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Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) re...
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Context 1
... of PDE5 inhibition is expressed as ratio between the IC 50 for a given PDE and the IC 50 for inhibition of PDE5. From the selectivity ratios listed in Table 2, it becomes obvious that potential side effects may arise from inhibition of PDE1, PDE6, or PDE11 during the pharmacotherapy with PDE5 inhibitors. [38][39][40] For PDE1, selectivity ratios for sildenafil and vardenafil are clearly below those of tadalafil, but have a relative wide margin of 41-136-fold selectiv- ity. ...
Context 2
... FDA recently reported a potential link between a small number of cases of vision loss owing to non-arteritic anterior ischemic optic neuropathy and the use of sildenafil, varde- nafil, and tadalafil. Tadalafil is clearly more selec- tive than either vardenafil or sildenafil towards PDE5 relative to PDE6 inhibition (Table 2). This difference in the selectivity ratio of tadalafil com- pared to sildenafil or vardenafil may account for the Pharmacokinetics and pharmacodynamics in PD-5 inhibitor therapy B Meibohm et al lower frequency of visual side effects with tadalafil (o0.1%) compared to sildenafil (e.g., color tinge to vision (chromatopsia), increased sensitivity to light or blurred vision in p3% of patients), or vardenafil (e.g. ...
Similar publications
There are no randomised and properly blinded trials directly comparing one PDE-5 inhibitor with another in a normal home setting. Valid indirect comparisons with a common comparator must examine equivalent doses, similar duration, similar populations, with the same outcomes reported in the same way.
Published randomised, double-blind trials of oral...
We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (...
Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation. Oral treatment with the drugs may be associated with adverse haemodynamic effects. We hypothesised that inhaled P...
One hundred and fifty dietary supplements (DS) marketed to increase sexual performance were analyzed. All these formulations were claimed to contain only natural compounds, plant extracts and/or vitamins. (1)H NMR spectroscopy was used for detecting the presence of adulterants and for their identification and quantification. Mass spectrometry was u...
Despite the marked adverse impacts of erectile dysfunction (ED) on quality of life and well-being, many patients (and/or their partners) do not seek medical attention for this problem, do not receive treatment or discontinue such treatment even when it has effectively restored erectile responses to sexual stimulation. Phosphodiesterase type 5 (PDE5...
Citations
... Nevertheless, both systems exhibited a proper potential for the ASX-controlled release applications, and this behaviour may be extended to other phytotherapeutics and other applications in which high initial concentrations must be avoided [21,49,50]. Additionally, a delayed release may be useful in applications that require a time gap before the full release of the entrapped compound, such as imagining diagnostics applications, among others [32]. ...
In recent years, composite biomaterials have attracted attention for drug delivery applications due to the possibility of combining desired properties of their components. However, some functional characteristics, such as their drug release efficiency and likely side effects, are still unexplored. In this regard, controlled tuning of the drug release kinetic via the precise design of a composite particle system is still of high importance for many biomedical applications. This objective can be properly fulfilled through the combination of different biomaterials with unequal release rates, such as mesoporous bioactive glass nanoparticles (MBGN) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microspheres. In this work, MBGNs and PHBV-MBGN microspheres, both loaded with Astaxanthin (ASX), were synthesised and compared in terms of ASX release kinetic, ASX entrapment efficiency, and cell viability. Moreover, the correlation of the release kinetic to phytotherapeutic efficiency and side effects was established. Interestingly, there were significant differences between the ASX release kinetic of the developed systems, and cell viability differed accordingly after 72 h. Both particle carriers effectively delivered ASX, though the composite microspheres exhibited a more prolonged release profile with sustained cytocompatibility. The release behaviour could be fine-tuned by adjusting the MBGN content in the composite particles. Comparatively, the composite particles induced a different release effect, implying their potential for sustained drug delivery applications.
... The maximum plasma concentrations are achieved about 1-2 h after administration. However, the bioavailability of PDE5 inhibitors after oral administration is limited due to the hepatic first-pass metabolism by CYP3A5 and/ or CYP3A4 (Mehrotra et al. 2007). Moreover, PDE5 inhibitors have active metabolites that contribute to the overall efficacy of these drugs (Cheitlin et al. 1999). ...
Peptic ulcer disease (PUD) continues to be a cause of significant morbidity and mortality worldwide. Almost two-thirds of PUD cases are asymptomatic. In symptomatic patients, epigastric pain is the most common presenting symptom of PUD, which is manifested by nausea, abdominal fullness, bloating, and dyspepsia. Most PUD cases are associated with the use of COX inhibitors or Helicobacter pylori infection, or both. The traditional management of PUD includes the use of proton pump inhibitors to reduce the gastric acid secretion and antibacterial drugs to combat H. pylori. Timely diagnosis and treatment of PUD are vital to reduce the risk of associated morbidity and mortality, as is prevention of PUD among patients at high risk, including COX inhibitors users and those infected with H. pylori. PDE5 inhibitors have been used for the management of erectile dysfunction and pulmonary hypertension for decades. In recent years, studies have mentioned tremendous pleiotropic effects of PDE5 inhibitors on gastrointestinal, urogenital, musculoskeletal, reproductive, cutaneous, and neurologic disorders. Recent data shows that PDE5 inhibition augments gastric mucosa protection, and here, we review the most recent findings regarding the use of PDE5 inhibitors for the prevention and management of PUD.
... The therapeutic window refers to a range of drug concentration within a patient which allows for the optimal treatment. Above this range, the drug becomes toxic or causes intolerable adverse side effects and below which the drug is ineffective and unable to produce the desired effects [2] . Thus ensuring that the drug concentration stays within the therapeutic window is essential for providing effective treatment to the patient. ...
Drug delivery devices which can control the release of drugs on demand allow for improved treatment to a patient. These smart drug delivery devices allow for the release of drugs to be turned on and off as needed, thereby increasing the control over the drug concentration within the patient. The addition of electronics to the smart drug delivery devices increases the functionality and applications of these devices. Through the use of 3D printing and 3D-printed electronics, the customizability and functions of such devices can also be greatly increased. With the development in such technologies, the applications of the devices will be improved. In this review paper, the application of 3D-printed electronics and 3D printing in smart drug delivery devices with electronics as well as the future trends of such applications are covered.
... Although some findings may propose PDE5i as promising tools for PTC, the lack of consistent amount of data and the existence of opposite results suggest being cautious. First, the aforementioned studies evaluated the effect of PDE5i different than vardenafil, i.e. sildenafil and tadalafil, which share the same enzyme as a main target, but demonstrated different binding affinities [54,55], and targeting of other PDEs [30,56]. Since the PDE5 is not the unique cGMP-specific enzyme [57], these differences between PDE5i may explain tissue-and cell-specific effects. ...
Introduction:
Type 5 phosphodiesterase (PDE5) inhibitors (PDE5i) lead to intracellular cyclic-guanosine monophosphate (cGMP) increase and are used for clinical treatment of erectile dysfunction. Studies found that cGMP may up/downregulate the growth of certain endocrine tumor cells, suggesting that PDE5i could impact cancer risk.
Aim:
We evaluated if PDE5i may modulate thyroid cancer cell growth in vitro.
Materials and methods:
We used malignant (K1) and benign (Nthy-ori 3-1) thyroid cell lines, as well as the COS7 cells as a reference model. Cells were treated 0-24 h with the PDE5i vardenafil or the cGMP analog 8-br-cGMP (nM-μM range). cGMP levels and caspase 3 cleavage were evaluated by BRET, in cGMP or caspase 3 biosensor-expressing cells. Phosphorylation of the proliferation-associated extracellularly-regulated kinases 1 and 2 (ERK1/2) was evaluated by Western blotting, while nuclear fragmentation by DAPI staining. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Results:
Both vardenafil and 8-br-cGMP effectively induced dose-dependent cGMP BRET signals (p≤0.05) in all the cell lines. However, no differences in caspase 3 activation occurred comparing PDE5i-treated vs untreated cells, at all concentrations and time-points tested (p>0.05). These results match those obtained upon cell treatment with 8-br-cGMP, which failed in inducing caspase 3 cleavage in all the cell lines (p>0.05). Moreover, they reflect the lack of nuclear fragmentation. Interestingly, the modulation of intracellular cGMP levels with vardenafil or the analog did not impact cell viability of both malignant and benign thyroid tumor cell lines, nor the phosphorylation of ERK1/2 (p>0.05).
Conclusions:
This study demonstrates that increased cGMP levels are not linked to cell viability or death in K1 and Nthy-ori 3-1 cell lines, suggesting that PDE5i do not impact the growth of thyroid cancer cells. Since different results were previously published, further investigations are recommended to clarify the impact of PDE5i on thyroid cancer cells.
... to the American College of Cardiology, furthermore, a close hemodynamic monitoring should be performed (Abrams, 2004). According to the pharmacokinetic theory of sildenafil, it is primarily metabolized via CYP3A4, a potential drug interaction is with strong CYP3A4 inhibitors, which could cause elevated and prolonged serum concentrations of PDE5is and may resulted in hemodynamic disturbance (Mehrotra et al., 2007). Due to the hypotensive effect of sildenafil, the concomitant utilization of alpha-blockers may lead to orthostatic hypotension. ...
Background: To investigate the function of sildenafil on diseases other than urogenital system, an umbrella review was conducted. Methods: Meta-analysis and systematic reviews on this topic were comprehensively evaluated in this umbrella review. Quality of evidence was evaluated through AMSTAR and the Grading of Recommendations, Assessment, Development and Evaluation system to generate a reliable and valid conclusion. Results: 77 out of 1164 meta-analysis were enrolled. 33 significant outcomes and 41 non-significant outcomes were extracted from all eligible articles. We found sildenafil did significant help in reducing arterial systolic pressure, mean pulmonary arterial pressure, pulmonary arterial pressure, systolic pulmonary arterial pressure in patients with pulmonary and cardiovascular diseases. Besides, sildenafil also improved exercise capacity or performance in patients with pulmonary and cardiovascular diseases. Other than these patients, this drug contributed great help in pregnant women with fetal growth restriction and preeclampsia by increasing the weight of newborns and lowering uterine and umbilical pulsatility indices. Additionally, it was reported that utilization of sildenafil has brought increased risk of melanoma. Conclusion: We can conclude from our study that sildenafil played an important role in many fields, especially in vascular protection. This finding provides a strong evidence for further expansion of sildenafil utilization in other diseases.
... This gradual release can also Frontiers in Biomaterials Science frontiersin.org prevent sudden high concentrations of drugs during the early administration stages, in contrast to conventional drug delivery devices, which once dissolved, release the complete concentration in the media (Mehrotra et al., 2007;Liechty et al., 2010). Additionally, this release behavior may be helpful in applications that require a time window for positioning the microspheres in specific tissues or organs before starting the release. ...
Superparamagnetic iron oxide nanoparticles have been developed for various biomedical applications for decades. In this work, lauric acid-coated SPION (SPION LA ) were incorporated into poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) at different ratios to produce composite microspheres, which were evaluated for their properties, including potential cytotoxicity. Additionally, a phytotherapeutic extract, curcumin, was loaded into the resulting microspheres to develop magnetic drug delivery capsules. The results show a significant improvement in the cytocompatibility after 7 days of SPION LA administrated in cells through the composite microspheres compared to pristine SPION LA . The composite also exhibited prolonged cumulative release of curcumin in a simulated body fluid environment. The results confirmed the efficacy of the mixture of PHBV and curcumin in attenuating potential side effects due to direct administration of high initial amounts of SPION LA while maintaining magnetic properties in the resulting composite. The results add evidence to the potential of these composite devices for targeted drug delivery applications.
... According to Mehrotra et al., 36 pharmacokinetics (PK-'what the body does to the drug') describes the time course of the concentration of a drug in a body fluid (plasma or blood) that results from the administration of a certain dosage regimen. Pharmacodynamics (PD-'what the drug does to the body'), on the other hand, describes the intensity of a drug effect in relation to its concentration in a body fluid, usually at the site of drug action. ...
... Pharmacodynamics (PD-'what the drug does to the body'), on the other hand, describes the intensity of a drug effect in relation to its concentration in a body fluid, usually at the site of drug action. 36 The HFIM system has the advantage that it is a highly controlled system. Multiple variables such as dosing and drug administration time can be accurately adjusted. ...
Conventional cell culture systems involve growing cells in stationary cultures in the presence of growth medium containing various types of supplements. At confluency, the cells are divided and further expanded in new culture dishes. This passage from confluent monolayer to sparse cultures does not reflect normal physiological conditions and represents quite a drastic physiological change that may affect the natural cell physiobiology. Hollow-fibre bioreactors were in part developed to overcome these limitations and since their inception, they have widely been used in production of monoclonal antibodies and recombinant proteins. These bioreactors are increasingly used to study antibacterial drug effects via simulation of in vivo pharmacokinetic profiles. The use of the hollow-fibre infection model (HFIM) in viral infection studies is less well developed and in this review we have analysed and summarized the current available literature on the use of these bioreactors, with an emphasis on viruses. Our work has demonstrated that this system can be applied for viral expansion, studies of drug resistance mechanisms, and studies of pharmacokinetic/pharmacodynamic (PK/PD) of antiviral compounds. These platforms could therefore have great applications in large-scale vaccine development, and in studies of mechanisms driving antiviral resistance, since the HFIM could recapitulate the same resistance mechanisms and mutations observed in vivo in clinic. Furthermore, some dosage and spacing regimens evaluated in the HFIM system, as allowing maximal viral suppression, are in line with clinical practice and highlight this 'in vivo-like' system as a powerful tool for experimental validation of in vitro-predicted antiviral activities.
... This PDE6 affinity of the sildenafil accounts for its visual abnormalities at higher dose. It has been reported that dose higher than 200 mg daily or AUC higher than 2600 ng.hr/ml or Cmax greater than 500 ng/ml intensify the risk of visual, gastrointestinal or vascular side effects [41,42]. ...
... Not only that, but older patients are also frequently advised to take lower dose. And if the patient is taking any kind of medication that inhibits or alters the metabolism of sildenafil by P450 enzymes, the dose of the drug must be matched that way [41,42]. ...
... The average ED50 value calculated from an Emax model experimentation was around 40 mg. However, for the diabetic patients the ED50 value was found to be more than 180 mg [41,42]. ...
Introduction: Erectile Dysfunction (ED) is the inability to achieve or/and maintain a sufficient penile erection for successful, satisfactory, and pleasant vaginal intercourse. National Institute of Health's division of NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) defines erectile dysfunction as a condition in which one person cannot get or keep an erection firm enough for satisfactory sexual intercourse. The usual symptoms include problems achieving a solid erection, difficulties maintaining the erected condition of the penis, and decreased sexual desire. Several factors can contribute to these penile disorders. These include neurogenic injury, endocrinological disorders, drug-affected pathology, cardiovascular disease, etc. The aim of this review was to discuss the mechanism, structure-activity relation (SAR), and pharmacokinetic properties of sildenafil.
Methods: A careful literature search was conducted to compile all the recent information available for sildenafil PK. Primary literature searches included PubMed, Google Scholar, Wiley online resources, etc.
Results: After the completion of the lengthy process of drug discovery, sildenafil citrate was approved by the FDA to be used for erectile dysfunction in March 1998. It was the very first oral treatment for erectile dysfunction.
Conclusion: Although several selective PDE 5 inhibitors are available now, sildenafil citrate is still one of the most prescribed drugs for treating penile erectile disorders.
... The bioavailability of a drug represents the fraction of the administered dose which reaches the circulatory system unchanged (Mehrotra et al., 2006). Drug absorption mainly occurs in the small intestine (Murakami, 2017) and is subject to many influencing factors. ...
Children require palatable medicines. Excipients can improve the acceptability of a formulation, enabling children to take their dose as prescribed to achieve therapeutic exposure to the active pharmaceutical ingredient (API). Sweeteners have traditionally been used but there are safety concerns associated and limited success with highly aversive API. Thus there is a need to identify new approaches, such as those which steer towards a taste-neutral formulation. In order to assess the efficacy of novel taste-masking excipients, appropriate preclinical models are needed. The Brief Access Taste Aversion (BATA) model is one such method which has been used successfully for predicting the aversiveness of API but more work needs to be done to understand the translatability when excipients are present. Some taste-masking excipients can have a negative impact on drug bioavailability and can decrease drug absorption in the gut as shown in adults. Children have a unique gut environment and therefore, there is a need to assess taste-masking excipients for such an effect in age-appropriate models. To further understanding of excipients’ impact on API bioavailability in children, this work achieved the following: 1) identified promising bitter-blockers (sodium acetate, sodium gluconate and Adenosine monophosphate sodium salt) using a novel ranking methodology. The three bitter-blockers were then assessed within liquid formulations but were unable to sufficiently taste-mask therapeutic doses of API. 2) Compared BATA and human data for taste-masking efficacy of a cyclodextrin and a maltodextrin. Differences in species tolerance to the dextrins were seen due to rat neophobia which, if not accounted for, would prevent an accurate pre-clinical prediction of the human response. 3) Compared the effect of sorbitol, a widely used sweetener, on API blood levels in juvenile and adult rats. Sorbitol negatively impacted the bioavailability of model drug in the same way independent of age. The knowledge generated helps inform how taste-masking excipients can be used safely and efficiently in children’s medicines.
... These reactions participate in different metabolic pathways according to their functions. Therefore, knowing which metabolic pathways that the molecular compounds in a drug are involved can help researchers understand how the drug is absorbed, distributed, metabolized, and excreted [2,3]. Specifically, a metabolic pathway is a series of biochemical reactions catalyzed by enzymes in cells, which form metabolites to use, store and trigger another metabolic pathway [4]. ...
Background
Making clear what kinds of metabolic pathways a drug compound involves in can help researchers understand how the drug is absorbed, distributed, metabolized, and excreted. The characteristics of a compound such as structure, composition and so on directly determine the metabolic pathways it participates in.
Methods
We developed a novel hybrid framework based on the graph attention network (GAT) to predict the metabolic pathway classes that a compound involves in, named HFGAT, by making use of its global and local characteristics. The framework mainly consists of a two-branch feature extracting layer and a fully connected (FC) layer. In the two-branch feature extracting layer, one branch is responsible to extract global features of the compound; and the other branch introduces a GAT consisting of two graph attention layers to extract local structural features of the compound. Both the global and the local features of the compound are then integrated into the FC layer which outputs the predicted result of metabolic pathway categories that the compound belongs to.
Results
We compared the multi-class classification performance of HFGAT with six other representative methods, including five classic machine learning methods and one graph convolutional network (GCN) based deep learning method, on the benchmark dataset containing 6999 compounds belonging to 11 pathway categories. The results showed that the deep learning-based methods (HFGAT, GCN-based method) outperformed the traditional machine learning methods in the prediction of metabolic pathways and our proposed HFGAT method performed better than the GCN-based method. Moreover, HFGAT achieved higher F1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$F_1$$\end{document} scores on 8 of 11 classes than the GCN-based method.
Conclusions
Our proposed HFGAT makes use of both the global and local information of the compounds to predict their metabolic pathway categories and has achieved a significant performance. Compared with the GCN model, the introduction of the GAT can help our model pay more attention to substructures of the compound that are useful for the prediction task. The study provided a potential method for drug discovery with all types of metabolic reactions that may be involved in the decomposition and synthesis of pharmaceutical compounds in the organism.
