Pakistan journal of pharmaceutical sciencesMuhammad Sajid Nawaz, Muhammad Zaman, Huma Hameed, Waqar Siddique, Ahmad Salawi, Yosif Almoshari, Jawaher Abdullah Alamoudi
BACKGROUND: Multiparticulate Drug Delivery (MDD) system are particularly considered as well suited systems for controlling oral preparations that have low risk of dose-dumping. OBJECTIVES: The current research work was aimed to prepare Fexofenadine HCl immediate release (IR) and Paracetamol sustained release (SR) pellets in a single dosage unit for the treatment of Allergic Rhinitis. Extrusion-spheronization was used to fabricate pellets. METHODS: The formulations were analyzed for several parameters, including micromeritic studies, Friability, Weight variation test, Swelling, X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), in-vitro release and stability studies. RESULTS: The results showed that the formulated pellets have an excellent flowability (23.01° to 25.23°), bulk density falls in the range of 1.23 g cm -3 to 1.42 g cm -3 , tapped density ranges 1.43 g/cm 3 1.58 g/cm 3 , carr's compressibility index lie between 10.31 % to 15.17 %, Hausner's ratio ranges 1.11 to 1.18 which concluded pellets had good flow properties. Friability was less than 1%; the T6 formulation showed the maximum swelling of 99.28%. No interaction between excipient and drug was found. T6 showed a drug release of 99.08% in 24 hours. CONCLUSION: The research effectively demonstrated that preparing a single-unit dosage form of paracetamol and fexofenadine is a safe, simple and promising technique for SR of Paracetamol, thereby increasing patient compliance by reducing the dosage frequency.
Pakistan journal of pharmaceutical sciencesSana Hassan, Sadia Jafar Rana, Saman Zafar, Tahir Ali Chohan, Qalander Khan, Khizar Abbas, Muhammad Sohail Arshad
BACKGROUND: Chemotherapy-induced alopecia negatively impacts the mental health of cancer patients. Topical minoxidil, a widely recommended drug for hair regrowth, causes scalp irritation and contact dermatitis. Oral minoxidil causes multiple cardiovascular and neurological side effects. Cetirizine hydrochloride, an antihistamine with a better safety profile than minoxidil, may stimulate hair follicle activity by modulating prostaglandin levels. OBJECTIVES: The present study aimed to develop a cetirizine hydrochloride-loaded emulgel and evaluate its potential, in combination with microneedling, for the treatment of chemotherapy-induced alopecia. METHODS: Different emulgel formulations comprising cetirizine HCl, liquid paraffin, carbopol 940, propylene glycol, oleic acid, Tween 20, Span 20 and propylparaben were optimized using central composite design and response surface methodology. Physicochemical evaluation of the prepared emulgel included physical examination, determination of pH, viscosity, spreadability, drug content and stability. Interactions and compatibility among formulation constituents were assessed using In-silico analysis and Fourier transform infrared spectroscopy. In-vitro drug release, ex-vivo permeation and in-vivo hair growth studies were carried out to evaluate the performance efficiency of emulgel. RESULTS: The prepared emulgels exhibited acceptable physicochemical properties and remained stable for 3 months. Constituents were found to be compatible with each other. The optimized formulation F4 released >95% drug at pH 5.5 within 360 minutes. During an ex-vivo study, ~94% of the drug permeated across rat skin within 6 hours following application of emulgel on the microneedle-pretreated skin. In cyclophosphamide-induced alopecia in rats, application of emulgel to microneedle-pierced skin for 15 days promoted hair growth. CONCLUSION: The prepared cetirizine HCl-loaded emulgel and microneedle combination may be a promising approach to treating chemotherapy-induced alopecia.
Pakistan journal of pharmaceutical sciencesWeimin Kong, Yiting Yang, Xinru Guan, Yanting He, Caixia Yan, Tao Ma
BACKGROUND: Drug metabolism may be influenced by pregnancy. Use of acetaminophen (APAP) is prevalent among pregnant women, necessitating the development of effective methods for predicting its in-vivo disposition. OBJECTIVES: A whole physiologically based pharmacokinetic model was developed to predict the pharmacokinetic behavior of APAP following oral or intravenous administration in both healthy subjects and pregnant women across different trimesters (first, second, and third trimesters). METHODS: Phoenix WinNonlin 8.4 was used to establish the model, which was verified by literature data and the fold error method. Sensitivity analysis was used to identify the factors most sensitive to the model results. RESULTS: The model was established successfully. The clearance rate and half-life of intravenous APAP increased during pregnancy and the changes were more obvious with the increase of pregnancy trimesters. Theoretically, adjusting the oral and intravenous doses for pregnant women in the third trimester to 1.23 and 1.16 times those administered to healthy individuals may yield a comparable area under the curve in healthy subjects. According to the sensitivity analysis results, the influencing factors were ranked from largest to smallest as follows: activity of sulfatase > activity of glucuronidase > the constant of the gastrointestinal transport rate > activity of CYP450. CONCLUSION: Pregnancy affects the metabolism of APAP and more attention should be paid to pregnant women in clinical medication.
Environmental monitoring and assessmentMohammadreza Ahmadi, Rasool Zamani-Ahmadmahmoodi, Seyed Mehdi Amininasab, Atefeh Chamani
Anthropogenic expansion has intensified heavy metal pollution in aquatic ecosystems, posing a severe threat to avian biodiversity. This study utilizes bird eggshells as non-invasive biomarkers to assess lead (Pb) and cadmium (Cd) contamination in the Gandoman Wetland, Iran. During the 2023 breeding season, eggshells were collected from three species with distinct ecological roles: the common tern (Sterna hirundo), the black-necked grebe (Podiceps nigricollis), and the Eurasian coot (Fulica atra). Metal concentrations were determined using an Agilent 240FS AA atomic absorption spectrometer (Agilent Technologies, USA). The results revealed that Pb concentrations consistently exceeded Cd levels across all species, a phenomenon attributed to the ionic mimicry of Pb2+ with Ca2+ during shell mineralization. Notably, mean concentrations for both metals significantly exceeded established hazard thresholds (Pb: 4 mg/kg; Cd: 2 mg/kg) in all species. The common tern, a high-trophic level piscivore, exhibited the highest mean concentrations (Pb: 424.29 mg/kg; Cd: 23.39 mg/kg), while lower concentrations were recorded in the black-necked grebe (Pb: 174.60 mg/kg; Cd: 1.75 mg/kg) and the Eurasian coot (Pb: 44.58 mg/kg; Cd: 2.38 mg/kg). One-way ANOVA confirmed significant interspecific differences (P < 0.05), supporting the trophic level hypothesis of bioaccumulation. Pearson correlation analysis showed nonsignificant relationships between Pb and Cd, suggesting distinct pollution sources, likely industrial effluents for Pb and agricultural runoff for Cd. These findings characterize Gandoman Wetland as a high-risk environment and highlight the urgent necessity for stringent pollution control and management strategies to safeguard wetland-dependent bird populations.
European journal of nutritionChristina Breidenassel, Volker Böhm, Ibrahim Elmadfa, Maren Podszun, Karl-Heinz Wagner, Stefan Lorkowski
PURPOSE: The scientific knowledge for the essential fat-soluble vitamin E (VitE) remains inconclusive. There is still a lack of valid status parameters and deficiency symptoms for insufficient intake. Therefore, the derivation of a dietary reference value (DRV) for VitE is challenging and differs between the different organizations and countries. The aim of the current paper is to provide an overview of selected international DRVs and discuss the different derivation procedures. METHODS: DRVs from sixteen countries and international organizations were retrieved, compared and evaluated. RESULTS: The DRVs are inconsistent in the absolute value as well as the employed concept of derivation. Due to the uncertainty of the available data some organizations did not specify a DRV. Others used plasma cut off levels or the required amount for the protection of polyunsaturated fatty acids against oxidation. Many DRVs are based on population intake data and given as adequate intake. But this approach may overestimate the VitE needs. CONCLUSION: In conclusion, due to missing symptoms and markers of insufficient supply, the compensation of daily losses with the consideration of the bioavailability appears to be a good basis for deriving a DRV for VitE intake. A balanced and plant-based diet (without supplements) appears to be sufficient for an adequate VitE supply.
The AAPS journalLaura G Al-Amiry Santos, Chara Litou, Karen Rowland Yeo
Nilotinib is reported to have a reduced maximal drug concentration (Cmax) in patients with hepatic impairment (HI). Given this compound is poorly soluble, highly lipophilic and has a positive food effect, reduced absorption in HI may be due to impaired micelle-mediated solubility resulting from reduced intestinal bile salts. PBPK modelling can be used to test this hypothesis as well as being a diagnostic tool to elucidate other potential mechanisms not captured by the base model. In this study, a mechanistic PBPK model for nilotinib was developed and its performance was evaluated in HI patients. A 'learn-and-confirm' approach was taken, using clinical food effect data to validate the model's mechanistic sensitivity to bile salt-mediated solubility. The final model recovered clinical studies well, with area-under-the-curve (AUC) and Cmax being within 0.8 - 1.25-fold for fasted studies and 1.5-fold for fed/fasted ratios. AUC and Cmax were well recovered in mild HI (within 0.8 - 1.25-fold) and reasonably well recovered in moderate HI (within twofold) but significantly overpredicted in severe HI (> twofold). Bile salt concentrations were reduced across gastrointestinal segments for moderate and severe HI in line with in vitro data. Following twofold and 2.5-fold reductions in bile salts in moderate and severe HI, respectively, sensitivity was minor. Given uncertainty around the fugut, this was reduced to better recover the Cmax (within two-fold). PBPK modelling can be used as a diagnostic tool to evaluate impaired mechanisms in HI.
The AAPS journalChandrika Chaturvedi, Carman Giacomantonio, H P Vasantha Rupasinghe
Skin cancer continues to pose a significant global health burden, with conventional therapeutic modalities limited by systemic toxicity, poor tumor selectivity, and the development of therapeutic resistance. Glucosinolates (GLs) and their hydrolyzed product, sulforaphane, have attracted considerable interest as chemopreventive and therapeutic agents owing to their potent antioxidant, anti-inflammatory, and pleiotropic anticancer activities. However, the clinical translation of these phytochemicals is severely hindered by their chemical instability, rapid metabolism, and poor bioavailability. Nanocarrier systems, particularly biodegradable polymeric nanoparticles such as poly(lactic-co-glycolic acid) nanoparticles, offer a promising strategy to overcome these barriers by enhancing compound stability, improving bioavailability, and enabling tumor-targeted delivery via the enhanced permeability and retention effect. This review critically evaluates recent progress in the development of GL and sulforaphane-loaded nanocarriers, detailing their physicochemical properties, in vitro and in vivo anticancer efficacy, and safety profiles, highlighting their potential to advance more effective and less toxic therapeutic strategies for skin cancer prevention and treatment.
Annals of medicineHong-Yu Long, Yong-Mei Wu, Xue Li, Bai-Qing Chen
BACKGROUND: To compare the predictive performance of computed tomography (CT) body composition indices, anthropometric indices, and laboratory indices for gallstones occurrence, and to construct machine-learning models to improve performance. METHODS: The dual-center retrospective cohort enrolled patients who underwent initial abdominal CT between January 2017 and January 2023, had no gallstones detected, and completed at least 3 years of follow-up. The data analysis was performed in April 2026. They were divided into gallstone group and non‑gallstone group by follow‑up findings. A deep-learning tool, Body and Organ Analysis (BOA), was used to quantify fat, muscle, and bone at the level of the third lumbar vertebra. The area under the receiver operating characteristic curve (AUC) of these indices was compared with that of anthropometric and laboratory indices. Predictive models were developed in the training cohort. Model performance was evaluated using fivefold cross-validation and an independent test cohort. RESULTS: 1,944 patients were evaluated, including 1,437 in the training cohort (Center 1; median age, 63 years [25th-75th percentile, 55-72]; 699 males) and 507 in the test cohort (Center 2; median age, 63 years [55-71]; 266 males). In univariate analysis, neutrophil-to-lymphocyte ratio (NLR) showed the highest AUC (0.627, 95% confidence interval [CI]: 0.586-0.668). The extreme trees (ET) model performed best, with a test-set AUC of 0.772 (95% CI: 0.714-0.822). SHapley Additive exPlanations (SHAP) analysis identified the area ratio of subcutaneous to total fat as the most important feature. CONCLUSIONS: NLR was the best single predictor but had limited standalone utility. Among models integrating the three indicator categories, the ET performed best.
Extremophiles : life under extreme conditionsSrijana Tiwari, Prasansah Shrestha, Bashu Dev Pardhe, So-Ra Han, Tae-Jin Oh
Rahnella species are environmentally versatile bacteria widely distributed in terrestrial and aquatic ecosystems; however, the genomic basis of formaldehyde detoxification and stress adaptation in cryoconite-associated Rahnella remains poorly understood. In this study, we performed phylogenomic, comparative genomic, pan-genomic, stress-response, and functional analyses of Rahnella sp. PAMC25617 isolated from polar cryoconite to investigate glutathione (GSH)-dependent formaldehyde detoxification and its evolutionary conservation. Genome-based phylogeny, average nucleotide identity (ANI), and digital DNA-DNA hybridization (dDDH) analyses demonstrated that PAMC25617 represents a distinct genomic lineage within the genus Rahnella. The draft genome comprised 5.33 Mb with a GC content of 52% and encoded multiple genes associated with formaldehyde detoxification and one-carbon metabolism, including frmA, yeiG, yeiP, yeiR, and a putative formate dehydrogenase gene cluster. Comparative genomic analyses further showed that these detoxification genes were consistently associated with GSH transport (gsiA-D), redox-associated (frdA-D), and regulatory (fnr) genes, suggesting coordinated roles in detoxification and redox homeostasis. Comparative stress-response gene profiling across 121 Rahnella genomes further revealed widespread conservation of oxidative stress defense systems, including oxidoreductases, aldehyde dehydrogenases, GSH-associated enzymes, thioredoxin, catalase, and molecular chaperones. Notably, PAMC25617 possessed an enriched repertoire of oxidative stress and detoxification-related genes, indicating enhanced stress adaptation potential in cold and chemically challenging environments. Pan-genome analysis indicated a highly diverse and open pan-genome structure with a low Heap's law exponent (γ = 0.336), reflecting ongoing genome diversification and ecological adaptation. Multiple sequence alignment (MSA) further demonstrated strong conservation of catalytic motifs and active-site residues in FrmA and YeiG among phylogenetically diverse bacteria. Physiological assays showed that PAMC25617 exhibited tolerance to formaldehyde stress under liquid culture conditions. These findings suggest that R. sp. PAMC25617 employs an integrated GSH-dependent detoxification and oxidative stress response system that may facilitate survival and adaptation in extreme polar environments.
Daru : journal of Faculty of Pharmacy, Tehran University of Medical SciencesShweta Yadav, Prashant Singh, Madhusudan Purohit, Shashikant Singh, Shobha Singh
BACKGROUND: Diabetes mellitus, a chronic metabolic disorder affecting over 537 million individuals worldwide, represents one of the most burdensome global health challenges of the 21st century. Despite the availability of numerous oral antidiabetic agents, their therapeutic effectiveness is significantly compromised by poor aqueous solubility, chemical instability in the gastrointestinal (GI) environment, extensive hepatic first-pass metabolism, low membrane permeability, and inadequate systemic bioavailability. Nanotechnology-based drug delivery systems have emerged as transformative platforms capable of circumventing these multifaceted physiological and biopharmaceutical limitations. OBJECTIVE: This comprehensive review critically evaluates the landscape of nanostructured platforms designed to enhance oral bioavailability and therapeutic outcomes of antidiabetic agents, with particular emphasis on mechanistic insights into nanoparticle-epithelial interactions, surface functionalization strategies using targeting ligands (lectins, transferrin, folic acid, bile acid conjugates), and stimuli-responsive release mechanisms. METHODS: A structured literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and ScienceDirect for articles published between January 2010 and 2026, with emphasis on publications from 2022 to 2026. We systematically analyzed and compared eleven distinct nanocarrier platforms, including polymeric nanoparticles, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), self-emulsifying drug delivery systems (SEDDS), liposomes, nanoemulsions, dendrimers, cyclodextrin inclusion complexes, mesoporous silica nanoparticles, metal-organic frameworks (MOFs), and hybrid nanocomposites, evaluating how each platform addresses specific absorption barriers including GI enzymatic degradation, mucus layer penetration, enterocyte uptake, and efflux pump activity. RESULTS: Rational formulation design, in vitro-in vivo correlations, and pharmacokinetic enhancement data indicate that nanoformulated antidiabetic drugs consistently outperform conventional formulations in bioavailability and absorption across multiple drug classes and delivery platforms. Emerging paradigms including exosome-inspired nanocarriers, CRISPR-integrated systems, and artificial intelligence-guided formulation optimization further extend the mechanistic and translational scope of oral nanomedicine for diabetes management. CONCLUSION: Nanostructured platforms offer a mechanistically diverse and increasingly translatable strategy for overcoming the physiological and biopharmaceutical barriers that limit oral antidiabetic therapy. Realizing their full clinical potential will require continued progress in addressing translational challenges, harmonizing regulatory frameworks, and advancing scalable manufacturing toward clinically viable oral nanomedicines for diabetes management.
European journal of clinical pharmacologySeerwan Hamadameen Sulaiman, Rebaz Anwar Omer, Hunar Yasin Muhammad, Amjad Mahmood Qadir, Hemn A H Barzani
PURPOSE: Quercetin is one of the most abundant dietary flavonoids and has attracted considerable interest because it can modulate xenobiotic metabolism by inhibiting and regulating drug-metabolizing enzymes and membrane transporters. However, the clinical relevance of these interactions remains uncertain because available evidence is fragmented and largely derived from preclinical studies. This systematic review critically evaluates quercetin's effects on human phase I cytochrome P450 enzymes, phase II conjugation pathways, drug transporters, and clinically relevant pharmacokinetic drug interactions. METHODS: A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Embase, and Google Scholar following PRISMA 2020 guidelines. We identified and critically synthesized original studies investigating quercetin-mediated modulation of xenobiotic metabolism, prioritizing mechanistic studies in humans, human pharmacokinetic investigations, and clinically documented drug interactions. RESULTS: Available evidence indicates that quercetin modulates several CYP450 isoforms, phase II enzymes, and major drug transporters, including P-glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptides. Nevertheless, clinically significant pharmacokinetic interactions have been demonstrated for only a limited number of substrates, primarily involving CYP2C9, CYP2E1, and P-glycoprotein, whereas many experimentally predicted interactions have not translated into clinically meaningful effects in humans. Current evidence further highlights the importance of extensive phase II metabolism, circulating conjugated metabolites, transporter-enzyme interplay, and dose-dependent systemic exposure in determining interaction risk. CONCLUSION: Current evidence supports the biological plausibility of quercetin-mediated drug interactions but indicates that their clinical significance is substrate-dependent and remains insufficiently characterized for most therapeutic agents. Well-designed human pharmacokinetic studies using standardized quercetin formulations, validated probe substrates, quantitative pharmacokinetic endpoints, and pharmacogenetic approaches are required to establish evidence-based recommendations for the safe co-administration of quercetin with conventional medications.
European journal of clinical pharmacologyLu Zhang, Lizhi Chen, Chen Ye, Xiaohong Liu, Zhijun Huang, Kejing Tang, Pan Chen, Xiaoyun Jiang
OBJECTIVE: To identify determinants of mycophenolic acid (MPA) pharmacokinetics (PK) in pediatric patients with lupus nephritis (LN), and to develop a limited sampling strategy (LSS) for estimating MPA-AUC0-12 h. METHODS: A single-center observational study enrolled biopsy-proven LN receiving mycophenolate mofetil (MMF) at least 7 consecutive days. Univariate analysis were performed to assess associations between MPA PK parameters and demographics, genetic polymorphisms, clinical variables. LSS models for predicting MPA-AUC0-12 h were developed via multivariate stepwise regression analysis. RESULTS: Statistically significant correlations were observed between MPA-AUC0-12 h and MMF dose, plasma albumin level, estimated glomerular filtration rate, and genetic polymorphisms in HNF1A (rs56097722) and CYP2C8 (rs1058932). CES2 (rs11075646) was significantly associated with MPA half-life (T₁/₂). Single timepoint MPA concentrations demonstrated poor predictive performance for AUC0-12 h(R2 = 0.194-0.553). The optimal LSS model was achieved with four timepoints: MPA-AUC0-12 h = 2.935 + 0.716·C0.5 + 1.305·C1.5 + 3.176·C4 + 4.705·C9 (R2 = 0.945). This model demonstrated good predictive performance (MPE = 1.84%, MAPE = 9.47%, RMSE = 12.53%). The LSS model was validated internally and externally for stability and applicability. CONCLUSION: Reduced MPA exposure was associated with MMF doses < 20 mg·kg⁻1·day⁻1, hypoproteinemia, preserved or mildly impaired renal function, and HNF1A rs56097722 C/C or CYP2C8 rs1058932 G/G genotypes. CES2 rs11075646 C/C tended to correlate with a shorter MPA T₁/₂. The validated LSS models are recommended for estimating MPA-AUC0-12 h in pediatric LN, which are expected to simplify the therapeutic drug monitoring process.
Clinical pharmacology in drug developmentZhichao Jiang, Wen Zhang, Chunxia Du, Yongkun Sun, Aiping Zhou
Nimotuzumab is an anti-epidermal growth factor receptor antibody. This Phase I study evaluated the pharmacokinetics and safety of nimotuzumab plus irinotecan in Chinese patients with advanced solid tumors. At single ascending dosage (SAD) stage, four cohorts (100, 200, 400, and 600 mg) of patients received nimotuzumab intravenously on Day 1, alongside irinotecan 180 mg/m2 on Day 8. Three weeks later, all patients in the four cohorts transferred to multiple ascending dosage (MAD) stage: nimotuzumab was administrated weekly for 6 weeks, alongside irinotecan (Days 1, 15, 29, 43, and 57, 180 mg/m2). Primary objective was pharmacokinetics, safety and tolerability was also examined. From December 2012 to October 2014, in SAD and MAD stages, there were 28 and 39 patients with Stage IV solid tumors. The area under the concentration curve (AUC0-∞) for a single dose of nimotuzumab was 10.2 ± 2.7 (100 mg), 37.6 ± 10.0 (200 mg), 114.8 ± 35.5 (400 mg), 197.6 ± 32.0 (600 mg) (×100 h µg/mL), and for multiple dose, it was 26.7 ± 3.4 (100 mg), 87.1 ± 12.0 (200 mg), 193.4 ± 46.9 (400 mg) and 446.3 ± 100.7 (600 mg) (×100 h µg/mL). There was low incidence of rash and no dose-limiting toxicities occurred. This study indicated that nimotuzumab at doses ranging from 100 to 600 mg exhibited a manageable and tolerable safety profile.
CPT: pharmacometrics & systems pharmacologyNazanin Ahmadi Daryakenari, Mohammad Kohandel
Inverse problems in pharmacometrics and quantitative systems pharmacology (QSP) often involve sparse, noisy data, limited measurable states, and complex dynamical systems. Traditional parameter estimation methods can struggle with ill-posed problems, stiffness, discontinuities, and gray-box scenarios where only part of the system dynamics is known or observable. This tutorial provides an end-to-end, reproducible workflow for applying physics-informed neural networks (PINNs) to PK/PD/QSP inverse problems and gray-box discovery tasks. We present three worked case studies: (1) constant parameter recovery in a three-state compartmental system, (2) gray-box discovery of an unknown right-hand-side function, and (3) inference of a time-varying chemotherapy efficacy function under partial observation. For each, we provide implementation guidance, validation checks, and practical advice on collocation design, feature expansion, optimizer selection, numerical precision, constraint enforcement, loss weighting, and residual-based attention. We also discuss when to consider newer architectures such as Kolmogorov-Arnold networks (KANs) as drop-in alternatives to standard multilayer perceptrons. All code and notebooks are provided through our PhINs library, short for Pharmacometrics-Informed Networks, and are publicly available at https://github.com/NazAhmadi/PhINs/.
Cerenkov luminescence imaging (CLI) enables noninvasive and real-time tracking of the in vivo distribution of radiopharmaceuticals by detecting Cerenkov optical signals generated during radionuclide decay. However, biological tissues exhibit strong scattering and absorption in the visible spectrum, which not only markedly attenuate Cerenkov signals but also cause discrepancies between the detected optical signals and the actual in vivo distribution of radiopharmaceuticals, thereby limiting the imaging accuracy of CLI. Here, we demonstrate that skin optical clearing alleviates this limitation and enhances the spatial fidelity of CLI images. An absorbing-molecule-based optical clearing treatment markedly decreased the tissue reduced scattering coefficient, increasing visible light transmittance through mouse skin by more than 50-fold (from 0.47% to 24.55%) while reducing skin reflectance by approximately 68.8%. Using 68Ga as the radiotracer, the agreement between CLI and positron emission tomography (PET) was substantially improved, with the Pearson correlation coefficient increasing from 0.55 to 0.78 and the Spearman correlation coefficient from 0.63 to 0.82. After a 15-day recovery period following optical clearing treatment, the treated mouse showed hair regrowth and signs of skin recovery. These results support the potential of optical clearing as a simple and effective strategy for improving the spatial correspondence of CLI with radiopharmaceutical distribution.
Archives of microbiologyAshok Shivaji Jagtap, Ajith Chandrasekar, Cathrine Sumathi Manohar, Ashutosh Shankar Parab, R Rajyashree, Nagaraj P Vijay Sankar
Enzyme-assisted extraction is an emerging sustainable alternative to solvent based methods for recovering bioactive molecules from seaweed or macroalgal biomass. This study investigated the macroalgae-associated fungi as sources of extracellular enzymes for bioconversion of macroalgal biomass and the concurrent enhancement of bioactive properties. About 100 fungal isolates associated with macroalgae were isolated and characterized based on qualitative plate assays and quantitative enzyme activity for the production of cellulase, xylanase, agarase, alginate lyase, and ulvan lyase. Based on enzyme activity ranging from 1063 to 10,234 U ml- 1, four yeast isolates and one filamentous fungus were selected for solid-state fermentation of macroalgae Gracilaria corticata, Sargassum cinereum and Chaetomorpha antennina. The biochemical composition of reducing sugar, total phenolic and protein content in the seaweed hydrolysates obtained from solid state fermentation was significantly higher than the uninoculated control. The enzymatic hydrolysates of all the three macroalgal biomass, exhibited almost twice the antioxidant activity than its non-enzymatic control. However, antiglycemic activity was observed only in S. cinereum hydrolysate which ranged about 20 to 40%, which was significantly higher than the control. Significant correlation between the biochemical constituents and antioxidant activity was observed in the enzymatic hydrolysates of G. corticata, S. cinereum and C. antennina. Positive correlation was also observed between the protein content with antioxidant and antiglycemic activity in the hydrolysate of S. cinereum. This shows that the microbial enzymes have the potential for the bioconversion of macroalgal biomass, into bioactive molecules for sustainable diabetes management and for related health care applications.
CPT: pharmacometrics & systems pharmacologyTrevor N Johnson, Fiskani Kondowe, Joyce van der Heijden, Saskia N de Wildt, Iain Gardner, Karen Rowland Yeo
Physiologically based pharmacokinetic (PBPK) models are increasingly used in pediatric drug development and matching such models to the target population is an important consideration. A US pediatric PBPK model was developed incorporating four sub-groups describing physiology and enzymatic/transporter levels for White, African American, Hispanic/Latino and Asian subjects. Virtual populations could then be created reflecting the demographics of the clinical study design. Ten different drugs (14 studies) were used to verify the pediatric PBPK model performance. Predicted PK parameters showed reasonable agreement with observed data, 50% of the predicted: observed values were within 0.8-1.25-fold, 74% within 0.67-1.5-fold, and 97% within 0.5-2-fold. There was minimal difference for most drugs in performance between the mixed US and North European pediatric populations. This was partly due to reported studies having low numbers of subjects and under-representation of some ethnicities. Power calculations showed that to detect a pharmacokinetic difference for the CYP3A4/5 substrates midazolam, sirolimus and tacrolimus between African American and White American children with a power of 80%, 25, 18 and 12 subjects respectively, in each group would be needed. Developing adult and pediatric PBPK models to closely match study populations is important due to their increased regulatory use and with the move to their application in personalized medicine. Such models may also help to bridge some of the ethnic differences not captured in pediatric clinical studies due to the low numbers of subjects.
Pharmacology research & perspectivesKowser Miah, Jitendar Reddy, Pradeep Sharma, Ike Igwegbe, Simon Nelson, Caitlin Muldoon, Ronald Goldwater, Karthick Vishwanathan
Savolitinib is an oral, potent, selective CNS-penetrant MET-tyrosine kinase inhibitor that in vitro studies indicate is metabolized by cytochrome P450 (CYP) enzymes, including CYP1A2, and by non-CYP enzymes, such as aldehyde oxidase (AO). Savolitinib primary metabolites, M2 and M3, are formed mainly by CYP1A2 and AO, respectively. This Phase 1, open-label study evaluated the impact of CYP1A2 inhibition by fluvoxamine on the pharmacokinetics of savolitinib and its metabolites in 16 healthy male volunteers. Volunteers received a single oral dose of 300 mg savolitinib and, following a ≥ 10-day washout period, 50 mg twice-daily oral fluvoxamine for 6 days, with a single oral dose of 300 mg savolitinib co-administered on Day 5. Serial pharmacokinetic samples were collected during both study periods. Savolitinib, M2, and M3 were measured using high-performance liquid chromatography with tandem mass spectrometry. Systemic exposure of savolitinib increased by approximately 2-fold (maximum plasma concentration) and 3-fold (area under the plasma concentration-time curve from time 0 to infinity) when savolitinib was administered with fluvoxamine compared with savolitinib alone. Systemic exposure of M2 and M3 decreased and increased, respectively, when savolitinib was administered with vs. without fluvoxamine, while the ratio of M2/savolitinib was reduced and that of M3/savolitinib remained unchanged. These data suggest a significant drug-drug interaction between savolitinib and the strong CYP1A2 inhibitor, fluvoxamine, and that CYP1A2 is involved in the formation of M2, but not M3. No new safety concerns were observed when savolitinib was administered alone or with twice-daily fluvoxamine.
Medical physicsZhen Jiang, Stephen Sawiak, Alexandra Lipka, Xin Shen, Uzay Emir, Ali Özen, Mark Chiew, Justin Geise, Joseph Speth, Deng-Yuan Chang, Jessica Veenstra, Mitchell…
BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIONs), such as ferumoxytol, are promising theranostic agents that can be assessed with MRI. Relaxation time mapping can provide reproducible and quantitative biomarkers of SPION distribution, suitable for longitudinal and cross-individual studies. However, conventional approaches suffer from strong susceptibility artifacts, long echo times (TE), and prolonged scan times, which limit the accurate quantification of SPION biodistribution. PURPOSE: To address the limitations of conventional approaches, this study aimed to develop a fast, B1 +-corrected T 1 mapping protocol based on PETALUTE (a 3D dual-echo ultrashort echo time MRI sequence with a petal-like rosette k-space trajectory) using a variable flip-angle (VFA) acquisition for T1 mapping to assess ferumoxytol distribution. METHODS: Agarose phantoms containing 0-5000 µg/mL ferumoxytol were scanned on a preclinical 7T MRI system using PETALUTE and RARE-VTR (rapid acquisition with relaxation enhancement and variable repetition time). PETALUTE T1 maps were computed from two VFA acquisitions (4° and 20°). Mean R1 values were correlated with ferumoxytol concentration to assess the method's reliability. For in vivo feasibility testing, mice bearing 4T1 mammary tumors and flank tumors were assigned to the control (n = 1) or ferumoxytol-injected group (n = 2; 40 mg/kg i.v.). Abdominal MRI scans were performed 24 h post-injection with both PETALUTE and RARE-VTR. Regions of interest in the thigh muscle, mammary tumors, and flank tumors were analyzed to compare the estimated T1 and R1 values obtained with both methods. RESULTS: In the phantom study, PETALUTE preserved positive contrast for ferumoxytol at all concentrations, whereas the conventional RARE-VTR sequence exhibited signal loss and hypointensity. For PETALUTE, there was a significant linear correlation between R1 and ferumoxytol concentration (R = 0.975, p < 0.01), while RARE-VTR showed no significant correlation (R = 0.672, p = 0.144). In vivo, PETALUTE provided high-resolution, non-gated, whole-abdominal images with short acquisition times (4 min 19 s). In ferumoxytol-injected mice, flank tumors exhibited T1 shortening, consistent with the expected iron accumulation. The dual-echo capabilities of PETALUTE facilitated observation of elevated T1 with preserved T2*-weighted signal in one of the mammary tumors. CONCLUSIONS: The proposed PETALUTE-based T1 mapping enables fast and positive-contrast ferumoxytol imaging with higher spatial coverage and more stable measurements across a wider concentration range than conventional RARE-VTR T1 mapping.
Pakistan journal of pharmaceutical sciencesAmina Arshad, Muhammad Zaman, Humayun Riaz, Muhammad Sajjad Haider, Wafa Ishaq, Sherjeel Adnan, Zeeshan Masood, Hammad Ahmed, Nabeela Ameer, Hafiz Muhammad Abd…
BACKGROUND: Pitavastatin (PVN), a BCS class-II drug, exhibits poor aqueous solubility leading to limited oral bioavailability and therapeutic efficacy. OBJECTIVES: This study aimed to enhance the solubility and anti-hyperlipidemic efficacy of Pitavastatin (PVN) by encapsulating it in chitosan-based polymeric nanoparticles. METHODS: Pitavastatin-loaded chitosan nanoparticles (NPs) were prepared using the ionic gelation method. Formulations were characterized by particle size, zeta potential, drug loading, In-vitro drug release and surface morphology. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal analysis (TGA and DSC), ex-vivo intestinal permeability and in-vivo pharmacodynamic analysis were also performed. RESULTS: The size of PVN-loaded NP ranged from 219.9±1.11 to 292.7±2.29 nm with PDI 0.2-0.4, surface charge of +28.4 ± 0.43 to 32.5 ± 1.02 mV and entrapment efficiency 65±1.12-93±1.23%. Solubility in different media (PBS (pH 6.8), 0.1N HCl (pH 1.2) and distilled water showed a 56-102-fold increase compared to PVN. SEM analysis revealed a smooth surface and spherical geometry of the NP. FTIR analysis confirmed that there was no physicochemical interaction between PVN and chitosan in NP formulations (NP1-NP5). XRD and thermal analysis indicated the amorphous nature of PVN-loaded NP. In-vitro drug release from NP formulations (NPI-NP5) ranged from 80.97±4.80 to 81±3.90% indicating sustained release, while ex-vivo intestinal permeability was 1.5-fold higher than PVN. The optimized formulation (NP1) followed Higuchi release model, indicating Fickian diffusion. Pharmacodynamic analysis of lipid profiles in hyperlipidemic albino rats suggested that NP1 reduced low-density lipoprotein (LDL) by 33±1.24 %, total cholesterol by 29±2.13% and triglycerides by 23±1.21%, showing better results than PVN. CONCLUSION: Chitosan-based Pitavastatin nanoparticles successfully enhanced drug solubility and provided sustained release, leading to improved ex-vivo permeability and greater in-vivo anti-hyperlipidemic activity in albino rats. This approach represents a promising strategy for enhancing therapeutic potential of Pitavastatin.
Molecular nutrition & food researchKawany de Faria Forato, Vinícius Dos Santos Domingues, Eduardo Lolato, Silvia Turroni, Semeh Bejaoui, Federica D'Amico, Volker Behrends, Solidea Amadei, Asia P…
Fermented foods are sources of highly bioavailable nutrients and compounds with health benefits. This exploratory study evaluated compound bioaccessibility, microbial survival and the effects of kombucha with Atlantic Forest fruits (jaboticaba, grumixama, juçara) on gut microbiota in healthy individuals. Samples underwent simulated digestion and 24 h fermentation with human fecal microbiota. Microbiota composition was analyzed by 16S rRNA amplicon sequencing, and SCFAs and BCFA were quantified. Yeasts, acetic acid bacteria, and lactic acid bacteria remained viable after digestion. Flavored kombucha (FK) showed high antioxidant activity. After 24 h, SCFAs increased, particularly acetate in FK; natural kombucha showed moderate effects, while tea and commercial kombucha caused minimal changes. Time was a major driver of variation in alpha and beta diversity, with the former declining especially with FK. The main taxonomic shifts included an increase in Enterobacteriaceae and a reduction in some beneficial taxa, with formulation-dependent specific modulation.
Molecular nutrition & food researchFrancisca Marques, M Rosário Domingues, Miguel Ângelo Cerqueira
Lipid-based nanosystems (LBNs) present a promising opportunity to harness algae-derived lipids for food and nutraceutical applications, addressing the growing consumer demand for natural and safe ingredients. Algal lipids have attracted increasing attention due to their sustainability and composition in bioactive lipids, particularly omega-3 and omega-6 polyunsaturated fatty acids and polar lipids. However, their poor aqueous solubility, susceptibility to oxidation, and variable bioaccessibility restrict their effective application in food systems. LBNs, including nanoliposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and self-nanoemulsifying systems, have been proposed to improve the delivery of algal lipids by improving their solubilization, protecting them from gastrointestinal degradation, and potentially enhancing their intestinal absorption. This review critically examines and integrates the available evidence from in vitro digestion models, cellular and ex vivo assays, as well as in vivo studies, to provide insights into how LBNs modulate bioaccessibility, intestinal absorption, bioavailability, and downstream biological activities of algal lipids. Key methodological limitations and knowledge gaps that currently hinder definitive conclusions are also discussed, with the aim of guiding future research toward more robust and translatable evidence in this field and to support the development and application of algal lipid-loaded nanosystems in functional foods, nutraceuticals, and clinical nutrition.
PharmacotherapyMaria-Stephanie A Hughes, Jeffrey C Pearson, Jasmine H Hughes
BACKGROUND: Bayesian software programs are recommended for area under the concentration-time curve (AUC)-guided vancomycin monitoring, but hesitancy remains for patients with acute kidney injury (AKI). Here, we assessed agreement between population pharmacokinetic model-based Bayesian predictions and observed vancomycin concentrations in patients with and without AKI. METHODS: Data were retrospectively analyzed from patients at 162 institutions in the United States. Courses with ≥ 2 vancomycin doses, ≥ 1 vancomycin level, and ≥ 2 serum creatinine values were included. Observed drug levels served as reference values and were classified as occurring in the absence of AKI, during new-onset AKI, or during persistent AKI. Adult, pediatric, and neonate pharmacokinetic models were assessed both a priori and a posteriori. Performance was measured using root mean squared error, mean percentage error, and the proportion of predictions within ±20% (P20) and ±30% (P30) of observed values. We also evaluated flattened priors and last-observation-only weighting as alternative Bayesian estimation approaches and reported agreement between model-predicted and model-estimated AUCs (classified as in or out of target). RESULTS: There were 30,561 adults, 5223 pediatrics, and 1865 neonates included. Prediction performance declined with AKI relative to no AKI, particularly in pediatrics, followed by neonates, with adults showing minimal deterioration. Flattened priors often improved performance, whereas last-observation-only typically worsened it. Overall AKI reduced P20 by 0%-33% and P30 by 0%-19% (absolute percentage points). AUC classification agreement was similar across no AKI, new-onset AKI, and persistent AKI groups (73%-83%, 72%-82%, and 72%-84%, respectively, a posteriori). CONCLUSION: Model predictiveness of vancomycin concentrations was worse in patients with AKI, especially in pediatrics and neonates, and generally less pronounced in persistent versus new-onset AKI. Further studies with denser pharmacokinetic sampling and elucidation of clinical implications of Bayesian-guided vancomycin dosing in AKI are needed.
Clinical pharmacology in drug developmentYing Cao, Wenping Wang, Xiaobin Li, Huawei Wang, Xiaoyan Dou, Ming Yu, Xiujun Wu, Ran Ma, Caixia Jiang, Jing Yu
The objective of the current study was to evaluate the rate and extent of absorption, and confirm the bioequivalence of a test formulation and a reference formulation of febuxostat 40 mg tablets in healthy Chinese subjects under both fasting and fed conditions. An open-label, randomized, single-dose, single-center, two-sequence, two-period crossover Phase I study was implemented to assess the pharmacokinetic bioequivalence of the two formulations in 64 healthy volunteers (32 for fasting group, 32 for fed group). Subjects received a single oral dose of either the test or reference febuxostat 40 mg tablet under the corresponding condition, with a 7-day washout period between cycles. The geometric mean ratios and their 90% confidence intervals (CIs) of the peak plasma concentration ( C max ), area under the plasma concentration-time curve from time 0 to the last quantifiable time point ( AU C 0 - t ), and area under the plasma concentration-time curve from time 0 to infinity ( AU C 0 - ∞ ) for the test versus reference formulation were calculated for bioequivalence evaluation. All 90% CIs fell within the pharmacokinetic bioequivalence acceptance range of 80%-125%. A total of 12 adverse events (AEs) were reported in 10 subjects in the fasting group and nine AEs in eight subjects in the fed group, all of which were mild in severity with no serious AEs observed. The test formulation of febuxostat 40 mg tablets was bioequivalent to the reference formulation in healthy Chinese subjects under both fasting and fed conditions, and both formulations were well tolerated.
Clinical pharmacology in drug developmentCheng Cui, Na Liu, Chang Chu, Shu Niu, Yang Huang, Fangqiong Li, Yaming Li, Haiyan Li, Dongyang Liu
This single-center, single-arm, Phase I study evaluated drug-drug interactions (DDIs) between cofrogliptin and metformin in healthy Chinese subjects. Twenty-two subjects sequentially received metformin monotherapy (Days 1-4), cofrogliptin monotherapy (Days 6-34), and combination therapy (Days 38-47). Serial blood/urine samples were collected for pharmacokinetic (PK) and pharmacodynamic (PD) analyses. Cofrogliptin showed no significant impact on metformin's PK and PD properties: the geometric mean ratios (GMRs, metformin + cofrogliptin/metformin) with 90% confidence intervals (CIs) for metformin AUC0-8 h, AUC0-12 h, CSS (max), Ae0-8 h and Ratio0-8 h, were 0.872 (0.809, 0.941), 0.900 (0.834, 0.971), 0.840 (0.743, 0.950), 0.899 (0.782, 1.032), and 0.994 (0.871, 1.136), respectively; 90% CIs for plasma glucose AUEC0-4 h, AUEC0-0.5 h, and ECmax of combination (combination vs cofrogliptin monotherapy) all fell within 0.80-1.25. Metformin did not statistically affect cofrogliptin's PK and PD properties, as the GMRs (metformin + cofrogliptin/cofrogliptin) (90% CIs) for cofrogliptin AUC over the dosing interval and Css (max) were 1.12 (1.072, 1.169) and 1.14 (1.057, 1.220), and AUEC0-168 h, ECmax, and ECmin for dipeptidyl peptidase-4 inhibition rate were 1.01 (1.003, 1.015), 1.00 (1.001, 1.009), and 1.03 (1.005, 1.040), respectively. No deaths, serious adverse events, or severe hypoglycemia occurred. In conclusion, the combination of cofrogliptin and metformin had no clinically significant PK or PD DDIs in healthy Chinese subjects.
Breviscapine injection (BI), a standardized botanical drug for cardiovascular and cerebrovascular diseases, lacks adequate characterization of its pharmacokinetics and tissue distribution. A UPLC-MS/MS method was developed and validated for simultaneous quantification of scutellarin and its metabolite iso-scutellarin in rat plasma and tissues after intravenous BI administration. Sample preparation used methanol protein precipitation, with detection via positive electrospray ionization MRM. Validation followed the Chinese Pharmacopoeia and bioanalytical PK guidance. The assay showed LLQs of 10.0 ng/mL (scutellarin) and 5.0 ng/mL (iso-scutellarin), good linearity (r2 ≥ 0.990), precision (RSD ≤ 11.1%), accuracy (91.7%-106.8%), and acceptable recovery and matrix effects. PK analysis revealed moderate-to-rapid systemic elimination of scutellarin. Both analytes distributed to tissues within 0.25 h postdose, with exposure ranking: bladder > small intestine > kidney > small intestine > kidney > stomach > liver > plasma > heart > skeletal muscle > pancreas > skin > fat > lung > ovary > testis > adrenal > heart > skeletal muscle > pancreas > thymus > spleen > brain. The method is suitable for BI studies. The limited brain penetration suggests formulation optimization to prolong plasma exposure may be worth exploring, and the relatively high hepatic distribution points to a potential need for monitoring liver and kidney function.
CPT: pharmacometrics & systems pharmacologyPeter Bloomingdale, Antari Khot
AI agents are transforming computational workflows, yet pharmacometric analyses remain manual, relying on significant data wrangling, custom scripts, and specialized software. We present PMxAgent, an open-source agentic platform for developing and deploying specialized agent-callable pharmacometric tools. The platform uses Docker to orchestrate an R-based API server alongside a Python-based model context protocol (MCP) server, which automatically generates agent-callable tools from OpenAPI specifications, making pharmacometric functions discoverable and usable by AI agents. To exemplify pharmacometric applications, five tools were developed: non-compartmental analysis (NCA) using PKNCA, exposure-response (ER) modeling, pharmacokinetic (PK) simulation using mrgsolve, data standardization (DATA), and generation of population PK datasets from the nlmixr2lib model library (LIBRARY). As a proof-of-concept case study, PMxAgent orchestrated a multistep pharmacometric workflow, consisting of a PK simulation of 60 subjects across three dose groups, NCA to derive individual exposure metrics, and ER analysis. To evaluate analytical accuracy and reproducibility, the agentic NCA workflow was benchmarked against four frontier AI agents across 182 drugs and 1820 simulated subjects, using PKanalix as reference. PMxAgent's NCA accuracy (98.3%) matched or exceeded that of all frontier agents evaluated. PMxAgent produced deterministic, reproducible results in contrast to GPT and Claude agents that performed NCA by generating new code each run. PMxAgent was demonstrated using two MCP-compatible AI agents (Cursor and Claude Code) and is designed to integrate with any AI agent supporting the MCP protocol. PMxAgent provides an extensible foundation for integrating pharmacometric tools into human-supervised AI-driven workflows while ensuring reproducibility, transparency, and detailed documentation required for model-informed drug development.
This research aims to investigate the stereoselective permeation differences and molecular recognition mechanisms of ketoprofen enantiomers in the chiral microenvironment of the stratum corneum (SC). This also aims to provide theoretical support for developing highly efficient and precise single-enantiomer transdermal drug delivery systems. The permeation behaviors of dexketoprofen and its racemate through excised full-thickness rat skin in three different solvent systems were studied using Franz diffusion cells. The solubility, apparent partition coefficients, and differential scanning calorimetry were used to assess the physicochemical and thermodynamic properties of both forms. Fourier transform infrared (FTIR), 13C NMR, attenuated total reflection-FTIR (ATR-FTIR), and Raman spectroscopic techniques were extensively performed to investigate micro-interactions between drug and core SC (ceramide NP and keratin) components. In addition, in order to affirm the mechanisms, binding energy, cohesive energy density, and the radial distribution function along with mean square displacement were evaluated using molecular docking and molecular dynamics simulations. Based on in vitro permeation results, the cumulative permeated amounts of dexketoprofen in all three solvent systems were significantly higher than those of racemic ketoprofen (approximately 1.2-fold). Characterizations by thermodynamic and physicochemical methods showed that dexketoprofen displayed a relatively low melting point (76.26°C), enthalpy of fusion (26.39 kJ/mol), lattice energy, and higher lipophilicity and solubility, which gave rise to a greater thermodynamic driving force for drug release. Both spectroscopic analyses and molecular simulations confirmed that dexketoprofen formed a stronger intermolecular hydrogen bonding network with ceramide NP (binding energy: -21.63 kcal/mol). This robust spatial affinity remarkably perturbed the tightly ordered arrangement of the SC lipid bilayer, which may induce a decrease in lipid orderliness and substantially increase the fluidity. The transdermal superiority of dexketoprofen within the chiral skin barrier is synergistically attributed to its high thermodynamic activity, driven by a lower lattice energy, and its stronger microscopic stereoselective interactions with SC components. This study systematically elucidates the stereoselective mechanisms underlying the transdermal permeation of chiral drugs, thereby providing a scientific basis for the development of transdermal formulations containing a single enantiomer.
Clinical pharmacology in drug developmentKarin Nicholson, Marianna Armogida, Morris S Gold, Paul J Desjardins
Diclofenac is a widely used topical nonsteroidal anti-inflammatory drug (NSAID) for pain and inflammation. This study evaluated the relative bioavailability of diclofenac from diclofenac sodium (DS) gel 1% versus diclofenac diethylamine (DEA) gel 1.16% and assessed whether adjunct heat or moderate exercise influences systemic absorption of diclofenac from DS gel 1%. General and local tolerability of DS gel 1% was also examined. Thirty-six adults aged ≥50 years were enrolled in a single-center, open-label, randomized, two-arm, three-way crossover study consisting of three 7-day treatment periods separated by 14-day washouts. Each sequence included DS gel 1%, DEA gel 1.16%, and DS gel 1% combined with either heat (one arm) or moderate exercise (other arm). Treatments were applied four times daily. Plasma diclofenac levels and 24-h urine samples were collected on Days 1 and 7 using a validated LC-MS/MS assay. Systemic exposure (AUC0-24) of DEA gel versus DS gel was comparable (GMR 90.7%; 90% CI: 82.7-99.5). Heat resulted in an excursion of the lower bound of the AUC0-24 90% confidence interval below the standard lower bioequivalence bound of 80% (GMR 92.5%; 90% CI: 77.3-111.0), while exercise showed no meaningful effect (GMR 103%; 90% CI: 87.8-120.0). As expected, given similar plasma exposure between treatments, urinary excretion was also similar (∼0.5% of the administered dose), supporting comparable systemic disposition.
Biomedical chromatography : BMCZhi-Min Lv, Ju Zhang, Guo Feng, Xiang-Ling Qu, Ting-Ting Liu, Xin-Ping Wei, Li Zhang, Shi-Qiong Qin, Yun-Li Wei, Gang Liu, Ke-Xin Ma, Jin-Xin Hou, Wei Li, Yi S…
Daphnoretin (DAP) has various pharmacological activities, but its in vivo disposition after nanomicellar formulation remains unclear. This study compared the pharmacokinetics and tissue distribution of free DAP and two polymeric nanomicellar formulations, PP-DAP and GA-DAP, following intravenous administration. Plasma DAP concentrations in rats were determined by UPLC-MS/MS, and DAP concentrations in mouse tissues were determined by LC-MS/MS. Compared with free DAP, PP-DAP and GA-DAP showed higher systemic exposure, longer apparent elimination half-lives, and lower apparent clearance. The AUC0-∞ values of DAP, PP-DAP, and GA-DAP were 5474.14, 11,211.04, and 15,019.86 h · ng/mL, respectively, and the corresponding T1/2 values were 6.84, 9.24, and 9.90 h. DAP was detected in the heart, liver, spleen, lung, and kidney, with the nanomicellar formulations showing altered tissue distribution and GA-DAP exhibiting relatively sustained hepatic distribution. These findings suggest that nanomicellar formulation alters the in vivo disposition of DAP. However, free and micelle-associated DAP were not separately quantified, precluding direct characterization of in vivo drug release, and the validation range of the tissue quantification method was limited. Further studies are warranted to evaluate the in vivo behavior and liver-directed delivery potential of GA-DAP.
Archives of environmental contamination and toxicologyXuan-Quang Nguyen, Van-Hao Duong, Marckasagayam Priyadharshini, Mohamed Saiyad Musthafa, Khai M Nguyen, Thanh-Xuan Pham-Thi, Nguyen Duc Hieu, Hoang Bao Anh, Hi…
The presence of potentially toxic elements (PTEs) in the marine environment poses potential risks to both marine ecosystems and human health. This study investigated concentrations, bioaccumulation patterns, and associated health risks of PTEs in oysters (Crassostrea spp.) collected from the coastal waters of Quang Ninh, Vietnam. Zinc (Zn) had the highest concentrations (65.4 mg/kg in muscle tissue and 56.8 mg/kg in hepatopancreas), wherea mercury (Hg) showed the lowest concentrations (0.0064 mg/kg and 0.0034 mg/kg, respectively) in both organs. There was a positive correlation between shell size and weight with PTE concentrations in both organs, suggesting increased bioaccumulation with long-term exposure to the environment. Principal component analysis (PCA) identified three distinct sources of PTEs: anthropogenic inputs from industrial, agricultural, and transportation activities (PC1, variance 33.0%), mixed anthropogenic and natural sources (PC2, variance 22.9%), and natural sources combined with the impact of coal mining in the region (PC3, variance 16.8%). Health risk assessment using the Risk Quotient (RQ) revealed that cadmium (Cd) in the hepatopancreas posed the most significant health concern, with RQ values exceeding 1 under the worst-case scenarios. These findings provided a valuable scientific basis for regional environmental pollution monitoring and control measures. In addition, the results emphasize the need for continuous monitoring of Cd concentrations for sustainable aquaculture development in the region.
Statins are widely regarded as the gold standard first-line treatment for hyperlipidemia, as they inhibit HMG-CoA reductase in the liver. This effectively reduces LDL cholesterol levels and reduces cardiovascular risks, such as heart attack and stroke. Simvastatin is a well-established, effective, and cost-efficient statin for lowering LDL cholesterol and reducing cardiovascular risk. However, it causes myopathy, rhabdomyolysis, myalgia, constipation, kidney failure, headache, abdominal pain, diarrhoea, nausea, and increased blood sugar levels with its use and higher doses of 80 mg/day. To address this, a liposomal simvastatin formulation with particle sizes of 150-250 nm was developed for intravenous administration. This formulation can potentially accumulate in the liver via passive targeting via the RES, thereby enhancing hepatic uptake and improving safety. The liposome was formulated using the thin-film hydration method and optimised using a central composite design. The optimized formulation's vesicle size was 204.66 ± 2.84 nm, with a PDI of 0.27 and a zeta potential of -58.11 mV, indicating uniform distribution and high stability. In-vitro drug release demonstrated controlled release of up to 92.46% over 60 h. The cellular toxicity assay showed that the optimized liposome was 10 times safer than pure simvastatin. In-vivo, the liposomal formulation significantly reduced lipid levels after administration of a 5 mg/kg dose in Triton X-100-induced hyperlipidemic rats, outperforming marketed formulations and standard drugs. Simvastatin-liposomes are safe, stable, and a more potent alternative to traditional oral simvastatin, offering improved liver targeting and a reduced toxicity profile.
Accessible tools for pharmacokinetic education and routine clinical pharmacokinetic analysis remain limited. Commercial software carries licensing costs and on the other hand existing open-source alternatives lack integrated workflows spanning study planning through bioequivalence assessment and are not user-friendly. We developed NCA Assistant, a browser-based application for non-compartmental pharmacokinetic analysis, bioequivalence testing, and power and sample size calculations within a single platform designed for pharmacokinetic research and teaching. NCA Assistant was designed with Anthropic Claude AI as coding assistant, with multi-expert prompting. The app was developed in R/Shiny with a hub-based architecture connecting six workflow modules. Core computations rely on established R packages for non-compartmental analysis, power and sample size calculations and analysis of variance. For the interface, there was an emphasis for transparency through interactive visualization, configurable analysis settings and exportable audit trails. The application supports extravascular and intravenous dosing scenarios, handles both single-subject and batch analyses and accommodates standard crossover, replicate, and parallel bioequivalence designs.A dedicated visualization module generates publication-ready concentration-time plots. Features include interactive terminal half-life review with point selection override and configurable thresholds for elimination half-life calculation. A validation package, consisting of draft validation documents and a validation script, accompanies the application and is supplied in the supplemental materials. NCA Assistant provides an accessible entry point for pharmacokinetic data analysis suitable for graduate training and routine clinical pharmacology applications, with extensibility for use in more regulated environments.
AAPS PharmSciTechMariame A Hassan, Bhanu Prakash Dongala, Annette DeSantiago, Ziyaur Rahman, Mansoor A Khan
Divalproex Sodium (DVS) is an antiepileptic agent with a narrow therapeutic window and a wide range of side effects. Its delayed-release forms demonstrated better tolerability in terms of gastrointestinal side effects. DVS has high sensitivity to temperature and humidity. Owing to a high frequency of daily administration, outpatients may keep their medication supply accessible in places that might not qualify for proper drug storage. In this study, five FDA-approved DVS delayed-release tablet products (A-E) were assessed for physical integrity, physicochemical changes and drug release pattern before and after repackaging in amber-colored closed pharmacy vials and storage at 30°C/75%RH. Initially, one product showed dissimilarity to the others (f1 = 19.6, f2 = 41.6). Upon storage, tablets showed signs of physical damage after 1 month. At 3 months, A, B and E tablets lost their integrity completely. Product C displayed high variability in acid (44.9 ± 31.5% drug release). Tablets that remained intact after storage failed the f1 and f2 tests. The images showed evidence of chemical changes in all products. The results indicated that repackaging and improper in-use keep could result in unpredictable drug release. It is debated that the total daily systemic bioavailability of DVS, rather than the peak-to-trough differences, is the primary determinant of seizure control. However, variability in drug release can result in gastric irritation, systemic side effects, drug intolerance and patients' noncompliance. This unnecessary burdening of the health care system can be avoided when revising dispensing and storage recommendations of DVS products.
World journal of microbiology & biotechnologyRui Huang, Ziling Yuan, Yujie Liu, Liwen Zhang, Guanhua Li, Ruihua Liu, Chao Yang
The vast majority of agricultural wastes are burned or buried in soil currently, causing environmental pollution and resource waste worldwide. To achieve the eco-friendly bioconversion of agricultural waste, this study utilized an engineered Streptomyces albulus for solid-state fermentation (SSF) to convert rapeseed cake into ε-poly-L-lysine (ε-PL), the L-lysine homopolymer widely applied as a natural and safe food preservative. Firstly, based on genome analysis and the property characterization of agricultural waste, the bioconversion potential of S. albulus toward lignocellulosic waste was revealed, followed by preliminary experimental validation. Secondly, the high-titer engineered strain was obtained by overexpressing key genes eno1, eno2, pepc, ask and pls of ε-PL biosynthesis pathway, thereby promoting the bioconversion of rapeseed cake. Among the mutants, S. albulus PLS got the highest ε-PL titer, which was 9.3-fold that of the control strain in SSF. And the ε-PL titer was further increased to 1.6 times the original via optimizing SSF process. Finally, we characterized the growth and development status and the lignocellulose biodegradation of S. albulus PLS during the bioconversion process. Overall, this study identified a strategy for the valorization of agricultural waste, and the engineered strain offers a promising SSF microbial chassis for ε-PL production from lignocellulosic waste.
International journal of pharmaceuticsBhanu P Dongala, Mohammad T H Nutan, Maen Abdelrahim, Mariame A Hassan, Abdullah Esmail, Ziyaur Rahman, Mansoor A Khan
Tolfenamic acid (TFA), a Biopharmaceutics Classification System (BCS) class II drug, exhibits dissolution-limited absorption and significant gastric irritation when administered as conventional immediate-release formulations, limiting its potential for high-dose and long-term applications, including emerging anticancer indications. The present study aimed to develop a delayed-release, dose-flexible matrix tablet of TFA using enteric polymers incorporated directly into the tablet matrix, eliminating the need for external enteric coating. A 2 × 3 factorial formulation screening design was employed to systematically evaluate the influence of enteric polymers (HPMC-AS, Eudragit S100, and cellulose acetate phthalate) and diluent/binder (microcrystalline cellulose, spray-dried mannitol, and lactose monohydrate) on acid resistance and buffer-stage drug release. Tablets were prepared by wet granulation and characterized for physicochemical properties, solid-state stability, surface morphology, chemical uniformity, assay, presence of impurities, disintegration, and two-stage dissolution performance. The optimized formulation maintained complete integrity in an acidic medium for 2 h with no drug release and achieved > 96% drug release in phosphate buffer (pH 8.2) in 3 h, meeting USP dissolution criteria. Solid-state analysis confirmed preservation of the crystalline form and the absence of drug-excipient incompatibility, while stability studies under accelerated and intermediate conditions demonstrated maintained physicochemical integrity and release performance. The developed matrix system provides a cost-effective and process-efficient alternative to conventional enteric coating and supports modular dose adjustment within a single strength, offering a promising platform for delayed-release, dose-flexible oral therapy suitable for combination regimens and personalized cancer treatment strategies.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VSohaila A Shoala, Haidy Abbas, Heba M Elbedaiwy, Marium M Shamaa, Manal A Elsheikh
Andrographolide (AG) has been reported for its anticancer activity. However, it is classified as a class IV in the biopharmaceutics classification system (BCS). Therefore, AG possesses low bioavailability due to its low solubility and permeability. In this study, hyaluronic acid-coated chitosan nanoparticles (Hyalo-CS-NPs) were formulated to enhance AG delivery and allow the active targeting of CD44 receptors overexpressed on breast cancer cells. Results showed optimized AG-Hyalo-CS-NPs with a size of 388.2 ± 1.41 nm, a zeta potential of -25.7 ± 1.58 mV, and an entrapment efficiency of 95.3%±1.01%. In vitro release profile revealed a sustained pH-responsive release from coated and uncoated CS-NPs with greater AG release under acidic conditions that mimic the tumor microenvironment. The MTT assay demonstrated the sharpest decline in the MCF-7 cell viability. Moreover, flow cytometry studies illustrated a significant apoptosis compared to uncoated nanoparticles and AG suspension. In addition, biochemical marker evaluation showed upregulating of the pro-apoptotic protein Bax and downregulating of Bcl-2, HER2, and Cyclin D1, confirming the underlying mechanism of the anticancer activity. Finally, confocal imaging showed higher intracellular uptake from coated and uncoated CS-NPs by 2.2-fold and 1.85-fold, respectively. In conclusion, AG-Hyalo-CS-NPs is a smart, targeted nanoplatform that improves AG anticancer efficacy in breast cancer management.
Sheng wu gong cheng xue bao = Chinese journal of biotechnologyHao Fang, Yuan Li, Haotian Cheng, Fuping Lu, Yi-Heng P J Zhang
Galacto-N-biose (GNB), a core structural unit of O-glycan and a key component of gastrointestinal mucins, plays important physiological roles in regulating intestinal microecology and maintaining the mucosal barrier. Traditional enzymatic routes for the synthesis of GNB rely on the supplies of ATP and UDP-sugars. To address this disadvantage, we designed an in vitro ATP-free and UDP-sugar-free enzymatic pathway to synthesize GNB directly from lactose and N-acetylgalactosamine (GalNAc). This pathway consisted of two core enzymes, lactose phosphorylase (LacP) and lacto-N-biose phosphorylase (LnbP), as well as one auxiliary enzyme, polyphosphate glucokinase (PPGK). By incorporating PPGK to remove the byproduct glucose, this pathway not only pushed the reaction equilibrium toward the biosynthesis of GNB, but also achieved the regeneration of inorganic phosphate. Through the systematic optimization of key parameters such as reaction temperature, pH, and enzyme dosage, a molar yield of 76% was achieved with 10 mmol/L GalNAc. This in vitro biotransformation pathway provides a technical basis for the low-cost, large-scale green production of GNB and other high-value functional oligosaccharides.
Journal of pharmacokinetics and pharmacodynamicsSeweryn Ulaszek, Bartek Lisowski, Monika Jesionek, Barbara Wiśniowska, Sebastian Polak
We developed a workflow based on a human-derived dataset, aiming to predict the human heart-to-plasma partition coefficient, [Formula: see text]. The workflow combines established mechanistic tissue-composition models with an AI/ML-based selector that supports compound-specific selection among mechanistic heart [Formula: see text] prediction methods. Three published mechanistic approaches were implemented and parameterized in a harmonized manner consistent with the described methodologies to generate baseline [Formula: see text] predictions. The ML-based selector was trained using physicochemical, ADME, and pharmacokinetic descriptors to recognize compound-specific differences in model performance. This hybrid strategy preserves mechanistic interpretability while using empirical pattern recognition to formalize a priori model choice across compounds. In internal cross-validation, the selector reduced extreme outliers and provided a reproducible, data-driven rule for compound-specific method selection, although it did not materially outperform the strongest standalone mechanistic baseline in numerical error. Although no individual mechanistic method performed consistently across the full chemical space, the Poulin-Theil approach showed the best overall performance on human whole-heart data. The workflow was also applied prospectively to transthyretin stabilizers, for which reliable heart [Formula: see text] estimates may support further mechanistic modelling of cardiac drug exposure and downstream pharmacological effects. Together, these findings suggest that combining mechanistic calculators with an AI/ML-based selector may provide a practical basis for a priori, compound-specific method selection, reducing reliance on subjective choice of a single mechanistic approach.
Annals of medicineYequan Xu, Ying Zhang, Danni Ye, Shanyu Jiang, Renqiang Yu
BACKGROUND: Despite advances in perinatal care and improved survival of preterm infants, bronchopulmonary dysplasia (BPD) remains a major neonatal morbidity with long-term consequences. Accurate early risk prediction is therefore clinically important. Conventional models may be limited in capturing the complex and nonlinear interactions underlying BPD, whereas machine learning offers greater flexibility for high-dimensional clinical data. However, limited interpretability remains a barrier to clinical implementation. METHOD: This retrospective study included 1,083 preterm infants with gestational age <32 weeks and birth weight <2,500 g admitted to the Affiliated Women's Hospital of Jiangnan University from January 2011 to December 2025. Data were split 7:3 into training and validation sets. Seven models were evaluated, with hyperparameters optimized by 10-fold cross-validation using AUC. Missing data were handled by complete case analysis. Performance was assessed using AUC-ROC, Brier score, and decision curve analysis (DCA), while SHAP and partial dependence plots (PDP) were used for interpretation. The optimal model was externally validated in an independent cohort of 1,000 neonates. RESULT: GBM showed the best internal performance, with an AUC of 0.880, accuracy of 0.793, sensitivity of 0.827, specificity of 0.759, and Brier score of 0.141. Birth weight, gestational age, and 1-minute Apgar score were the leading predictors. Neonatal anemia was strongly associated with BPD (aOR = 5.036, 95% CI: 3.35-7.57). PDP demonstrated a nonlinear association between birth weight and BPD risk, with a sharp increase between 1,250 and 1,500 g. DCA indicated favorable net clinical benefit across relevant threshold probabilities. CONCLUSION: The GBM model provides interpretable, individualized early BPD risk estimates using routinely available clinical variables and may support identification of high-risk preterm infants. It is intended for risk stratification rather than treatment guidance. Prospective multicenter validation is required before routine clinical implementation.