Duration Of Action Research Articles

A novel sustained-release agent based on disulfide-induced recombinant collagen hydrogels for the prevention and treatment of Schistosoma infections.

Schistosomiasis is commonly managed using the praziquantel, but it is only effective against adult worms and duration of action is short. Liver fibrosis will worsen if eggs are still present after stopping treatment. Therefore, this study aimed to develop a sustained drug release system for effectively preventing and treating schistosomiasis. A disulfide bond-induced three-dimensional (3D) recombinant collagen hydrogel was developed for sustained praziquantel release. Three collagen sequences were developed based on the sequence for Scl2 of S. pyogene, with different substitutions of residues for cysteine (S-VCL-S1, S-VCL-S2, and S-VCL-S3). Their properties were tested. Mice were infected with Schistosoma japonicum cercariae and treated either with praziquantel collagen hydrogel or niclosamide collagen hydrogel. The worm-killing effect was examined. The application of hydrogel-niclosamide on the skin for 24 h effectively prevented Schistosome cercariae from infecting mice and showed 70.95% and 81.73% reduction in the number of eggs and worms, respectively. The combined use of niclosamide and anti-cercariae cream showed 100% protection after 24 h. The hydrogel-praziquantel also showed a 100% reduction of worms and eggs after 24 h of subcutaneous injection. The subcutaneous injection of praziquantel after 28 days of infection showed 95.19% and 80.12% reduction of worm and egg counts, respectively, and the development of larvae was significantly slowed down. Liver analysis showed no infection after 7 days of treatment. These results suggest developing a novel type of sustained-release agent against schistosomiasis based on the recombinant collagen hydrogel that provides a potential new treatment for schistosomiasis.IMPORTANCEThis study introduces an new way for treating schistosomiasis: a special collagen hydrogel that gradually releases medication to treat schistosomiasis effectively. This innovation provides a promising way to treat schistosomiasis. It represents a significant step forward in the fight against this disease and offers hope for more effective and safer treatments in the future.

Phycocyanin/Hyaluronic Acid Microneedle Patches Loaded with Celastrol Nanoparticles for Synergistic Treatment of Diabetic Nephropathy.

Although multifunctional drug delivery systems have shown significant potential in the treatment of diabetic nephropathy (DN), developing an efficient synergistic drug delivery strategy remains a major challenge. The purpose of this paper is to develop a nanoparticle-loaded microneedle (MN) patch transdermal drug delivery system aimed at achieving blood glucose control and reactive oxygen species (ROS) scavenging for the synergistic treatment of DN. MNs are composed of hyaluronic acid and phycocyanin (PC), both exhibiting excellent biocompatibility and degradation properties. Subsequently, insulin and celastrol (CEL)-based nanoparticles were incorporated into the MN to create the transdermal drug delivery platform (MN-IN&NPs). MN-IN&NPs can penetrate through the stratum corneum of skin and reach the dermis layer. Accompanied by the dissolution of MN, PC, insulin, and CEL-based NPs are continuously released. PC possesses anti-inflammatory and antioxidant properties that enable it to scavenge excessive ROS, thereby exerting synergistic effects alongside CEL nanoparticles. Furthermore, MN-IN&NPs significantly enhance drug transdermal delivery efficiency, while prolonging insulin's action duration. Therefore, MN-IN&NPs effectively integrate blood glucose control with ROS scavenging functions, presenting a promising therapeutic strategy for DN.

Covalent Proximity Inducers.

Molecules that are able to induce proximity between two proteins are finding ever increasing applications in chemical biology and drug discovery. The ability to introduce an electrophile and make such proximity inducers covalent can offer improved properties such as selectivity, potency, duration of action, and reduced molecular size. This concept has been heavily explored in the context of targeted degradation in particular for bivalent molecules, but recently, additional applications are reported in other contexts, as well as for monovalent molecular glues. This is a comprehensive review of reported covalent proximity inducers, aiming to identify common trends and current gaps in their discovery and application.

Threshold for oscillatory-flow ripple initiation on cohesive and non-cohesive mixtures of sand and mud

ABSTRACT The threshold hydraulic condition of wave ripple initiation has been essential in a wide range of disciplines, including coastal engineering and geology, but remains unclear for the case of sand-mud mixtures as substrates. Scale experiments were conducted using an oscillating-bed to study wave ripple initiation in sand-mud mixtures, considering bed material, wave period and maximum orbital velocity. Four kinds of sand-mud mixtures were employed as bed material with different muds (cohesive kaolin and non-cohesive silt) and mixing ratios. Ripple initiation in the cases with sand-mud mixtures tended to require larger orbital velocity than pure sand, indicating that mud mixed in bed material hinders ripple formation and spreading of the ripple field. The results of the threshold for pure sand and 10% kaolin mixture show that cohesive mixed sand-mud hindered ripple formation and spreading. In contrast, in the case of the non-cohesive sand-silt mixture beds, the results differed depending on the proportion of sand and silt, which implied the effect of the strength of network structure. The inhibition of ripple initiation due to mud mixing observed in the present experiments is considered to have a significant effect, particularly in environments with limited wave action duration, such as intertidal zone.

Detection of Over 110 Anabolic-Androgenic Steroids, Corticosteroids and/or Their Esters in Horse Hair Using Ultra-High-Performance Liquid Chromatography-High-Resolution Mass Spectrometry and Gas Chromatography-Tandem Mass Spectrometry After Solid-Supported Liquid Extraction.

Anabolic-androgenic steroids (AAS) are banned substances in both human and equine sports. They are often administered intramuscularly to horses in esterified forms for the purpose of extending their duration of action. As such, the detection of intact esters of endogenous steroids in hair is particularly advantageous, as it can provide unequivocal proof of their external origin. Compared with urine and blood matrices, hair in general allows a longer detection window as long as the administered drug can be incorporated into hair and has not degraded. This can be useful in doping control of equine sports, where the timing of sample collection may be critical due to the transient nature of AAS in other biological fluids. This paper describes the detection of AAS and/or their esters, as well as corticosteroids, in horse hair using ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) after solid-supported liquid extraction (SLE) at basic pH. The developed UPLC-HRMS and GC-MS/MS methods in combination allowed the detection of 117 AAS, corticosteroids and/or their esters with estimated limits of detection down to sub-ppb levels and with good inter-day precision. Method applicability has been demonstrated through the detections of (i) boldenone undecylenate, nandrolone phenylpropionate and trenbolone acetate in three proficiency testing hair samples and (ii) nandrolone as a metabolite in a post-administration hair sample collected from a castrated horse having been administered nandrolone decanoate.

New insights into the use of dexamethasone-dexmedetomidine as perineural adjuvants in peripheral nerve and fascial blocks: an up-to-date narrative review.

The discovery of the mechanism of action of local anesthetics, involving the blocking of sodium ion channels is considered a milestone in anesthesia. Potentially lethal toxic effects occur in the case of intravascular injection of local anesthetic (LA) or in case of exceeding dosages, as a result of systemic reabsorption. Attempts to prevent these life-threatening events have been made by developing novel LA and by adding adjuvants. The aim of this up-to-date review was to provide the newest insights on the two adjuvants dexamethasone and dexmedetomidine for regional anesthesia. The addition of perineural dexamethasone-dexmedetomidine combination has shown a faster onset, longer duration of action and increased intensity of neuronal blockade of regional anesthesia compared to perineural single adjunct. This is consistent with clinical studies (trials, observational studies and reports) of a marked prolongation of the local anesthetic effect. Nevertheless, further studies are needed to ascertain the full potential of this technique and all possible associated risks.

ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023.

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.

What’s in a word? Defining “gene therapy medicines”

Gene therapy medicinal products (GTMPs) have emerged as a transformative class of medicines. Defining what a certain class of medicines encompasses, and what it does not, is key, with ample implications and consequential regulatory requirements. In April 2023, the European Commission proposed new pharmaceutical legislation safeguarding the public health within the European Union with a new, broader definition of GTMP, including genome editing medicines and nucleic acids of either source, regulating, replacing, or adding a genetic sequence that mediates its effect by transcription or translation. This definition is all-encompassing for any "genetic" intervention and is agnostic to mechanism of action, duration of action, location of action, and associated risk. Here, we take this as a paradigm to discuss how terminology and definitions are more than just words and can have meaningful regulatory, scientific, and public health implications.

Vesicle-based formulations for pain treatment: a narrative review.

Pain, a complex and debilitating condition, necessitates innovative therapeutic strategies to alleviate suffering and enhance patients' quality of life. Vesicular systems hold the potential to enhance precision of drug localisation and release, prolong the duration of therapeutic action and mitigate adverse events associated with long-term pharmacotherapy. This review critically assesses the current state-of-the-art in vesicle-based formulations (liposomes, polymersomes, ethosomes, and niosomes) for pain management applications. We highlight formulation engineering strategies used to optimise drug pharmacokinetics, present preclinical findings of experimental delivery systems, and discuss the clinical evidence for the benefits of clinically approved formulations. We present the challenges and outlook for future improvements in long-acting anaesthetic and analgesic formulation development.

Dopamine D4 receptors in the lateral habenula regulate anxiety-related behaviors in a rat model of Parkinson's disease

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D4 receptors affects anxiety-like behaviors, particularly in Parkinson’s disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D4 receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D4 receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D4 receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

Effects of physical practice on the duration of motor imagery

Motor Simulation Theory proposes that imagined actions are produced using the brain’s motor system, and should therefore always be temporally equivalent to physical movements. However, empirical results are not always consistent with this prediction. Studies indicate that the durations of unfamiliar imagined actions are over-estimated, whereas the durations of more familiar actions may be closer to (or even faster than) actual movement execution. We therefore examined the effects of different levels of practice on the durations of both physically performed and imagined actions. Participants (N=31) completed an initial assessment in which the durations of physically performed and imagined finger movement sequences were measured. Participants then completed three days of physical training in which different sequences received either extensive training (150 repetitions/session), minimal training (10 repetitions/session), or no training. In a subsequent assessment session, we found that the time taken to both physically execute and imagine performing sequences decreased with training. However, contrary to the predictions of Motor Simulation theory, imagined movement durations consistently over-estimated those of physically performed movements. While the difference in the timing of imagined and physically executed movements decreased between the initial and final assessment, this effect was not modulated by training. These results extend our understanding of the relationship between motor imagery and physical practice, and highlight a key limitation in the predictions of Motor Simulation Theory.

Synthesis and Characterization of Inulin Polymer and Study Its Role on Wound Healing

Inulin is a particularly effective drug delivery vehicle as compared to other biodegradable polysaccharides because of its unique and flexible structure, protective and stabilizing properties, and organ targeting abilities. This strategy may result in targeted, delayed, and regulated release of medications and biomolecules as well as increased bioavailability and improved cellular absorption. In the present study, thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), 1H-NMR, and ultraviolet spectroscopy were among the techniques used to further characterize the physicochemical properties of inuline. The inulin-g-[N-sulfamethoxazole maleic amic acid] (INMS) was prepared and used. INMS efficacy against bacterial activity was also examined. In order to examine the activity of INMS in vivo, mice were underwent to second-degree burn. The results showed, after three days, the basic media produced better regulated drug release than the acidic one. This was discovered by contrasting the pace at which the amide drug polymer hydrolyzed in each media. It was discovered that a drug polymer with altered drug release and a prolonged duration of action has as an adhesive probity. The present results found that INMS has a significant antibacterial effect on burned wound isolated bacteria. The in vivo performance using a natural polymer as a drug carrier results a great healing of skin wound of mice. Thus, the present study is aimed to modify the inulin to serve as a scaffold for various drug delivery systems.

Oral Capsule FMT Combined With Bezlotoxumab Is a Successful Rescue Protocol Following Failure of FMT Alone in the Treatment of Recurrent C. difficile Infection.

Evaluate the benefit of adding bezlotoxumab to repeat fecal microbiota transplantation (FMT) in patients with recurrent Clostridioides difficile infections after the failure of FMT alone. The initial failure of FMT in breaking the cycle of recurrent Clostridium difficile(C. difficile) infections is associated with a greater risk of subsequent failure. Our previous analysis showed that FMT failure is associated with delayed repair of fecal microbiota at 1 week after administration. We hypothesized that increasing the symptom-free interval by adding bezlotoxumab would improve the outcomes of a second FMT. A new rescue protocol that combines FMT with bezlotoxumab for patients who previously failed FMT alone was implemented in 2 academic medical centers. The clinical outcomes of a new protocol were captured in a prospective registry. The results were compared in a retrospective analysis of clinical outcomes of prior experience with repeat FMT by itself. All FMT preparations were standardized for dose. Bezlotoxumab administration was synchronized temporally with the second FMT to maximize its duration of action. Our historical cure rate of second FMT in treatment of recurrent C. difficile infection was 48% (15/31 patients). Addition of bezlotoxumab to the second FMT resulted in a cure rate of 89% (24/27 patients). Addition of bezlotoxumab markedly improved the cure rate of the second FMT following initial FMT failure. The rationale for the protocol design highlights the importance of understanding the pharmacokinetics of both bezlotoxumab and FMT. Similar principles may apply to other live biotherapeutic products that are becoming available for prevention of C. difficile infection recurrence.

Lysine-Targeted Covalent Inhibitors of PI3Kδ Synthesis and Screening by In Situ Interaction Upgradation.

Targeting the lysine residue of protein kinases to develop covalent inhibitors is an emerging hotspot. Herein, we have reported an approach to develop lysine-targeted covalent inhibitors of PI3Kδ by in situ interaction upgradation of the H-bonding to covalent bonding. Several warhead groups were introduced and screened in situ, leading to lysine-targeted covalent inhibitors bearing aromatic esters with high bioactivity and PI3Kδ selectivity. Compound A11 bearing phenolic ester was finally optimized to show a long duration of action in SU-DHL-6 cells by multiple assays. Docking simulation and further protein mass spectrometry confirmed that A11 bound to PI3Kδ by covalent-bonding interactions with Lys779. Furthermore, A11 exhibited potently antitumor efficacy without obvious toxicity in the SU-DHL-6 and Pfeiffer xenograft mouse models. This study identified A11 to be a much more effective antitumor agent in vitro and in vivo as a lysine-targeted covalent inhibitor, and it also provided a practical approach for the development of lysine-targeted covalent inhibitors.

Dual cross-linking with tannic acid and transglutaminase improves microcapsule stability and encapsulates lemon essential oil for food preservation

The microencapsulation of essential oils by complex coacervation technology has attracted considerable attention. This paper deals with the preparation of gelatin-chitosan microcapsules through dual cross-linking using transglutaminase (TGase) and tannic acid (TA). Lemon essential oil (LEO) was successfully encapsulated with 82.5 % encapsulation efficiency. Compared to single cross-linking microcapsules (TG), dual cross-linking microcapsules (TG-TA) exhibit superior thermal stability and swell stability. In vitro release studies demonstrated that TG-TA exhibited better controlled-release behavior with a longer duration of action. Meanwhile, the lipid oxidation of TG-TA was 1.45 mg MDA/kg that of control group was 2.23 mg MDA/kg which showed their excellent antioxidant effects. Moreover TG-TA have higher antibacterial rate, more inhibition zone diameters and better effect for preventing the growth of total viable count than TG and LEO. This study has theoretical implications for the use of TG-TA ideal carriers for protecting various active substances, thus facilitating their applications in food preservation.

Achieving High Performance with Less Energy Consumption: Intermittent Ultrasonic-Mediated Operation Mode for Fe/V Non-Aqueous Redox Flow Battery

Deep eutectic solvents (DESs) have attracted much attention as sustainable electrolytes for redox flow batteries. Despite the tremendous advantages of DES-based electrolytes, their high viscosity property has a negative effect on their mass transfer, limiting current density and power density. The ultrasonic effect has been demonstrated as an efficient strategy to improve mass transfer characteristics. Incorporating ultrasonic waves into a deep eutectic solvent (DES) electrolyte enhances the mobility of redox-active ions, thereby accelerating the reaction dynamics of the Fe(III)/Fe(II) redox pair. This enhancement makes it suitable for use in non-aqueous electrolyte-based redox flow batteries. However, it is necessary to consider the loss of ultrasonic on the internal structure of the battery, as well as the loss of battery component materials and ultrasonic energy consumption in practical applications. Moreover, the continuous extension of the duration of ultrasonic action not only hardly leads to a more significant improvement of the battery performance, but is also detrimental to the energy and economic savings. Herein, intermittent ultrasound is used to overcome the quality transfer problem and reduce the operating cost. Good electrochemical performance enhancement is maintained with a roughly 50% reduction in energy consumption values. The mechanism as well as the visualization of the pulsed ultrasonic field on each half cell has been envisaged through fundamental characterization. Finally, the feasibility of interrupted ultrasonic activation applied to Fe/V RFB using DES electrolytes has been demonstrated, demonstrating similar behavior with continuous ultrasonic operation. Therefore, the interrupted ultrasonic field has been found to be a more effective operation mode in terms of energy cost, avoiding alternative undesirable effects like overheating or corrosion of materials.

Expert consensus on the multifaceted utility of alginates in addressing diverse manifestations of acid reflux

Gastroesophageal reflux disease (GERD) is one of the most frequent reasons for seeking outpatient gastroenterology consultations. Current professional guidelines advocate the use of proton pump inhibitors (PPIs) as the primary medical approach to manage GERD. However, PPIs may not be as effective, especially for certain patients like those with non-erosive reflux disease (NERD). An alternative strategy for addressing symptomatic GERD involves obstructing the flow of acidic refluxate. Alginate-based pharmaceutical formulations have proven effective in alleviating symptoms of acid reflux for many years and provide rapid relief of symptoms with a long duration of action. Alginic acid derivatives, or alginates, combat acid reflux through a unique mechanism: they create a physical barrier that displaces the post-prandial acid pocket. Alginates have recently garnered renewed interest for promoting symptomatic relief especially when employed alongside antacids or PPIs. Here, the role of alginates is reviewed in the treatment of various profiles of acid reflux, including post-prandial acid reflux, nocturnal GERD, refractory GERD, and GERD during pregnancy, along with the opinion of expert gastroenterologists on the same. The experts believed that not all alginate formulations are equivalent and raft strength is the most important physicochemical property to be considered while selecting the alginate-based product. The physicochemical properties of the rafts eventually impact their effectiveness in relieving symptoms in clinical settings.

Therapeutic Potential of Cannabinoids in Glaucoma – Hit or Myth? - A Review

Introduction: Glaucoma is a leading cause of irreversible blindness, characterized by elevated intraocular pressure (IOP) that damages the optic nerve. Current treatments mainly focus on reducing IOP, but some patients do not respond adequately to conventional therapies. Cannabinoids, particularly Δ9-tetrahydrocannabinol (Δ9-THC), have been investigated as potential adjunctive treatments for glaucoma. Studies have shown varying effects of cannabinoids on IOP regulation, though their precise mechanisms remain unclear. Aim of Study: This study aims to evaluate the therapeutic potential of cannabinoids in the treatment of glaucoma by examining their effects on IOP, their mechanisms of action, and the risks and benefits associated with their use. Material and methods: A comprehensive literature review of studies on the therapeutic potential of cannabinoids in glaucoma was conducted using the PubMed database. Results and Conclusions: Cannabinoids, especially Δ9-THC, have demonstrated the ability to reduce IOP in both healthy individuals and glaucoma patients. However, the effect is typically short-lived, lasting only 3-4 hours. The efficacy of cannabinoids in reducing IOP is influenced by the method of administration (oral, intravenous, inhalation) and the delivery system used for topical application. Despite some promising results, the use of cannabinoids as a mainstream glaucoma treatment is limited by factors such as the short duration of action, the potential for addiction, and the occurrence of adverse effects like tachycardia, hypotension, and cognitive impairment. Although cannabinoids offer a unique approach to glaucoma management, further research is necessary to address these limitations and determine their long-term therapeutic viability.

Evaluation of ethanolic extract of Piper methysticum leaves on anxiolytic activity of mice

The ethanol extract of Piper methysticum, commonly known as kava, has shown promising results in reducing anxiety. Studies suggest it may have anxiolytic effects, potentially offering a natural alternative to conventional anxiety treatments. The ethanolic extract of Piper methysticum can increase the duration of action. It can also increase the time spent in open arm, entry in open arm (in elevated plus model) as well as increase the time spent in light field (in Light Dark field) thus we can conclude that it can also possesses Anxiolytic action. The ethanolic extract of Piper methysticum possesses an anxiolytic like activity without sedative side effect. The corticosterone level in mice is increased when they got anxiety. So when the plasma corticosterone level of mice is checked in control group its turn out to be 10.28±0.52. It gets decreased with increase in doses. When treated with low dose of Aqueous extract is 7.28±1.44 is less effective than low dose of Ethanolic extract that is 6.22±1.28. Same as that high dose of extract shows the corticosterone level was 6.24±2.28 which was also less effective than high dose of ethanolic extract which was 5.52±0.32. Most effectively stress was decreased when treated with the Standard drug (Alprazolam) which shows plasma corticosterone level was 1.24±0.36. The mice of Piper methysticum extract (300 &600 mg/kg/ p.o.) treated group showed significantly (p<0.05) increased in body water intake as compared to the control group. Results showed that synthesized extract is very effective for the treatment of anxiety. Keywords: Piper methysticum; anxiolytic activity; Anthraquinones; Light Dark model

Erectile Dysfunction Therapy of Bariatric Patients: Tadalafil Biopharmaceutics and Pharmacokinetics Before vs. After Gastric Sleeve/Bypass

Bariatric surgery introduces significant changes in the gastrointestinal tract, which may affect oral drug absorption/bioavailability. Here we investigate the phosphodiesterase-5 inhibitor (PDE5i) tadalafil for potentially impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in vitro in different pHs, and ex vivo in gastric content aspirated from patients pre/post-surgery. Dissolution was studied in conditions mimicking pre/post-surgery stomach. Finally, the experimental data were used in physiologically-based pharmacokinetic (PBPK) model (GastroPlus®) to simulate pre- vs. post-surgery tadalafil PK. Tadalafil demonstrated low and pH-independent solubility, both in vitro and ex vivo. Tadalafil release from all drug products and under all gastric conditions was incomplete, with particularly poor dissolution (2%) of the highest dose under post-bariatric conditions. PBPK simulations revealed altered tadalafil PK after gastric bypass—but not after sleeve gastrectomy—compared to unoperated individuals, with 44–48% decreased Cmax, 35–56% decreased AUC and 44% shorter Tmax. This mechanistic analysis suggests that tadalafil may be as effective after sleeve gastrectomy as before the procedure; meanwhile, results after gastric bypass raise concerns regarding the bioperformance of the drug. In addition, the drug's duration of action may be much shorter after gastric bypass. Thus, the effectiveness of tadalafil, widely regarded as the ‘weekend pill’, may be shorter than expected among gastric bypass patients.Graphical