Search Results (327)

The ongoing emergence of New Psychoactive Substances represents a growing threat to public health, as newly synthesized compounds continuously enter the illicit drug market, evading standard detection methods and challenging regulatory frameworks. Among New Psychoactive Substances, nitazenes are potent non-fentanyl opioids associated with severe cases of intoxication. This study evaluated the genotoxic potential of metodesnitazene and etodesnitazene in the human TK6 cell line. Cells were exposed to increasing concentrations of studied compounds, with and without S9 metabolic activation system. Preliminary assessments and micronuclei frequency analyses were performed by flow cytometry in at least three independent experiments. Metodesnitazene induced an increase in micronuclei frequency starting from 12.5 μM (p < 0.05), whereas etodesnitazene induced an effect only at 50 μM. Metabolic activation increases micronuclei formation at higher concentrations of metodesnitazene 25 μM, but did not substantially affect the response to etodesnitazene. Both compounds also induced intracellular reactive oxygen species production, measured through a chemiluminescent-based bioassay, suggesting oxidative stress as a potential contributing mechanism. These findings highlight the need for compound-specific toxicological profiling to better anticipate the acute and long-term risks associated with nitazene consumption. Full article

Spectrophotometry offers the advantage of low cost and less time consumption, making it still attractive as a method of analysis, especially when coupled with multivariate calibration models. This enhancement solves the majority of the drawbacks of UV–VIS spectrophotometry, which have to do with the entangled spectra of complex mixtures. In this study, a multivariate model was developed and validated for the determination of perindopril erbumine, amlodipine besylate and indapamide, addressing previously unresolved challenges by systematically covering three fixed-dose combinations with differing component ratios and by achieving accuracy suitable for the assay determination. The experimental plan involved a Taguchi orthogonal array design with three factors at five levels. In order to create multivariate calibration models, principal component regression, partial least squares and concentration residual augmented least squares regression algorithms were tested. Principal component regression combined with a genetic algorithm for feature selection was chosen as the optimal model based on prediction performance estimated by nested cross-validation with cluster-based sample splitting. The developed method was also evaluated for its environmentally friendly potential while the analytical method validation procedure confirmed its applicability for the assay testing of the fixed-dose drug combination. Full article

Diabetes mellitus is a complex metabolic disorder whose management has moved from glycemic control to the control of risk factors through the use of new antihyperglycemic drugs with pleiotropic effects. Despite the multiple cardio–renal benefits of sodium-glucose co-transporter 2 (SGLT2) inhibitors, their prescription is often avoided due to concerns regarding side effects. This review aims to discuss the multiple benefits of SGLT2 inhibitors in balance with one of the most concerning side effects, the risk of euglycemic diabetic ketoacidosis (EDKA). A literature search was performed to identify and select articles relevant to this topic. We accessed several databases, including PubMed, Web of Science and Scopus, using appropriate keywords. We selected and evaluated randomized controlled trials, retrospective studies, systematic reviews and meta-analysis published between 2014 and 2024 supporting the multifaceted benefits of SGLT2 inhibitors and the limitations of their recommendations and focusing on the risk of EDKA. Initially designed as antidiabetic agents, SGLT2 inhibitors have demonstrated important cardio–renal benefits, these drugs being the first-line medication in patients with established cardiovascular disease, heart failure and chronic kidney disease. SGLT2 inhibitors are associated with some potential side effects, but with contradictory data concerning their prevalence and clinical relevance. From the possible side effects, EDKA is a life-threatening metabolic emergency whose incidence and recognition has increased, in particular with the use of SGLT2 inhibitors. These drugs can cause this disorder through several mechanisms, including reduced insulin secretion and increased glucagon levels, leading to free fatty acid production, which generally occurs in the presence of some risk factors such as reduced dietary carbohydrates, intercurrent illnesses, surgical stress and alcohol consumption. Through awareness of these risk factors as well as of the clinical symptoms, this condition could be promptly avoided or managed and SGLT2 inhibitors could be safely used. Full article

Background: Robust antimicrobial consumption monitoring and correlation with antibiotic resistance trends is critical to informing evidence-based antimicrobial stewardship and is recommended by the World Health Organization Global Action Plan on the containment of antimicrobial resistance. We estimated national and hospital-level antibacterial consumption patterns in Kenya. Materials and methods: National consumption data (January 2023–December 2024) was derived from aggregated import and donation permits at the Pharmacy and Poisons Board and standardized using the WHO ATC/DDD Index 2025. Consumption data for 2020 and 2021 that had been previously submitted by Kenya to WHO GLASS was retrieved and incorporated to allow a description of trends. Hospital-level data was collected from ten facilities across the country for the period from January 2024 to April 2025. Quality of use was evaluated using the WHO Access, Watch, and Reserve (AWaRe) categorisation with high-consumption antibiotics identified using the Drug Utilization 75% metric. Results: There was a gradual increase in national antibiotic consumption from 14.3 DID in 2020 to 22.2 DID in 2024. Oral formulations accounted for more than three quarters of antibiotics consumed. Access category antibiotic consumption ranged from 50.4% to 56.9% nationally and was 61.2% at hospital level. The national consumption of Watch antibiotics increased from 38.9% in 2020 to 46.1% in 2023 and declined to 40.7% in 2024. Amoxicillin and amoxicillin/clavulanic acid were the most commonly consumed antibiotics nationally in 2020 (40%), 2021 (27%) and 2024 (33%). Azithromycin was the most commonly consumed antibiotic in 2023 (27%), rising from 10% in 2020. Among parenteral antibiotics, benzylpenicillin was the most commonly consumed in 2020 and 2021, while ceftriaxone was the most commonly consumed agent in 2023 (24%) and 2024 (41%). At hospital level, ceftriaxone accounted for 56.5% of parenteral antibiotic use in county referral hospitals. Conclusions: Kenya’s antibacterial consumption is increasing. Use of Access antibiotics remains below the WHO target of 60%. The increasing use of Watch antibiotics, and in particular ceftriaxone and azithromycin, needs to be addressed to support Kenya’s efforts against antimicrobial resistance. Full article

Background: Potentially malignant oral disorders (OPMDs) and oral carcinomas represent a significant oncological concern in incarcerated populations, where multiple modifiable risk factors such as tobacco use, illicit drug consumption, oncogenic human papillomavirus infections, and poor oral hygiene coexist with limited access to preventive and routine dental care. This combination may increase the risk of delayed diagnosis and malignant transformation. Objective: This PRISMA-compliant systematic review aimed to evaluate the prevalence of OPMDs and associated risk factors in prison populations, with a particular focus on identifying gaps in the current evidence. Methods. A systematic literature search was conducted in PubMed, Scopus and Cochrane Library using predefined search strategies. The final search yielded 24 records, which were screened according to PRISMA 2020 guidelines. After title and abstract screening, 10 full-text articles were assessed for eligibility, and 5 cross-sectional studies were included in the qualitative synthesis following independent review. Results: The included studies revealed a substantial burden of oral mucosal lesions in incarcerated populations. Premalignant lesions were reported in a significant proportion of inmates, with oral submucous fibrosis particularly prevalent in some cohorts. Additionally, a high prevalence of oral high-risk HPV infection and widespread oral manifestations were observed. Tobacco use, often combined with betel quid, alcohol, or illicit drugs, emerged as the primary and consistently associated risk factor for oral lesions. Conclusions: Prison populations appear to represent a high-risk group for OPMDs due to the combined effect of behavioral and structural risk factors. However, the limited number of available studies, their cross-sectional design, and methodological heterogeneity prevent definitive conclusions. Further longitudinal and methodologically robust studies are needed to better define prevalence patterns and support targeted screening and prevention strategies in correctional settings. Full article

(1) Background: Metabolic disorders, including hypertension, hyperlipidemia, and hyperglycemia (HHH), rank at the top of the disease burden in China. However, population-level assessment of pharmacological treatment remains limited by the lack of scalable metrics for monitoring medication use and outcomes. (2) Methods: We pioneered the use of standardized combined “HHH” medication usage—encompassing antihypertensive, antidiabetic, and lipid-lowering agents—as an integrated proxy for evaluating interventions for cardiovascular diseases and diabetes. Leveraging wastewater-based epidemiology (WBE), we quantified HHH medication loads (mg/d/1000 persons) across 30 prefectures covering all regions in China, and mapped the associated geographical disparities using independent t-tests. Associations with environmental, socioeconomic, demographic, social service, and health-related behavioral and lifestyle factors were further examined via correlation analysis. (3) Results: Our findings confirmed a pronounced north–south gradient in HHH medication uses (the mean standardized loads in the north were approximately twice as high as those in the south, p < 0.05). Furthermore, aging, sex ratio, nicotine consumption, obesity rate, the comprehensive Air Quality Index (AQI), precipitation and the Urban Wellness and Healthcare Index were identified as the top seven influencing factors (|r| values ranging from 0.37 to 0.71, all p < 0.05). (4) Conclusions: As a comprehensive national-scale analysis of multi-drug use for HHH via WBE, this study provides valuable insights into national multi-disease pharmacological treatment, offering evidence-based support for refining clinical prescribing guidelines and rationalizing the allocation of healthcare resources. Full article

Background/Objectives: Postoperative pain remains a significant clinical challenge, often requiring multimodal strategies to mitigate opioid-related adverse events. The fixed-dose combination (FDC) of Diclofenac, a non-steroidal anti-inflammatory drug, and Orphenadrine, a muscle relaxant, targets distinct nociceptive pathways to potentially enhance analgesia and reduce opioid consumption. This systematic review aims to evaluate the analgesic efficacy and safety profile of the fixed-dose combination of Diclofenac and Orphenadrine for postoperative pain management and quantify its opioid-sparing effect compared to standard monotherapies or placebo. Methods: A systematic search of electronic databases (MEDLINE, Scopus) and clinical trial registries (including ClinicalTrials.gov and CTIS) was conducted up to 20 September 2025. Fourteen (14) randomized controlled trials (RCTs) involving 981 adult patients undergoing various surgical procedures were included. Due to high clinical and methodological heterogeneity, a Synthesis Without Meta-analysis (SWiM) approach was utilized. The certainty of evidence was assessed using the GRADE methodology. Results: The synthesis demonstrated that the FDC may improve pain relief (measured by the Visual Analog Scale and Numeric Rating Scale scores) and may reduce opioid consumption compared to active comparators and placebo. The opioid-sparing effect could be correlated with a reduced incidence of dose-dependent adverse events, particularly nausea and vomiting. However, the overall certainty of the evidence was graded as “Very Low” due to the high risk of bias and lack of transparency in the included studies. Conclusions: The FDC of Diclofenac and Orphenadrine is a rational addition to multimodal postoperative analgesic regimens, which may potentially reduce the perioperative opioid burden without compromising pain control. Nevertheless, because almost all included studies suffer from severe methodological flaws, these apparent efficacy findings must be interpreted with caution. Future high-quality, pre-registered, and low-bias randomized controlled trials are required to draw firm clinical conclusions. Full article

Wet stirred-media milling (WSMM) is among the most widely used techniques for producing high-drug-loaded stable nanosuspensions, owing to its ease of scale-up, good repeatability, operational versatility and broad applicability. However, WSMM is also associated with high energy demand, substantial heat generation, and extended milling times. To reduce energy consumption, optimize the process and gain a deeper understanding of breakage kinetics, robust mechanistic models should be investigated. In this study, a microhydrodynamic (MHD) model framework is examined, and the first closed-form analytical solution for granular temperature $\theta$, a key parameter in the MHD model, is derived. In addition, an existing power consumption correlation from the literature is adopted and extended by introducing an additional parameter that accounts for bead-size effects, and the resulting improved formulation is embedded into the analytical framework. This integration facilitates continuous evaluation of power consumption, $\theta$ and the additional MHD parameters across the milling parameter space. With backward compatibility and high-quality fitting performance, the improved power consumption model enables robust, reliable, and systematic evaluation of sensitivities and trade-offs over diverse milling conditions, including varying stirrer speeds, bead loadings, and bead sizes. Full article

Background and Objectives: Sleep is a vital psychological function for health and well-being in all age groups, from children to adolescents, to adults and the elderly, and impacts quality of life. This study evaluated temporal changes in sleep quality and lifestyle behaviors among medical students in North-Western Romania (Transylvania) between the COVID-19 pandemic and the post-pandemic period. Materials and Methods: A cross-sectional design was employed involving 709 medical students assessed during the first pandemic wave (2020) and the 2023–2024 academic year. Online questionnaires collected data on demographics, body mass index (BMI), substance use, and physical activity. Sleep quality was measured using the validated Athens Insomnia Scale (AIS), and multiple linear regression was performed to identify predictors of sleep outcomes. Results: Post-pandemic data revealed a significant decline in sleep quality, with female gender and lower academic performance identified as significant predictors of insomnia symptoms (R² of 0.258, p < 0.05). While physical activity levels improved significantly in 2024 compared to the confinement period, this was accompanied by increased fast-food consumption and a rise in overweight and obesity rates. Conversely, illicit drug use decreased, and alcohol consumption patterns shifted, characterized by reduced weekly frequency among females but persistent binge drinking episodes. Conclusions: The transition to post-pandemic education yielded mixed health outcomes; while physical activity rebounded, sleep quality and nutritional status deteriorated. These findings highlight the necessity for university-based interventions focusing on sleep hygiene, nutrition, and stress management to support the well-being of medical students. Full article

Background: Magnesium sulfate (MgSO₄) added to local anesthetics has been investigated as an adjuvant in regional anesthesia, but its role in ultrasound-guided erector spinae plane block (ESPB) remains uncertain. Methods: We conducted a PRISMA 2020-compliant systematic review of randomized controlled trials evaluating MgSO₄ added to the local anesthetic solution in ESPB. In the predefined core comparison (MgSO₄ added to local anesthetic vs. local anesthetic alone in adult postoperative surgery), four trials (225 participants enrolled; 160 contributing to the comparison) informed the qualitative synthesis. Results: Eight randomized controlled trials were included. In the predefined core comparison, 24 h pain intensity was reported heterogeneously and was frequently not extractable as continuous data, precluding pooling. Opioid consumption or rescue analgesia more often favored MgSO₄; however, outcome metrics, analgesic drugs, and assessment windows were not harmonized, and these effects were not consistently accompanied by reductions in pain intensity at 24 h, limiting their interpretation as true analgesic benefit. Safety reporting was frequently incomplete and often lacked structured adverse event tabulation. Risk of bias varied across domains, and GRADE certainty for all core outcomes was very low. Conclusions: Current randomized evidence does not support routine use of MgSO₄ as an adjuvant in ESPB. Future trials using standardized ESPB techniques, harmonized magnesium dosing strategies, and core outcome sets are required to determine whether magnesium provides clinically meaningful incremental analgesic benefit. Full article

Background: Ectopic fat deposition has been demonstrated to play a critical role in the onset and progression of renal dysfunction. However, research on renal parenchymal fat deposition and its association with renal dysfunction in type 2 diabetes mellitus (T2DM) remains limited, particularly regarding its association with early kidney injury. The present study aimed to further investigate the relationship between renal fat fraction (FF) and biomarkers of kidney injury, thereby providing new evidence for the potential link between intrarenal fat accumulation and early renal impairment in T2DM. Methods: This cross-sectional study enrolled 60 patients with T2DM. Renal FF was quantitatively assessed using magnetic resonance imaging (MRI). Clinical characteristics, body composition parameters, and biochemical indices were collected. Levels of kidney injury biomarkers, including tumor necrosis factor receptors 1 (TNF-R1), tumor necrosis factor receptors 2 (TNF-R2), chitinase-3-like protein 1 (YKL-40), and kidney injury molecule-1 (KIM-1), were measured using enzyme-linked immunosorbent assay (ELISA). To evaluate the correlations between fat distribution and inflammatory biomarkers, Pearson correlation analysis was performed. Furthermore, linear regression analysis was conducted to explore the associations between renal FF and kidney injury biomarkers with adjustments for potential confounders such as smoking status, diabetes duration, and visceral fat. Lasso regression was used to screen variables. Results: The results demonstrated that renal FF was significantly positively correlated with serum YKL-40 (r = 0.3, p = 0.021), TNF-R1 (r = 0.246, p = 0.042), and urinary KIM-1 (r = 0.396, p = 0.004), indicating a close association between renal fat accumulation and early kidney injury biomarkers. In regression analyses adjusted for age, sex, and duration of diabetes, the associations between renal FF and these biomarkers remained significant. After further adjustment for potential confounders, including smoking history, alcohol consumption, hypertension, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, glucagon-Like Peptide-1 (GLP-1) receptor agonists, and lipid-lowering drugs, renal FF remained significantly associated with TNF-R1 (β = 0.327, p = 0.015), KIM-1 (β = 0.352, p = 0.021), and YKL-40 (β = 0.275, p = 0.025). Moreover, even after additional adjustment for visceral fat, the associations of renal FF with TNF-R1 and KIM-1 persisted. After using the Benjamini–Hochberg procedure for false discovery rate, the relationship between renal FF and KIM-1 had a significant difference. Variables of age and gender were excluded to build the parsimonious modeling using Lasso regression. It suggested that renal fat accumulation may contribute to kidney injury independently of visceral adiposity. Conclusions: The study systematically demonstrates a significant association between renal FF and early biomarkers of kidney injury in T2DM, which may suggest the potential role of renal fat accumulation in the pathogenesis of diabetic nephropathy. These findings provide clinical data support for the development of a fat-targeted intervention study. Future research should further elucidate the long-term mechanistic role of renal FF in diabetic nephropathy, as well as its potential value in early diagnosis and therapeutic applications. Full article

Background and Objectives: Ketamine and magnesium sulfate (MgSO₄) are NMDA receptor antagonists that act through distinct mechanisms. Preclinical data indicate that their analgesic interaction is sequence-dependent: ketamine administered before MgSO₄ produces synergistic antinociception, whereas the reversed sequence is antagonistic. The primary outcomes were postoperative pain intensity (Numerical Rating Scale, NRS 0–10, at rest and on movement) and cumulative intravenous morphine consumption over 48 h, evaluated in patients undergoing open radical nephrectomy to test the hypothesis of sequence-dependent analgesic interaction. Materials and Methods: In this randomized, double-blind, placebo-controlled trial, 208 patients scheduled for elective open radical nephrectomy received two sequential intravenous boluses intraoperatively: Drug A immediately after induction, Drug B 10 min later. Agents were ketamine 0.2 mg/kg, MgSO₄ 15 mg/kg, or placebo (0.9% NaCl) in all nine possible combinations. Primary outcomes were postoperative pain intensity (NRS 0–10, at rest and on movement) and cumulative intravenous morphine consumption, assessed at 14 time points over 48 h. Secondary outcomes included sedation, nausea, vomiting, and the presence of hallucinations. Results: The ketamine → MgSO₄ (K → Mg) sequence significantly reduced NRS pain scores compared to placebo at multiple time points, including 30 min, 1 h, 3 h, 6 h, and 32 h postoperatively, with differences exceeding the minimum clinically important difference of 2 NRS points at the earliest assessments. The MgSO₄ → ketamine (Mg → K) sequence did not differ from placebo at any time point. Cumulative morphine consumption was comparable across groups. No hallucinations or psychomimetic events were observed. Conclusions: Intraoperative ketamine followed by MgSO₄ (K → Mg) provides clinically meaningful postoperative analgesia after open radical nephrectomy; the reversed sequence (Mg → K) offers no benefit over placebo. These findings provide the first clinical confirmation of sequence-dependent NMDA receptor antagonism and support the K → Mg protocol as a safe, simple addition to multimodal perioperative analgesia. Trial registration: ISRCTN registry, ISRCTN83633282. Full article

Background/Objectives: Non-specific chronic neck pain is one of the biggest problems in the current population, with high levels of pain and disability and a decrease in the quality of life. The aim of this study is to assess possible variables that may be associated with neck pain, such as disability, pain, quality of life, sex, neck muscle endurance, active range of motion (AROM) and frequency of drug use. Methods: We performed a cross-sectional study of non-specific chronic neck pain with a total of 105 subjects. The variables pain-related disability, pain, quality of life, sex, AROM and frequency of drug use were evaluated. Results: A total of 105 patients with chronic neck pain were included (mean age 40.47 ± 12.18 years; 67.6% women). Neck pain–related disability showed significant negative correlations with all cervical AROM variables, particularly left rotation (r = −0.507) and right rotation (r = −0.489) (p < 0.001). Disability was also negatively correlated with health-related quality of life (r = −0.604) and positively correlated with pain intensity (r = 0.414) and frequency of drug consumption (r = 0.546) (p < 0.001). Regression analyses indicated that disability was associated with reduced left rotation mobility and higher drug consumption (R² = 0.424). Pain intensity was associated with female sex, reduced right rotation mobility, and higher drug consumption (R² = 0.246). Lower health-related quality of life was associated with higher drug consumption and female sex (R² = 0.174). Conclusions: Being female, having a reduction in active rotational mobility, and a high frequency of drug consumption are associated with greater pain-related disability and pain intensity, and a lower HRQoL in subjects with non-specific chronic neck pain. Full article

Background: Oral squamous cell carcinoma (OSCC) is an aggressive cancer closely associated with smoking and alcohol consumption, with a higher incidence in men. Despite changes in treatment strategies, poor survival persists in most patients, highlighting the need for novel and improved therapeutic options. Naphthoquinone analogs are being investigated because of their active redox structure and broad pharmacological profile; they demonstrate cytotoxic antitumor activity, making them potential candidates for new drug agents. Objective: This study investigated new benzyl-naphthoquinone compounds as potential anticancer agents for various genotypes of oral squamous cell carcinoma (OSCC) and other cancer cells. Methods: This study reports the synthesis and evaluation of a series of eight benzyl-naphthoquinone compounds against oral squamous cell carcinoma. Results: Four compounds 1–4 showed the best cytotoxic profiles, with a selectivity index ≥ 3 for all OSCC cell lines tested. Compound 1 was the most selective compound in all OSCC models, showing a higher selectivity index than both carboplatin and shikonin. Furthermore, compound 1 induced DNA fragmentation, cell-cycle arrest, and caspase-3/7 activation, changes consistent with apoptosis, and time-lapse imaging corroborated the apoptotic phenotype. Hemolysis assays showed minimal toxicity in human erythrocytes, and acute in vivo evaluation in mice revealed no evident adverse effects under the conditions tested, indicating low acute toxicity, although more detailed histopathological and biochemical studies will be required to fully establish the safety profile. Molecular modeling suggested that compound 1 may interact with topoisomerase II, RSK2, and PKM2, which could contribute to the activation of apoptotic pathways, although these interactions remain predictive and require biochemical validation. Finally, in silico analysis of physicochemical and ADMET parameters indicated properties compatible with oral absorption and systemic exposure, together with predicted low toxicity; however, these results are model-based and should be confirmed experimentally. Conclusions: Based on these findings, compound 1 emerges as a promising lead candidate for the development of a novel chemotherapeutic agent against OSCC, with potential therapeutic efficacy against other cancer types. Full article

Background/Objectives: Among the antiretroviral therapies (ARTs) recently introduced for people living with HIV (PLWH), the fixed-dose combination of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) became reimbursable in Italy in June 2019. Methods: This study evaluated drug utilization, healthcare resource consumption and direct costs among ART-naïve adults initiating B/F/TAF or other non-bictegravir-based regimens, identified from June 2019 to September 2022 within administrative databases of healthcare entities covering approximately nine million citizens. Baseline clinical characteristics at first ART prescription were compared across B/F/TAF-treated patients, those receiving other ART regimens, and non-HIV controls, while treatment outcomes during follow-up were evaluated among PLWH receiving B/F/TAF or other ARTs; healthcare consumption and costs were assessed after propensity score matching within the PLWH cohorts only. Results: Overall, 374 individuals initiated B/F/TAF and 5576 other ARTs. Patients treated with B/F/TAF showed greater adherence and persistence, with multivariate analyses confirming a lower risk of discontinuation or switching (HR = 0.66, 95% CI 0.57–0.76, p < 0.001) and a higher likelihood of adherence (HR = 2.40, 95% CI 1.58–3.64, p < 0.001). After matching, the B/F/TAF group exhibited lower 12-month consumption of non-HIV medications, fewer non-HIV hospitalizations, and reduced total healthcare costs, particularly for non-HIV drug prescriptions compared to other ART users. Conclusions: Overall, B/F/TAF was associated with better treatment continuity and meaningful cost savings. Full article