European Journal of Pharmaceutical Sciences

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0...

Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are challenging and often intractable complex medical conditions, with a substantial impact on the quality of life. Mirogabalin, a novel voltage-gated Ca2+ channel α2δ ligand, was approved for the indication of DPNP and PHN. However, the time course of effects has not yet been clarified.We aimed to establish pharmacodynamic and placebo effect models of mirogabalin and pregabalin in DPNP and PHN, and to quantitatively compare the efficacy characteristics (maximum efficacy, onset time, and other pharmacodynamic parameters) and safety of mirogabalin and pregabalin...

Research on pharmaceutical dry powders has been increasing worldwide, along with increased therapeutic strategies for an application through the pulmonary or the nasal routes. In vitro methodologies and tests that mimic the respiratory environment and the process of inhalation itself are, thus, essential. The literature frequently reports cell-based in vitro assays that involve testing the dry powders in suspension. This experimental setting is not adequate, as both the lung and the nasal cavity are devoid of abundant liquid...

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1-3-9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75-69-46 or 45-13-50% of birth rates...

Cytochrome P450 (CYP) system is a critical elimination route to most pharmaceuticals in human, but also prone to drug-drug interactions arising from the fact that concomitantly administered pharmaceuticals inhibit one another's CYP metabolism. The most severe form of CYP interactions is irreversible inhibition, which results in permanent inactivation of the critical CYP pathway and is only restored by de novo synthesis of new functional enzymes. In this study, we conceptualize a microfluidic approach to mechanistic CYP inhibition studies using human liver microsomes (HLMs) immobilized onto the walls of a polymer micropillar array...

BACKGROUND: Preclinical models of cancer can be of translational benefit when assessing how different biomarkers are regulated in response to particular treatments. Detection of molecular biomarkers in preclinical models of cancer is difficult due inter-animal variability in responses, combined with limited accessibility of longitudinal data. METHODS: Nonlinear mixed-effects modelling (NLME) was used to analyse tumour growth data based on expected tumour growth rates observed 7 days after initial doses (DD7) of Radiotherapy (RT) and Combination of RT with DNA Damage Response Inhibitors (DDRi)...

Triple-negative breast cancer (TNBC) is a unique breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Since TNBC lacks ER, PR, and HER2, there are currently no drugs that specifically target TNBC. Therefore, the development of new drugs or effective treatment strategies to target TNBC has become an urgent clinical need. Research has shown that the application of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors leads to genomic and epigenomic instability...

Pharmaceutical residues are widely detected in aquatic environment worldwide mainly arising from human excretions in sewage systems. Presently, publicly available, high quality environmental risk assessment (ERA) data for pharmaceuticals are limited. However, databases like the Swedish Fass offer valuable resources aiding healthcare professionals and environmental scientists in identifying substances of significant concern. In this review, we provide a concise overview of the regulatory ERA process for medicinal products intended for human use...

One of the most frequent causes of respiratory infections are viruses. Viruses reaching the airways can be absorbed by the human body through the respiratory mucosa and mainly infect lung cells. Several viral infections are not yet curable, such as coronavirus-2 (SARS-CoV-2). Furthermore, the side effect of synthetic antiviral drugs and reduced efficacy against resistant variants have reinforced the search for alternative and effective treatment options, such as plant-derived antiviral molecules. Curcumin (CUR) and quercetin (QUE) are two natural compounds that have been widely studied for their health benefits, such as antiviral and anti-inflammatory activity...

Propolis has a long ethnopharmacological history for oral periodontal diseases treatment. Propolis flavonoids are main active components for anti-inflammation and tissue protection. However, the intractable dissolution properties of propolis flavonoids and complex oral environment pose great challenges for periodontal delivery. In addition, the therapeutic mechanism as well as the therapeutic correlation of inflammation resolution and tissue regeneration remain unclear for propolis flavonoids. In this study, we constructed an in situ thermosensitive depot systems using total flavonoids from propolis-loaded cubic liquid crystals (TFP-CLC) hydrogel for periodontal delivery...

Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure...

OBJECTIVE: PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated. METHODS: This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10-80 μg and 20-40 μg, respectively...

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism...

Inspired by nature, tissue engineering aims to employ intricate mechanisms for advanced clinical interventions, unlocking inherent biological potential and propelling medical breakthroughs. Therefore, medical, and pharmaceutical fields are growing interest in tissue and organ replacement, repair, and regeneration by this technology. Three primary mechanisms are currently used in tissue engineering: transplantation of cells (I), injection of growth factors (II) and cellular seeding in scaffolds (III). However, to develop scaffolds presenting highest potential, reinforcement with polymeric materials is growing interest...

To date, characterization of the first-pass effect of orally administered drugs consisting of local intestinal absorption and metabolism, portal vein transport and hepatobiliary processes remains challenging. Aim of this study was to explore the applicability of a porcine ex-vivo perfusion model to study oral absorption, gut-hepatobiliary metabolism and biliary excretion of midazolam. Slaughterhouse procured porcine en bloc organs (n=4), were perfused via the aorta and portal vein. After 120min of perfusion, midazolam, atenolol, antipyrine and FD4 were dosed via the duodenum and samples were taken from the systemic- and portal vein perfusate, intestinal faecal effluent and bile to determine drug and metabolite concentrations...

Increasing evidence suggests a beneficial role of vitamin D (VitD) supplementation in addressing the widespread VitD deficiency, but currently used VitD3 formulations present low bioavailability and toxicity constrains. Hence, poly(L-lactide-co-glycolide) (PLGA) nanoparticles (NPs), solid-lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were investigated to circumvent these issues. PLGA NPs prepared by emulsification or nanoprecipitation presented 74 or 200 nm, and association efficiency (AE) of 68 % and 17 %, respectively, and a rapid burst release of VitD3...

Xuebijing injection (XBJ) is widely used to treat nephrotic syndrome (NS) in clinic, but its bioactive components and therapeutic mechanism are still unclear. In this study, the bioactive components of XBJ were determined by ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS). The therapeutic effect of XBJ on NS was evaluated in BALB/c mice induced by adriamycin (ADR, 10 mg/kg) via a single tail vein. The protective effect of XBJ and its bioactive components on podocytes was demonstrated using mouse podocytes (MPC-5) induced by lipopolysaccharide (LPS, 4 μg/mL)...

BACKGROUND: Lenvatinib's efficacy as a frontline targeted therapy for radioactive iodine-refractory thyroid carcinoma and advanced hepatocellular carcinoma owes to its inhibition of multiple tyrosine kinases. However, as a CYP3A4 substrate, lenvatinib bears susceptibility to pharmacokinetic modulation by co-administered agents. Schisantherin A (STA) and schisandrin A (SIA) - bioactive lignans abundant in the traditional Chinese medicinal Wuzhi Capsule - act as CYP3A4 inhibitors, engendering the potential for drug-drug interactions (DDIs) with lenvatinib...

The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification...

PURPOSE: Youkenafil is a novel oral selective PDE5 inhibitor for treating Erectile Dysfunction. This investigation assessed pharmacokinetics (PK), safety, and tolerability of youkenafil and its main metabolite (M459) after taking 100 mg youkenafil hydrochloride tablets in elderly and young subjects. METHODS: This Phase I, single-center, open-label, parallel-group, single-dose study was conducted on 24 individuals (12 elders and 12 youngsters). Each subject received a single oral 100 mg youkenafil hydrochloride tablets...