly expressed in breast cancer and represents a potential...
Breast cancer seriously endangers women's health worldwide. Protein arginine methyltransferase 5 (PRMT5) is highly expressed in breast cancer and represents a potential druggable target for breast cancer treatment. However, because the currently available clinical PRMT5 inhibitors are relatively limited, there is an urgent need to develop new PRMT5 inhibitors. Our team previously found that the FDA-approved drug tadalafil can act as a PRMT5 inhibitor and enhance the sensitivity of breast cancer patients to doxorubicin treatment. To further improve the binding specificity of tadalafil to PRMT5, we chemically modified tadalafil, and designed three compounds, A, B, and C, based on the PRMT5 protein structure. These three compounds could bind to PRMT5 through different binding modes and inhibit histone arginine methylation. They arrested the proliferation and triggered the apoptosis of breast cancer cells in vitro and also promoted the antitumor effects of the chemotherapy drugs cisplatin, doxorubicin, and olaparib in combination regimens. Among them, compound A possessed the highest potency. Finally, the anti-breast cancer effects of PRMT5 inhibitor A and its ability to enhance chemosensitivity were further verified in a xenograft mouse model. These results indicate that the new PRMT5 inhibitors A, B, and C may be potential candidates for breast cancer treatment.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Enzyme Inhibitors; Female; Humans; Mice; Protein-Arginine N-Methyltransferases; Tadalafil
PubMed: 35563196
DOI: 10.3390/ijms23094806