Safety and dose-finding trial of tadalafil administered for fetus in labor: A phase I clinical study.

AIM: This study aimed to investigate the safety and efficacy of tadalafil in protecting the fetus from hypoxic stress caused by repeated labor pains during delivery and preventing fetal hypoxic-ischemic encephalopathy. METHODS: The study used a three-case cohort approach. Three patients were administered 10 mg tadalafil and monitored for serious adverse events. In the absence of serious tadalafil-associated adverse events as assessed by the Safety Evaluation Committee, three new patients were added to the study and treated with 20 mg/dose. The blood levels of tadalafil were recorded before and after 2, 4, 8, and 12 h of administration and 2 h after delivery. RESULTS: A total of seven patients were enrolled, and after excluding one patient who delivered before 37 weeks, tadalafil was administered to six patients. Maternal adverse events were considered acceptable from the maternal perspective, with grade 1 headache, anorexia, and myalgia and no obstetrical complications after delivery at both doses. No serious neonatal adverse events were associated with tadalafil. Tadalafil blood levels remained stable at both doses. In addition, the level of soluble fms-like tyrosine kinase-1 did not alter, while that of the placental growth factor differed significantly before and after tadalafil administration. CONCLUSIONS: The study confirmed the safety of tadalafil administration during delivery for both mothers and newborns. The stable tadalafil blood levels confirmed the efficacy of the tested administration regime at 12 h interval. These findings would assist in conducting phase II trials to further verify the optimal dose and safety of tadalafil.

Oral phosphodiesterase type 5 inhibitors and priapism: A VigiBase analysis.

PURPOSE: To explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs). METHODS: We queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the adverse drug reactions (ADR) with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the reporting odds ratio (ROR) of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients. RESULTS: From a total of 133 819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n = 550, 0.41%; intracavernousal drugs: n = 82, 9.92%). Priapism disproportionality signals from intracavernousal drugs were 25 times stronger than PDE5is (ROR = 34.7; confidence interval [CI] 95%: 27.12-43.94 vs. ROR = 1.38; 95% CI: 1.24-1.54). For all PDE5i agents, the 12-17 years age group had the highest ROR (9.49, 95% CI: 3.76-19.93) followed by 2-11 years (4.31, 95% CI: 1.57-9.4). Disproportionality signals for consumers under 18 for both all PDE5is as a whole (ROR = 4.57, 95% CI: 2.48-7.73) and sildenafil (ROR = 4.89, 95% CI: 2.51-8.62) were stronger than individuals 18 or older (ROR = 1.06, 95% CI: 0.93-1.21 and ROR = 1.08, 95% CI: 0.91-1.26, respectively). CONCLUSIONS: PDE5i use shows disproportionate priapism signals which are higher in young patients.

Erectile response profiles of men using PDE5 inhibitors combined with intracavernosal injections as part of a penile rehabilitation program after radical prostatectomy.

BACKGROUND: Phosphodiesterase type 5 (PDE5) inhibitor labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism occurring. AIM: We explored the risk of priapism and prolonged erections in men in our post-radical prostatectomy (RP) penile injection program who were using regular PDE5 inhibitor and intracavernosal injections (ICIs) as part of their rehabilitation program. METHODS: The study cohort included men on penile injection therapy who (1) were taking tadalafil 5 mg daily or taking sildenafil 25 mg on noninjection days, (2) had an RP, (3) were using their respective PDE5 inhibitor regularly at the time of penile injection training, and (4) complied with the program instructions regarding penile injection use. Demographics, comorbidity details, PDE5 inhibitor dose and utilization, and injection dose and utilization data were collected. All patients underwent in-office injection training and used trimix (papaverine/phentolamine/prostaglandin E1) as the intracavernosal medication. OUTCOMES: Priapism was defined as a patient self-reported penetration hardness erection ≥4 hours in duration, while prolonged erection was defined as a penetration hardness erection lasting ≥2 hours. RESULTS: A total of 112 tadalafil users and 364 sildenafil users were compared. Mean age and duration post-RP were 62 ± 14 years and 5.2 ± 12 months, respectively, and there was no difference between tadalafil and sildenafil groups. The mean trimix dose was tadalafil 24 ± 24 units and sildenafil 31 ± 37 units (P < .05). Priapism occurred in 2 (1.7%) of 112 tadalafil users and 5 (1.4%) of 364 sildenafil users (P = .47). Excluding those men experiencing priapism on any occasion, those with any reported penetration hardness erection lasting ≥2 hours were 7 (6.3%) of 112 tadalafil users and 12 (3.3%) of 364 sildenafil users (P < .01). A total of 53% of these prolonged erections occurred within the first 6 injections at home (no difference between tadalafil and sildenafil groups). CLINICAL IMPLICATIONS: We emphasize the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events in ICI and PDE5 inhibitor combination therapy. STRENGTHS & LIMITATIONS: This study has a relatively large patient population with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. However, there are some limitations, such as social desirability, confounding factors, and recall bias. CONCLUSION: There is no significant difference in the incidence of priapism in an ICI program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase.

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. MATERIALS AND METHODS: The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. RESULTS: After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. CONCLUSIONS: PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

Sildenafil Vs. Tadalafil for The Treatment of Benign Prostatic Hyperplasia: A Single-arm Self-controlled Clinical Trial.

PURPOSE: To compare the efficacy and adverse events of sildenafil monotherapy for benign prostatic hyperplasia (BPH) with its FDA-approved counterpart, tadalafil. MATERIALS AND METHODS: In this single-arm self-controlled clinical trial, 33 patients were enrolled. All patients underwent a 6-week treatment with sildenafil, followed by a 4-week washout period and finally a 6-week treatment with tadalafil. Patients were examined on each appointment and post-void residual (PVR) urine, International Prostate Symptom Score (IPSS) and Quality of life index (IPSS-QoL index) were recorded subsequently. Efficacy of each drug regimen was then evaluated by comparing these outcome parameters. RESULTS: Both sildenafil and tadalafil were shown to improve PVR (both p < .001), IPSS (both p < .001) and IPSS- QoL index (both p < .001) significantly. Sildenafil was more effective than tadalafil in reducing PVR (mean difference (95%CI) = 9.91% (4.11, 15.72), p < .001) and ameliorating IPSS-QoL index (mean difference (95%CI) = 19.3% (4.47, 34.41), p = .027). Moreover, although not significant, sildenafil reduced IPSS more than tadalafil (mean difference (95%CI) = 3.33% (-0.22, 6.87), p = .065). Concurrent erectile dysfunction did not affect responsiveness to therapy with either sildenafil or tadalafil but age was inversely related to post-treatment IPSS in both sildenafil (B = 0.21 (0.04, 0.37), p = .015) and tadalafil (B = 0.14 (0.02, 0.26), p = .021) regimens with a more prominent role in responsiveness to sildenafil (ß = 0.31) compared to tadalafil (ß = 0.19). CONCLUSION: Considering the significantly better improvement of PVR and IPSS-Qol index with sildenafil, this drug can be nominated as a suitable alternative for tadalafil as a BPH treatment, especially in younger patients who don't have any contraindications.

Adverse reactions of PDE5 inhibitors: An analysis of the World Health Organization pharmacovigilance database.

BACKGROUND: Despite their efficacy and general safety, rare but devastating adverse drug reactions have been associated with phosphodiesterase type 5 inhibitors. OBJECTIVES: To determine the safety profile of oral phosphodiesterase type 5 inhibitors with a particular focus on priapism and malignant melanoma. MATERIALS AND METHODS: In this case-non-case study, we queried the individual case safety reports for phosphodiesterase type 5 inhibitors within the World Health Organization global database of individual case safety reports (VigiBase) between 1983 and 2021. We included all individual case safety reports for sildenafil, tadalafil, vardenafil, and avanafil in men. For comparison, we also extracted the safety data from the Food and Drug Administration trials for these drugs. We assessed the safety profile of phosphodiesterase type 5 inhibitors by disproportionality analysis by measuring reporting odds ratio for their most commonly reported adverse drug reactions, once for all phosphodiesterase type 5 inhibitor reports and once for reports of oral phosphodiesterase type 5 inhibitor use in adult men (≥18 years old) with sexual dysfunction. RESULTS: A total of 94,713 individual case safety reports for phosphodiesterase type 5 inhibitors were extracted. A total of 31,827 individual case safety reports were identified relating to adult men taking oral sildenafil, tadalafil, vardenafil, or avanafil for sexual dysfunction. The most common adverse drug reactions included poor drug efficacy (42.5%), headache (10.4% vs. 8.5%-27.6% [Food and Drug Administration]), abnormal vision (8.4% vs. ≤4.6% [Food and Drug Administration]), flushing (5.2% vs. 5.1%-16.5% [Food and Drug Administration]), and dyspepsia (4.2% vs. 3.4%-11.1% [Food and Drug Administration]). Priapism showed significant signals for sildenafil (reporting odds ratio = 13.81, 95% confidence interval: 11.75-16.24), tadalafil (reporting odds ratio = 14.54, 95% confidence interval: 11.56-18.06), and vardenafil (reporting odds ratio = 14.12, 95% confidence interval: 8.36-22.35). Comparing with other medications in VigiBase, sildenafil (reporting odds ratio = 8.73, 95% confidence interval: 7.63-9.99) and tadalafil (reporting odds ratio = 4.25, 95% confidence interval: 3.19-5.55) had significantly higher reporting odds ratios for malignant melanoma. CONCLUSION: Phosphodiesterase type 5 inhibitors show significant signals correlating with priapism among a large international cohort. Further clinical study is needed to elucidate whether this is from proper or inappropriate use or other confounding conditions, as analysis of pharmacovigilance data does not allow for quantifying the clinical risk. Also, there appears to be a relationship between phosphodiesterase type 5 inhibitor use and malignant melanoma, which warrants additional study to better understand causation.

Tadalafil Improves Haemodynamics and Arterial Stiffness but Not Flow- Mediated Dilation in Grade 1 Obesity. A Single-dose, Placebo-controlled Clinical Trial.

OBJECTIVE: Obesity, a major health issue worldwide, is associated with increased cardiovascular risk, endothelial dysfunction, and arterial stiffness. Tadalafil has been demonstrated to improve vascular parameters. AIM: To evaluate the effect of a single 20 mg dose of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. METHODS: A randomized, double-blind, placebo-controlled study was conducted on 80 participants (41 assigned to placebo and 39 to tadalafil) with grade 1 obesity, to evaluate the acute effect of a single dose of 20 mg of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. RESULTS: Tadalafil did not modify flow-mediated dilation. However, it significantly lowered systolic blood pressure (SBP) (130.6±17.1 vs. 125.0±12.7 mmHg, p=0.011), diastolic blood pressure (82.7±18.2 vs. 76.5±11.8 mmHg, p≤0.001), central systolic blood pressure (116.33±19.16 vs. 109.90±15.05 mmHg, p=0.001), the augmentation index (69.1±17.1 vs. 65.7±14.4, p=0.012), and brachial-ankle pulse wave velocity (1229.7±218.4 vs. 1164.0±181.7, p=0.001). CONCLUSION: A single dose of tadalafil did not modify flow-mediated dilation in patients with grade 1 obesity but improved blood pressure and brachial-ankle pulse wave velocity.

Effects of furosemide and tadalafil in both conventional and nanoforms against adenine-induced chronic renal failure in rats.

BACKGROUND: Chronic renal failure (CRF) is a progressive loss of renal function that lead to reduced sodium filtration and inappropriate suppression of tubular reabsorption that ultimately leads to volume expansion. The aim of this study was to study the efficacy of furosemide and tadalafil nanoforms compared to conventional forms against adenine-induced CRF rat-model. METHODS: Addition of 0.75% adenine to the diet of rats for 4 weeks gained general acceptance as a model to study kidney damage as this intervention mimicked most of the structural and functional changes seen in human chronic kidney disease Urine analysis, histopathological changes and immunohistochemical expression of caspase-3 and interleukin-1 beta (IL-1ß) in renal tissues were performed. RESULTS: Our results showed that the combination of tadalafil and furosemide using conventional and nanoparticle formulations had better renoprotective effect than individual drugs. This was demonstrated by improvement of urinary, serum and renal tissue markers as indicative of organ damage. This was also reflected on the reduction of tubular expression of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Immunohistochemical studies showed that the deteriorated renal cellular changes indicated by increased expression of caspase-3 and IL-1ß were greatly improved by the combined treatment particularly with the nanoforms. CONCLUSIONS: The nanoforms of both furosemide and tadalafil had greater renopreventive effects compared with conventional forms against adenine-induced CRF in rats.

Bilateral neurosensory retinal detachment secondary to tadalafil treatment.

A 53-year-old male with no systemic disorders, other than controlled arterial hypertension, presented with asymptomatic, bilateral neurosensory retinal detachment (NRD) detected during a routine revision. The patient reported the use of tadalafil (a phosphodiesterase-5 inhibitor [PDE5I]) for erectile dysfunction. Following suspension of the drug, subretinal fluid reabsorption was confirmed, with the persistence of chronic alterations in the optical coherence tomography (OCT) and the visual field. PDE5Is have ocular side effects, including exudative retinal detachment. Although no direct causal relationship has been confirmed, PDE5 inhibition at chorioretinal level produces vasodilatation, increased choroid hydrostatic pressure, and exudation into the subretinal space. In cases of NRD, a thorough assessment of the drug treatment history is crucial. Patients who use PDE5I drugs should be alerted to their potential ocular side effects.

Maternal blood concentration of tadalafil in pregnancy: Comparison of pregnant and non-pregnant women.

OBJECTIVE: In this study, the drug kinetics of tadalafil were compared between pregnant and non-pregnant women to determine the ideal dosage to promote uterine blood flow. MATERIALS AND METHODS: We recruited five pregnant and five non-pregnant women, all of which were administered tadalafil (20 mg/day). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration. We investigated the side effects within 4 days of tadalafil administration and compared the cumulative frequency between the two groups. RESULTS: The mean area under the concentration-time curve and maximum blood concentration of tadalafil were not different between the pregnant and non-pregnant groups. Time to maximum blood concentration was delayed by 1 min on average in the pregnant group compared with the non-pregnant group. The cumulative frequency of side effects was significantly lower in the pregnant group than in the non-pregnant group (P = 0.026). No side effects were observed in either group after the fifth day of the tadalafil administration. CONCLUSION: Although there was no difference in maximum blood concentration between non-pregnant and pregnant women, the rate of side effects was lower in pregnant women than in non-pregnant women. Therefore, pregnant women may tolerate tadalafil better.

Desprendimiento neurosensorial retiniano bilateral secundario a tratamiento con tadalafilo / Bilateral neurosensory retinal detachment secondary to tadalafil treatment

Se presenta el caso de un varón de 53 años con desprendimiento retiniano neurosensorial (DNS) bilateral asintomático detectado en una revisión rutinaria. No se encontraron patologías sistémicas subyacentes, salvo hipertensión arterial controlada. En la anamnesis dirigida, el paciente reveló ingesta de tadalafilo, un inhibidor de la fosfodiesterasa 5 (IPDE5) utilizado en el tratamiento de la disfunción eréctil. Tras la retirada del fármaco, se observó una reabsorción del fluido subretiniano con persistencia de alteraciones crónicas y campimétricas en la tomografía de coherencia óptica (OCT). Los IPDE5 presentan efectos secundarios oculares entre los que se ha descrito el desprendimiento seroso retiniano. Aunque no se ha podido comprobar la relación causal directa, la inhibición de la fosfodiesterasa 5 (PDE5) a nivel coriorretiniano produce vasodilatación, aumento de la presión hidrostática coroidea y exudación al espacio subretiniano. En casos de DNS, es fundamental una historia farmacoterapéutica completa. Se debería advertir de los posibles efectos secundarios oculares de los IPDE5 a los pacientes usuarios de este tipo de fármacos (AU)

A 53-year-old male with no systemic disorders, other than controlled arterial hypertension, presented with asymptomatic, bilateral neurosensory retinal detachment (NRD) detected during a routine revision. The patient reported the use of tadalafil (a phosphodiesterase-5 inhibitor [PDE5I]) for erectile dysfunction. Following suspension of the drug, subretinal fluid reabsorption was confirmed, with the persistence of chronic alterations in the optical coherence tomography (OCT) and the visual field. PDE5Is have ocular side effects, including exudative retinal detachment. Although no direct causal relationship has been confirmed, PDE5 inhibition at chorioretinal level produces vasodilatation, increased choroid hydrostatic pressure, and exudation into the subretinal space. In cases of NRD, a thorough assessment of the drug treatment history is crucial. Patients who use PDE5I drugs should be alerted to their potential ocular side effects (AU)

Analysis of integrated clinical safety data of tadalafil in patients receiving concomitant antihypertensive medications.

This pooled safety analysis assessed the incidence of hypotension-related treatment-emergent adverse events (TEAEs) and major adverse cardiovascular events (MACEs) in patients with concomitant use of tadalafil and antihypertensive medications. Data were pooled from seventy-two Phase II-IV studies conducted on patients with a diagnosis of erectile dysfunction (ED) and/or benign prostate hyperplasia (BPH). Studies were categorized as either All placebo-controlled studies or All studies. The incidences of hypotension-related TEAEs and MACEs were analyzed by indication; by use of concomitant antihypertensive medications; and by the number of concomitant antihypertensive medications. A total of 15 030 and 22 825 patients were included in the analyses for All placebo-controlled studies and All studies, respectively. In the All placebo-controlled studies, the incidence of hypotension-related TEAEs and MACEs was ranging between 0.6-1.5% and 0.0-1.0%, respectively, across all indications. Tadalafil was associated with an increase in hypotension-related TEAEs only in the ED as-needed group not receiving any concomitant antihypertensive medications (p-value = .0070); no significant difference was reported between placebo and tadalafil in the groups of patients receiving ≥1 antihypertensive medication (p-values ≥ .7386). Similarly, no significant differences (p-values≥ .2238) were observed in the incidence of MACEs between tadalafil and placebo treatment groups, with or without concomitant use of antihypertensive medications, and across all indication categories. In the All studies group, results were similar. The pooled analysis showed no evidence that taking tadalafil alongside antihypertensive medications increases the risk of hypotension-related TEAEs or MACEs compared with antihypertensive medications alone.

Recreational Use of Oral PDE5 Inhibitors: The Other Side of Midnight.

BACKGROUND: Nowadays, Oral phosphodiesterase type 5 inhibitors (PDE5Is) are widely used for the treatment of erectile dysfunction (ED). However, these drugs have become abused among some men for recreational use to enhance their sexual performance. OBJECTIVE: To shed a light on the recreational use of oral PDE5Is. METHODS: A literature review was performed in the PubMed, Medline Medical Subject Heading, Science Direct, Scopus, Cochrane Library, EMBASE, CINAHL, Academic Search Complete, Google scholar, Egyptian Knowledge Bank (EKB) databases, Medline, Embase, and Chem ID using the keywords; sexual health, erectile dysfunction, recreational use/abuse, phosphodiesterase type 5 inhibitors, sildenafil, tadalafil, vardenafil, avanafil, and adverse effects. RESULTS: Overall, 52 studies were retained for review out of 166 papers. Twenty-two studies that assessed the prevalence of the problem were investigated including 25,279 men from different countries. Most of these studies were cross-sectional studies that depend on multiple questionnaires representing the extent as well as the attitude of the recreational use of PDE5Is. CONCLUSION: Oral PDE5Is have become used among some men for recreational use to enhance their sexual performance. To counteract the possible side effects of such abuse, the media, as well as health authorities, should be aware of the potential adverse effects of such abuse and strengthen the regulatory activity to protect the customers from such risks. Mostafa T, Alghobary MF. Recreational Use of Oral PDE5 Inhibitors: The Other Side of Midnight. Sex Med Rev 2022;10:385-395.

Population Pharmacokinetics of Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension: A Combined Adult/Pediatric Model.

BACKGROUND: Tadalafil 40 mg once daily is approved for adult patients with pulmonary arterial hypertension (PAH). To investigate and potentially fulfill an unmet need in pediatric patients with PAH, pharmacokinetic (PK) data were explored in a pediatric phase Ib/II study and pooled with prior phase III (pulmonary arterial hypertension and response to tadalafil [PHIRST-1]) adult data to develop the first population PK model for tadalafil in pediatric patients with PAH. METHODS: H6D-MC-LVIG (NCT01484431) was an open-label, multicenter, multiple ascending dose study in pediatric patients with PAH, while PHIRST-1 was a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel design study in adults with PAH who received one of five treatments (tadalafil 2.5, 10, 20, or 40 mg, or placebo orally, once daily). PK data from the studies were pooled to develop a pediatric population PK model for tadalafil that characterized relationships among dose, exposure, and the effects of covariates with an aim to develop a population PK model that could simulate concentration-time profiles and assess exposure-matched dosing strategies in a pediatric PAH population. RESULTS: In line with the observed data, modeling and simulation demonstrated that the doses studied in the pediatric population produced area under the concentration-time curves (AUCs) within the range of those associated with improved exercise ability in adults with PAH. The analyses included 1430 observations from 305 adult patients (PHIRST-1: 69 males and 236 females, 1102 observations) and 19 pediatric patients (LVIG: 6 males and 13 females, 328 observations) who received tadalafil once daily at different dose levels. The best-fit base model retained an effect of weight on apparent volume of distribution (V/F), fixed to the allometric scaling value of 1, and did not include an effect of weight on apparent clearance (CL/F). Other covariate effects were that bosentan increased CL/F, V/F decreased with decreasing body weight, and bioavailability (F) decreased with increasing dose and decreasing age. The PK model reliably predicted the observed concentrations and overall variability evident from the overlap of the individual observed concentrations with the distributions of simulated concentrations. CONCLUSIONS: A one-compartment model parameterized in terms of F, absorption rate constant, CL/F, and V/F described the data well. The model demonstrated that plasma tadalafil concentrations in pediatric patients aged 2 to < 18 years were similar to those in adults at similar doses, and confirmed that dosing of 40 mg once daily in pediatric patients with a bodyweight ≥ 40 kg, and a dose of 20 mg once daily in patients with a body weight < 40 kg and aged ≥ 2 years are suitable for phase III evaluation. TRIAL REGISTRATION NUMBER (DATE OF REGISTRATION): LVIG: ClinicalTrials.gov identifier: NCT01484431 (2 December 2011). PHIRST-1: ClinicalTrials.gov identifier: NCT00125918 (2 August 2005).

Pharmacokinetic and Bioequivalence Evaluation of 2 Tadalafil Tablets in Healthy Male Chinese Subjects Under Fasting and Fed Conditions.

Tadalafil is an effective, reversible, and competitive phosphodiesterase 5 inhibitor mainly used to treat erectile dysfunction. This study investigated the bioequivalence of generic and marketed formulations of 10-mg tadalafil tablets under fasted and fed conditions. This open-label, randomized, single-dose, 2-period crossover study included 53 healthy Chinese men (aged 20-43 years). Plasma samples were collected from 0.5 hours before treatment to 72 hours after each dose and analyzed using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety assessments were performed throughout the study. For the fasted state, the 90% confidence intervals of the geometric mean ratios between the generic and marketed formulations were 86.1% to 99.1% for the maximum plasma concentration and 88.4% to 100.3% for the area under the plasma concentration-time curve from time 0 to infinity, and the corresponding values under the fed state were and 99.9% to 108.4% and 95.7% to 104.3%, respectively. All data were within the accepted bioequivalence range of 80% to 125%. After consuming high-fat, high-calorie meals in the fed condition, the time to the maximum plasma concentration was similar between the formulations, and area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration were 10.2% and 6.55% higher, respectively, for the marketed formulation. Thus, food had no clinically relevant effect on tadalafil exposure following a single oral dose in healthy Chinese men. No serious adverse reactions were reported. These results indicated that the analyzed generic and marketed tadalafil tablets were bioequivalent with similar safety profiles.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Influencing Factors for Erectile Dysfunction of Young Adults with No Response to PDE5i.

Erectile dysfunction (ED) is a common male disorder. Although orally-administered phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are now recognized as the primary pharmacological treatment method for ED, 20%-30% of the patients treated with PDE5 inhibitors exhibit no significant effects. This study aims to investigate the influencing factors of ED in young adults with no response to PDE5 inhibitors. ED patients who would take PDE5 inhibitors were included and investigated with a questionnaire. Patients with no response to PDE5 inhibitors (tadalafil and sildenafil) served as study group, and those with response to PDE5 inhibitors as control group. Then Chi square test and logistic regression analysis were applied to find the potential influencing factors. In total, 378 ED patients were included. Ninety-three (24.6%) cases were non-responsive to PDE5 inhibitors, and the remaining 285 (75.4%) responded to PDE5 inhibitors. In multiple logistic regression analysis, we found that history of drinking (OR=3.152; 95%CI 1.672-6.975), spousal noncooperation (OR=2.994; 95%CI 1.589-5.638), number of fixed sex partners (OR=0.358; 95%CI 0.132-0.651), duration of ED (OR=3.356; 95%CI 1.352-8.333), and depression (OR=3.689; 95%CI 1.579-8.979) could be the influencing factors for ED patients' non-response to PDE5 inhibitors. In conclusion, history of drinking, spousal noncooperation, number of fixed sex partner, long duration of ED, and depression could be the influencing factors for ED patients' non-response to PDE5 inhibitors. Patients and doctors should pay attention to these factors.