Search Results (1,757)

In patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), antiplatelet therapy is the cornerstone of treatment for secondary prevention. Although dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y₁₂ inhibitor is the current standard of care, being, respectively, recommended for 6 and 12 months in patients with chronic and acute coronary syndrome without a need for oral anticoagulation, the continuous improvement in PCI technology and pharmacology have significantly reduced the need for long-term DAPT. Mounting evidence supports the administration of P2Y₁₂ inhibitor monotherapy, particularly ticagrelor, after a short period of DAPT following PCI as a strategy to reduce bleeding without a trade-off in ischemic events compared to standard DAPT. In addition, there is a growing literature supporting P2Y₁₂ inhibitor monotherapy also for long-term secondary prevention of ischemic events. However, the data to this extent are not as robust as compared to the first-year post-PCI period, with aspirin monotherapy still remaining the mainstay of treatment for most patients. This review aims to summarize the rationale for long-term antiplatelet therapy, the pharmacology of current antiplatelet drugs tested for long-term administration as monotherapy, and current evidence on the available comparisons between different long-term antiplatelet monotherapies in patients with CAD. Full article

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. The strongly hygroscopic metformin (1-1-dimethylbiguanide), first synthesized 1922 and resuscitated as an oral antidiabetic (type 2 of the elderly) compound first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977–1997). It was then released in the USA after a short-term prospective trial in healthy overweight “young” type 2 diabetics (mean age 53 years) in 1995 for oral treatment of type 2 diabetes. It was, however, prescribed to mostly multimorbid older patients (above 60–65 years of age). Metformin is now the most used oral drug for type 2 diabetes worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase in their intestinal concentration (up to 300-fold compared to that measured in the blood), to reduced absorption of glucose from the diet, to increased excretion of glucose through the stool, and to decrease in insulin serum level through increased hepatic uptake and decreased production. Intravenously injected F18-labeled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is like that observed in patients after bowel-cleansing or chronically taking different types of laxatives, where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to “attraction” of glucose from the hepatocyte into the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Furthermore, these compounds have also a diuretic effect (loss of sodium and water in the urine) Acute gastrointestinal side effects accompanied by fluid loss often lead to the drugs’ dose reduction and strongly limit adherence to therapy. Main long-term consequences are “chronic” dehydration, deficiency of vitamin B12 and of iron, and, as observed for all the biguanides, to “chronic” increase in fasting and postprandial lactate plasma level as a laboratory marker of a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Metformin is not different from the other biguanides: synthalin B, buformin, and phenformin. The mechanism of action of the biguanides as antihyperglycemic substances and their side effects are comparable if not even stronger (abdominal pain, nausea, vomiting, diarrhea, fluid loss) to those of laxatives. Full article

Background/Objectives: The novel compound 221s (2,9), derived from danshensu and ACEI-active proline, exhibits antihypertensive effects (50/35 mmHg SBP/DBP reduction in SHRs) with potential cough mitigation. However, its excretion kinetics remain unstudied. This study investigates 221s (2,9) elimination in rats to bridge this knowledge gap. Methods: Excretion of unchanged 221s (2,9) was quantified in urine, feces, and bile of Sprague-Dawley rats after oral administration (30 mg/kg). Concentrations of unchanged 221s (2,9) in all matrices were quantified using developed UPLC-MS/MS that underwent methodological validation. Excretion amount, excretion velocity, and accumulative excretion rate of 221s (2,9) were calculated. Results: Urinary excretion exhibited rapid elimination kinetics, reaching peak cumulative excretion rates (138.81 ± 15.56 ng/h) at 8 h post-dosing and plateauing by 48 h (cumulative excretion: 1479.81 ± 155.7 ng). Fecal excretion displayed an accelerated elimination phase between 4 and 8 h (excretion rate: 7994.29 ± 953.75 ng/h), followed by a sustained slow-release phase, culminating in a cumulative output of 36,726.31 ± 5507 ng at 48 h. Biliary excretion was minimal and ceased entirely by 24 h. Notably, total recovery of unchanged drug across all matrices remained below 1% (urine: 0.020 ± 0.021%; feces: 0.73 ± 0.069%; bile: 0.00044 ± 0.00002%) at 72 h. Conclusions: This study provides the first definitive excretion data for 221s (2,9). Quantitative analysis via a validated UPLC-MS/MS method revealed that fecal excretion is the principal elimination pathway for unchanged 221s (2,9) in rats, with direct excretion of the parent compound accounting for <1% of the administered dose over 72 h. Future studies will employ extended pharmacokinetic monitoring and concurrent UPLC-MS/MS analysis of the parent drug and phase II conjugates to resolve the observed mass imbalance and elucidate contributions to total elimination. Full article

Diabetes mellitus (DM) is a global health challenge marked by chronic hyperglycemia, which can result in complications such as diabetic cardiomyopathy. Sitagliptin, an oral anti-hyperglycemic drug, has demonstrated efficacy in alleviating cardiovascular complications associated with DM. This study explored the impact of Sitagliptin’s potential as a therapeutic agent, functioning not only to control blood sugar levels but also to enhance vascular health and strengthen cardiac resilience in diabetes. The investigation focused on alterations in the vascular endothelial growth factor (VEGF) and its receptor-1 (FLT-1) signaling pathways, as well as its potential to suppress inflammation and oxidative stress. A number of rats received a single dose of streptozotocin (STZ) 55 mg/kg (i.p.) to induce DM. Sitagliptin was administered orally (100 mg/kg/90 days) to normal and diabetic rats, after which samples were collected for investigation. Sitagliptin significantly mitigated weight loss in diabetic rats. Its administration significantly reduced blood glucose levels and improved serum troponin I and CK-MB levels. Heart sections from diabetic rats showed a marked increase in mTOR, VEGF, and FLT-1 immune reaction, while sitagliptin-treated diabetic rats’ heart sections showed moderate immune reactions. Sitagliptin’s protective effect was also associated with reduced inflammation, and apoptotic markers. In conclusion, Sitagliptin is suggested to offer beneficial effects on the vascular health of cardiac blood vessels, thereby potentially reducing myocardial stress in diabetic patients. Full article

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

Objectives: The oral route is the most widely used method of administration. However, the bitter taste of drugs is a prevalent issue compromising patient acceptance. This study aimed to develop a palatable amorphous trazodone hydrochloride (TRA) formulation via ion exchange with Amberlite IRP88 resin as the carrier. Methods: TRA-Amberlite IRP88 complexes (TRCs) were prepared using the static exchange method and their physical properties were then characterized. Molecular docking was carried out to elucidate the molecular interaction. Finally, the dissolution profiles and taste of TRCs were evaluated. Results: The Physical characterizations confirmed that TRA was amorphously dispersed in Amberlite IRP88. Importantly, the in vivo taste masking study suggested that the bitterness of TRA was effectively masked. The reason was that the dissociation of TRCs was suppressed in the saliva, resulting in reduced dissolution in the oral cavity. Conclusion: this study suggests that amorphization is effective in masking the bitterness of drugs and provides guidance for the development of palatable oral formulations. Full article

With ketamine gaining attention as a therapeutic drug, oral administration offers an effective alternative to traditional parenteral routes. However, a significant gap remains in understanding its use via voluntary ingestion. This preliminary study aimed to explore the feasibility of oral ketamine self-administration in mice (Mus musculus), while investigating the effects of low concentrations on the brain, liver, and kidney. Adult mice were divided into three groups and received ketamine in their drinking water for 16 days at 0 (control), 5 (K5), or 10 mg/L (K10). A transient decrease in water consumption was observed in both sexes in the K10 group; however, only females in this group showed differences in ketamine intake between groups on some days. Oxidative stress markers measured in the brain, liver, and kidney only revealed higher catalase activity in the brains of females. No significant alterations were observed in liver and kidney function in either sex, nor in inflammation, apoptosis, or DNA damage in kidney tissues. Overall, these findings support the viability of voluntary oral ketamine administration and accentuate the need to refine the proposed model, not only to prevent water consumption inhibition but also to extend the exposure period, explore potential sex-related differences in ketamine intake, and further confirm the safety of oral ketamine administration. Full article

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

Background/Objectives: The emergence of cathinone-based psychostimulants necessitates ongoing research and analysis of the characteristics and properties of novel derivatives. The metabolic fate of five novel cathinone-derived substances (ASProp, MASProp, MASPent, PySProp, and PySPent) containing a selenophene moiety was investigated in vitro and in vivo. Methods: All compounds were incubated individually with pooled human liver S9 fraction. A monooxygenase activity screening investigating the metabolic contribution of eleven recombinant phase I isoenzymes was conducted. Rat urine after oral administration was prepared by urine precipitation. Liquid chromatography–high-resolution tandem mass spectrometry was used for the analysis of all samples. Reversed-phase liquid chromatography (RPLC) and zwitterionic hydrophilic interaction liquid chromatography (HILIC) were used to evaluate and compare the metabolites’ chromatographic resolution. Results: Phase I reactions of ASProp, MASProp, MASPent, PySProp, and PySPent included N-dealkylation, hydroxylation, reduction, and combinations thereof. The monooxygenase activity screening revealed the contribution of various isozymes. Phase II reactions detected in vivo included N-acetylation and glucuronidation. Both chromatographic columns complemented each other. Conclusions: All substances revealed metabolic reactions comparable to those observed for other synthetic cathinones. Contributions from isozymes to their metabolism minimized the risk of drug–drug interactions. The identified metabolites should be considered as targets in human biosamples, especially in urine screening procedures. RPLC and HILIC can both be recommended for this purpose. Full article

This study aimed to investigate the effect of gender on the pharmacokinetics of meloxicam in goats following intravenous (IV, 0.5 mg/kg) and oral (PO, 1.0 mg/kg) administration. A crossover design was used with 12 clinically healthy Saanen goats (six females and six males). Plasma samples were collected up to 96 h post-administration and analyzed with an HPLC for meloxicam concentrations. Pharmacokinetic parameters were calculated and statistically compared between genders and administration routes. The results show that male goats exhibited significantly longer terminal half-life (T_1/2λz), a greater mean residence time (MRT_0–∞), and higher systemic exposure (AUC_0–∞) than females, particularly after oral administration. Oral bioavailability was calculated as 77.43% in females and 104.73% in males. These differences may be linked to gender-based variations in hepatic metabolism, enterohepatic recirculation, and the hormone-mediated modulation of cytochrome P450 activity. The findings are consistent with previous research demonstrating that gender can influence drug disposition through hormonal and enzymatic mechanisms. This study underscores the importance of considering gender as a biological variable in pharmacokinetic assessments of veterinary drugs, especially those used in food-producing animals, to optimize dosing strategies and ensure both therapeutic efficacy and food safety. Full article

Infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-Es) pose a significant global threat with notable increases in prevalence worldwide. Carbapenems are often used as the first line of treatment. However, their overuse accelerates resistance development, highlighting the urgent need for clinically viable carbapenem-sparing strategies. Cefmetazole (CMZ) and flomoxef (FMOX) are parenteral antibiotics that are widely used in Japan and have emerged as potential carbapenem alternatives. Repositioning these agents effectively addresses the clinical need for carbapenem-sparing strategies and outpatient ESBL-E management. This review aims to reposition CMZ and FMOX for real-world clinical practice by synthesizing basic research, clinical studies, and pharmacokinetics/pharmacodynamics (PKs/PDs) analyses, which suggest that these agents may be effective in treating ESBL-E infections—particularly urinary tract infections, as evidenced by their minimum inhibitory concentration (MIC) values. The clinical outcomes of these interventions have been comparable to those of carbapenems, which support their role in antimicrobial stewardship. Their PK/PD characteristics emphasize the importance of dose optimization to ensure therapeutic efficacy, whereas recent insights into resistance mechanisms provide a foundation for appropriate use. As novel antibiotic development takes substantial time, revisiting existing options is increasingly important. Notably, the Infectious Diseases Society of America’s 2024 guidance on antimicrobial resistance has omitted CMZ and FMOX, owing to which clinicians have limited guidance on their use, particularly in regions like Japan where these antibiotics are widely employed. By addressing this knowledge gap, the present review offers a comprehensive evaluation of these drugs and highlights their potential as intravenous agents in ESBL-E management. Furthermore, it highlights the ongoing challenge of ensuring effective oral step-down therapy in an outpatient setting to reinforce the global relevance of CMZ and FMOX in a broader treatment framework, underscoring their potential for outpatient administration where clinically appropriate. Full article

Oral administration remains the preferred drug delivery route but faces formidable gastrointestinal barriers, including enzymatic degradation, solubility limitations, and poor epithelial absorption. Zein-based nanocarriers (ZBNs), derived from maize prolamin, provide a transformative platform to address these challenges. This review synthesizes recent advances in ZBNs’ design, highlighting their intrinsic advantages: structural stability across pH gradients, self-assembly versatility, and a surface functionalization capacity. Critically, we detail how engineered ZBNs overcome key barriers, such as enzymatic/chemical protection via hydrophobic encapsulation, the enhanced mucus penetration or adhesion through surface engineering, and improved epithelial transport via ligand conjugation. Applications demonstrate their efficacy in stabilizing labile therapeutics, enhancing the solubility of BCS Class II/IV drugs, enabling pH-responsive release, and significantly boosting oral bioavailability. Remaining challenges in scalability and translational predictability warrant future efforts toward multifunctional systems, bio-interfacial modeling, and continuous manufacturing. This work positions ZBNs as a potential platform for the oral delivery of BCS Class II–IV drugs’ in the biopharmaceutics classification system. Full article

Background/Objectives: Hypertension is a pathological condition characterized by elevated systolic and/or diastolic blood pressure. A range of pharmacotherapeutic agents are available to treat this condition and prevent complications, including the angiotensin II AT1-receptor blocker losartan. Following oral administration, losartan is exposed to a variety of enzymes that facilitate its metabolism or transportation. The structural characteristics of the genes that encode the enzymes may potentially impact the pharmacokinetics and pharmacodynamics of losartan, thereby modulating its effects on the treatment process. Methods: In this study, a computational model of losartan pharmacokinetics was developed, taking into account the influence of different alleles of the CYP2C9 gene, which plays a pivotal role in losartan metabolism, and the ABCB1 gene, which is responsible for losartan transport. Results: Alterations in the modeled activities of the enzymes encoded by CYP2C9 and ABCB1 result in changes in the losartan and its metabolite profiles that are consistent with known experimental data in real patients with different CYP2C9 and ABCB1 genotypes. Conclusions: The findings of the modeling can potentially be used to personalize drug therapy for arterial hypertension. Full article

Background/Objectives: The oral cavity represents a convenient route of administration for drugs that exhibit significant hepatic first-pass extraction. In this study, the mucosal permeation properties of selected active pharmaceutical ingredients (APIs) incorporated into oral cavity drug products that are approved by the U.S. Food and Drug Administration were quantified using the human-derived sublingual HO-1-u-1 and buccal EpiOral™ in vitro tissue models. Methods: Epithelial barrier properties were monitored using propranolol and Lucifer Yellow as prototypic transcellular and paracellular markers. APIs were dissolved in artificial saliva, pH 6.7, and transepithelial flux from the apical to the basolateral compartment was quantified using HPLC. Results: Apparent permeability coefficients (Papp) calculated for these APIs in the sublingual HO-1-u-1 tissue model varied from Papp = 2.72 ± 0.06 × 10⁻⁵ cm/s for asenapine to Papp = 6.21 ± 2.60 × 10⁻⁵ cm/s for naloxone. In contrast, the buccal EpiOral™ tissue model demonstrated greater discrimination power in terms of permeation properties for the same APIs, with values ranging from Papp = 3.31 ± 0.83 × 10⁻⁷ cm/s for acyclovir to Papp = 2.56 ± 0.68 × 10⁻⁵ cm/s for sufentanil. The tissue-associated dose fraction recovered at the end of the transport experiment was significantly increased in the buccal EpiOral™ tissue model, reaching up to 8.5% for sufentanil. Conclusions: Experimental permeation data collected for selected APIs in FDA-approved oral cavity products will serve as a training set to aid the development of predictive computational models for improving algorithms that describe drug absorption from the oral cavity. Following a robust in vitro–in vivo correlation analysis, it is expected that such innovative in silico modeling strategies will the accelerate development of generic oral cavity products by facilitating the utility of model-integrated evidence to support decision making in generic drug development and regulatory approval. Full article