Search

The escalating issue of excessive alcohol consumption poses a significant health concern, leading to various disruptions across multiple physiological pathways. Argan oil (AO), derived from the fruit of "Argania spinosa L", an indigenous tree native to southwestern Morocco, is renowned for its diverse health and well-being advantages. In this study, we focused on the impact of alcohol on the oxidation-reduction system, a critical aspect frequently influenced by alcohol. To investigate the potential mitigating effects of argan oil on oxidative stress, we employed three distinct treatment groups of rats: (1) alcohol-treated (3 g/kg), (2) alcohol (3 g/kg) and argan oil-treated (10 ml/kg), and (3) water-treated (control). Following a one-month treatment period, the rats were sacrificed, and their organs were utilized for biochemical assays. Results revealed that argan oil treatment significantly mitigated oxidative stress markers, as evidenced by a reduction in malondialdehyde (MDA) levels and restoration of antioxidant enzyme activities, such as superoxide dismutase (SOD) and catalase (CAT), toward normal levels. At the molecular level, ADMET and docking analyses demonstrated favorable binding interactions between argan oil molecules and proteins implicated in oxidative stress pathways. These findings underscore the potential of argan oil to restore equilibrium in the oxidation-reduction system, offering neuroprotective and antioxidant effects. This study provides foundational insights into the protective effects of argan oil against alcohol-induced oxidative damage, highlighting its potential as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Embelin is one of the primary compounds present in the Embelia ribes fruit. Embelin has a broader pharmacological activity such as Anti-inflammatory, anti-bacterial, antioxidant, and many more. The ultimate aim of the study is to ensure the impact of reduced embelin in the management of Alzheimer's disease. Embelin was isolated and modified by the reduction method, and the Modified Embelin derivative (MED) 3-Undecylcyclohexa-2,5-diene-1,2,4,5-tetraol was analysed through FT-IR, NMR, and Mass Spectroscopic techniques. MED was docked against acetylcholinesterase (AChE) amyloid beta (Aβ) receptors PDB ID: 1EVE & 1B68, respectively. The docking scores remain similar to that of positive standards galantamine and Donepezil. [ABSTRACT FROM AUTHOR]

Higher alcohols are key factors affecting sensory quality and post-drinking comfort of alcoholic beverages. A strategy combining solid-phase extraction and gas chromatography-mass spectrometry (SPE-GC-MS) was established to analyze the metabolism pattern of higher alcohols in rat plasma after gavage of 4 common alcoholic beverages including huangjiu, baijiu, wine and brandy.7 mL of dichloromethane was determined as the optimal extraction condition, and 8 higher alcohols were precisely quantified with detection limits of 1.82−11.65 μg/L, recoveries of 89.07%−110.89% and fine repeatability. The fastest absorption and elimination rates of plasma total higher alcohols were observed in baijiu and huangjiu group, respectively, and the highest peak concentration was found in brandy group. Additionally, the metabolic rate of plasma isoamyl alcohol in huangjiu group was faster than that in wine group at the same intragastric administration dosage. This study may provide potential insight for evaluation of alcoholic beverage quality.

Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2–5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57–5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18 h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future. [ABSTRACT FROM AUTHOR]

Relevance. Planning the design of bioequivalence clinical studies of generic highly variable drugs requires non-standard approaches – the use of replicative (repeated) or adaptive design. However, both approaches entail an increase in organizational, time, and financial costs. Therefore, it becomes relevant to search for ways to pre-select volunteers with a lower initial level of variability in pharmacokinetic parameters to reduce the number of subjects.Objective. The aim of this study was to determine the potential subjects in clinical trials with a low initial level of variability in pharmacokinetic parameters using methods for assessing initial gender – age and anthropometric and clinical laboratory parameters.Material and methods. Data from clinical studies of the bioequivalence of drugs (valganciclovir, carebastine and raltegravir) with different levels of variability conducted in the period 2020–2022 in Russia were used for analysis. To achieve this goal, a model for grouping pharmacokinetic parameters (PhK) with known demographic and clinical laboratory parameters was developed using discriminant analysis. Discrimination was performed between optimal pharmacokinetics (OPhK) and variable pharmacokinetics (VPhK). Mathematical and statistical analyses of the results were performed using Microsoft Excel 2013 and Statistica 10.0.Results. During the study, the variability of the maximum concentration of the drug in plasma (Cmax), including its logarithmic values, was used as a basis. The levels of intra-individual variability (CVintra), which is the main characteristic of drug variability, in the OPhK group were several times lower than those in the VPhK group for all studied drugs, but for the highly variable drug raltegravir, they differed by almost 10 times.Conclusion. Therefore, the obtained results indicated that using traditional gender – age and anthropometric indicators alone is impossible to separate the OPhK and VPhK groups for the analyzed drugs with high PhK variability.

Simple Summary: This study investigated how dexmedetomidine, a sedative, works when given to healthy cats via intramuscular injection at a dose of 10 μg/kg. Nine adult cats were observed before and after receiving the drug, with blood samples taken at various times to measure drug levels. Dexmedetomidine acted quickly, causing sedation that lasted for at least an hour, with peak effects between 20 and 30 min and a half-life of about 70 min. Significant decreases in heart rate, respiratory rate, and blood pressure were observed in the first hour, along with an increase in blood sugar levels after 60 min. Overall, dexmedetomidine proved to be effective and safe for sedation in healthy cats, providing valuable information for veterinarians to ensure its safe and effective use in feline patients. This study investigated the pharmacokinetic profile of and pharmacodynamic response to dexmedetomidine administered intramuscularly (IM) at a dose of 10 μg/kg in healthy cats. Nine adult cats were evaluated before and after administration of the drug, with serial collections of plasma samples. Dexmedetomidine induced deep sedation, with a rapid onset of action and a duration of one hour, reaching a peak between 20 and 30 min after administration. The half-life (T½) was 70.2 ± 48 min, with a maximum concentration (Cmax) of 2.2 ± 1.9 ng/mL and time to reach maximum concentration (Tmax) of 26.4 ± 19.8 min. The area under the curve (AUC) was 167.1 ± 149.1 ng/mL*min, with a volume of distribution (Vd) of 2159.9 ± 3237.8 mL/kg and clearance (Cl) of 25.8 ± 33.0 mL/min/kg. There was a reduction in heart rate (HR) and respiratory rate (RR) in relation to the baseline, with a slight decrease in systolic (SBP), diastolic (DBP), and mean (MAP) blood pressure in the first hour. Blood glucose increased after 60 min. Dexmedetomidine proved to be effective and safe, with rapid absorption, metabolization, and elimination, promoting good sedation with minimal adverse effects after IM administration in healthy cats. [ABSTRACT FROM AUTHOR]

Context: Accurately predicting plasma protein binding rate (PPBR) and oral bioavailability (OBA) helps to better reveal the absorption and distribution of drugs in the human body and subsequent drug design. Although machine learning models have achieved good results in prediction accuracy, they often suffer from insufficient accuracy when dealing with data with irregular topological structures. Methods: In view of this, this study proposes a pharmacokinetic parameter prediction framework based on graph convolutional networks (GCN), which predicts the PPBR and OBA of small molecule drugs. In the framework, GCN is first used to extract spatial feature information on the topological structure of drug molecules, in order to better learn node features and association information between nodes. Then, based on the principle of drug similarity, this study calculates the similarity between small molecule drugs, selects different thresholds to construct datasets, and establishes a prediction model centered on the GCN algorithm. The experimental results show that compared with traditional machine learning prediction models, the prediction model constructed based on the GCN method performs best on PPBR and OBA datasets with an inter-molecular similarity threshold of 0.25, with MAE of 0.155 and 0.167, respectively. In addition, in order to further improve the accuracy of the prediction model, GCN is combined with other algorithms. Compared to using a single GCN method, the distribution of the predicted values obtained by the combined model is highly consistent with the true values. In summary, this work provides a new method for improving the rate of early drug screening in the future. [ABSTRACT FROM AUTHOR]

The primary objective of this work is to enhance the bioavailability of ferrous sulphate, which has low oral bioavailability and hence is subjected to frequent drug administration which results side effects. In this study, ferrous sulphate was microencapsulated with carbopol, a mucoadhesive polymer to form carbopolencapsulated ferrous sulphate microspheres and evaluated their surface morphology, mucoadhesiveness, in vitro drug release, swelling characteristics, in vitro cell cytotoxicity, acute systemic dose and oral bioavailability. Carbopol-encapsulated ferrous sulphate microspheres have good encapsulation efficiency, good mucoadhesive properties and superior swelling characteristics and offered a sustained drug release over 24 h of drug administration compared to pure ferrous sulphate. The median lethal dose of the developed formulation was estimated from the in vivo acute oral toxicity studies. It was also found from the bioavailability studies that microencapsulation of ferrous sulphate with carbopol improves systemic oral bioavailability of ferrous sulphate and can be of great potential as a mucoadhesive drug delivery system in the oral therapy of irondeficiency anaemia. [ABSTRACT FROM AUTHOR]

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with an extended Tofts linear (ETL) model for tissue and tumor evaluation has been established, but its effectiveness in evaluating the pancreas remains uncertain. Purpose: To understand the pharmacokinetics of normal pancreas and serve as a reference for future studies of pancreatic diseases. Material and Methods: Pancreatic pharmacokinetic parameters of 54 volunteers were calculated using DCE-MRI with the ETL model. First, intra- and inter-observer reliability was assessed through the use of the intra-class correlation coefficient (ICC) and coefficient of variation (CoV). Second, a subgroup analysis of the pancreatic DCE-MRI pharmacokinetic parameters was carried out by dividing the 54 individuals into three groups based on the pancreatic region, three groups based on age, and two groups based on sex. Results: There was excellent agreement and low variability of intra- and inter-observer to pancreatic DCE-MRI pharmacokinetic parameters. The intra- and inter-observer ICCs of K trans, k ep, ve, and vp were 0.971, 0.952, 0.959, 0.944 and 0.947, 0.911, 0.978, 0.917, respectively. The intra- and inter-observer CoVs of K trans, k ep, ve, vp were 9.98%, 5.99%, 6.47%, 4.76% and 10.15%, 5.22%, 6.28%, 5.40%, respectively. Only the pancreatic ve of the older group was higher than that of the young and middle-aged groups (P = 0.042, 0.001), and the vp of the pancreatic head was higher than that of the pancreatic body and tail (P = 0.014, 0.043). Conclusion: The application of DCE-MRI with an ETL model provides a reliable, robust, and reproducible means of non-invasively quantifying pancreatic pharmacokinetic parameters. [ABSTRACT FROM AUTHOR]

IR780 iodide is a commercially available targeted near‐infrared contrast agent for in vivo imaging and cancer photodynamic or photothermal therapy, whereas the accumulation, dynamics, and retention of IR780 in biological tissue, especially in tumor is still under‐explored. Diffuse fluorescence tomography (DFT) can be used for localization and quantification of the three‐dimensional distribution of NIR fluorophores. Herein, a homemade DFT imaging system combined with tumor‐targeted IR780 was utilized for cancer imaging and pharmacokinetic evaluation. The aim of this study is to comprehensively assess the biochemical and pharmacokinetic characteristics of IR780 with the aid of DFT imaging. The optimal IR780 concentration (20 μg/mL) was achieved first. Subsequently, the good biocompatibility and cellar uptake of IR780 was demonstrated through the mouse acute toxic test and cell assay. In vivo, DFT imaging effectively identified various subcutaneous tumors and revealed the long‐term retention of IR780 in tumors and rapid metabolism in the liver. Ex vivo imaging indicated IR780 was mainly concentrated in tumor and lung with significantly different from the distribution in other organs. DFT imaging allowed sensitive tumor detection and pharmacokinetic rates analysis. Simultaneously, the kinetics of IR780 in tumors and liver provided more valuable information for application and development of IR780. [ABSTRACT FROM AUTHOR]

Introduction: A northern goshawk back-propagation artificial neural network (NGO-BPANN) model was established to predict monohydroxycarbazepine (MHD) concentration in patients with epilepsy. Methods: The data were collected from 108 Han Chinese patients with epilepsy on oxcarbazepine monotherapy. The results of 14 genotype variates were selected as the input layer in the first BPANN model, and the variables that had a more significant impact on the plasma concentration of MHD were retained. With demographic characteristics and clinical laboratory test results, the genotypes of SCN1A rs2298771 and SCN2A rs17183814 were used to construct the BPANN model. The BPANN model was comprehensively validated and used to predict the MHD plasma concentration of five patients with epilepsy in our hospital. Results: The model demonstrated favorable fitness metrics, including a mean squared error of 0.00662, a gradient magnitude of 0.00753, an absence of validation tests amounting to zero, and a correlation coefficient of 0.980. Sex, BMI, and the genotype SCN1A rs2298771 were ranked highest by the absolute mean impact value (MIV), which is primarily associated with the concentration of MHD. The test group exhibited a range of − 20.84% to 31.03% bias between the predicted and measured values, with a correlation coefficient of 0.941 between the two. With BPANN, the MHD nadir concentration could be predicted precisely. Conclusion: The NGO-BPANN model exhibits exceptional predictive capability and can be a practical instrument for forecasting MHD concentration in patients with epilepsy. Clinical Trial Registration: www.chiCTR-OOC-17012141. [ABSTRACT FROM AUTHOR]

Scientific relevance. Studies of the toxicological and pharmacokinetic properties of medicinal compounds are a crucial stage of preclinical research; unsatisfactory results may invalidate further drug development. Therefore, the development of in silico methods for a preliminary pre-experimental assessment of toxicological and pharmacokinetic properties is a relevant and crucial task.Aim. The study aimed to review current approaches to in silico prediction of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters of pharmacologically active compounds, in particular, the most important toxicological and pharmacokinetic parameters, and to present the results of the authors’ own research in this area.Discussion. According to the review of models for predicting the toxicological properties of chemical compounds (acute toxicity, carcinogenicity, mutagenicity, genotoxicity, endocrine toxicity, cytotoxicity, cardiotoxicity, hepatotoxicity, and immunotoxicity), the accuracy of predictions ranged from 74.0% to 98.0%. According to the review of models for predicting the pharmacokinetic properties of chemical compounds (gastrointestinal absorption; oral bioavailability; volume of distribution; total, renal, and hepatic clearance; and half-life), the coefficient of determination for the predictions ranged from 0.265 to 0.920. The literature review showed that the most widely used methods for in silico assessment of the ADMET parameters of pharmacologically active compounds included the random forest method and the support vector machines method. The authors compared the literature data with the results they obtained by modelling 12 toxicological and pharmacokinetic properties of chemical compounds using the consensus method in the IT Microcosm system and artificial neural networks. IT Microcosm outperformed the models described in the literature in terms of predicting 2 toxicological properties, including carcinogenicity and blood–brain barrier penetration (the prediction accuracy reached 93.4%). Neural network models were superior in predicting 4 toxicological properties, including acute toxicity, carcinogenicity, genotoxicity, and blood–brain barrier penetration (the prediction accuracy reached 93.8%). In addition, neural network models were better in predicting 3 pharmacokinetic properties, including gastrointestinal absorption, volume of distribution, and hepatic clearance (the coefficient of determination reached 0.825).Conclusions. The data obtained suggest that artificial neural networks are the most promising and practically significant direction for the development of in silico systems for predicting the ADMET characteristics of new medicinal products.

Pharmacokinetic (PK) parameters, revealing changes in the tumor microenvironment, are related to the pathological information of breast cancer. Tracer kinetic models (e.g., Tofts-Kety model) with a nonlinear least square solver are commonly used to estimate PK parameters. However, the method is sensitive to noise in images. To relieve the effects of noise, a deconvolution (DEC) method, which was validated on synthetic concentration–time series, was proposed to accurately calculate PK parameters from breast dynamic contrast-enhanced magnetic resonance imaging. A time-to-peak-based tumor partitioning method was used to divide the whole tumor into three tumor subregions with different kinetic patterns. Radiomic features were calculated from the tumor subregion and whole tumor-based PK parameter maps. The optimal features determined by the fivefold cross-validation method were used to build random forest classifiers to predict molecular subtypes, Ki-67, and tumor grade. The diagnostic performance evaluated by the area under the receiver operating characteristic curve (AUC) was compared between the subregion and whole tumor-based PK parameters. The results showed that the DEC method obtained more accurate PK parameters than the Tofts method. Moreover, the results showed that the subregion-based Ktrans (best AUCs = 0.8319, 0.7032, 0.7132, 0.7490, 0.8074, and 0.6950) achieved a better diagnostic performance than the whole tumor-based Ktrans (AUCs = 0.8222, 0.6970, 0.6511, 0.7109, 0.7620, and 0.5894) for molecular subtypes, Ki-67, and tumor grade. These findings indicate that DEC-based Ktrans in the subregion has the potential to accurately predict molecular subtypes, Ki-67, and tumor grade. [ABSTRACT FROM AUTHOR]

Objective. Tracer kinetic models allow for estimating pharmacokinetic (PK) parameters, which are related to pathological characteristics, from breast dynamic contrast-enhanced magnetic resonance imaging. However, existing tracer kinetic models subject to inaccuracy are time-consuming for PK parameters estimation. This study aimed to accurately and efficiently estimate PK parameters for predicting molecular subtypes based on convolutional neural network (CNN). Approach. A CNN integrating global and local features (GL-CNN) was trained using synthetic data where known PK parameters map was used as the ground truth, and subsequently used to directly estimate PK parameters (volume transfer constant K trans and flux rate constant K ep) map. The accuracy assessed by the peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and concordance correlation coefficient (CCC) was compared between the GL-CNN and Tofts-based PK parameters in synthetic data. Radiomic features were calculated from the PK parameters map in 208 breast tumors. A random forest classifier was constructed to predict molecular subtypes using a discovery cohort (n = 144). The diagnostic performance evaluated on a validation cohort (n = 64) using the area under the receiver operating characteristic curve (AUC) was compared between the GL-CNN and Tofts-based PK parameters. Main results. The average PSNR (48.8884), SSIM (0.9995), and CCC (0.9995) between the GL-CNN-based K trans map and ground truth were significantly higher than those between the Tofts-based K trans map and ground truth. The GL-CNN-based K trans obtained significantly better diagnostic performance (AUCs = 0.7658 and 0.8528) than the Tofts-based K trans for luminal B and HER2 tumors. The GL-CNN method accelerated the computation by speed approximately 79 times compared to the Tofts method for the whole breast of all patients. Significance. Our results indicate that the GL-CNN method can be used to accurately and efficiently estimate PK parameters for predicting molecular subtypes. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effect of imaging time on the pharmacokinetic parameters calculation of dynamic 11C-acetate cardiac positron emission tomography (PET) scan and to investigate the feasibility of shortening the imaging time in clinical practice. Methods This study was a retrospective analysis and 46 subjects who underwent 11C-acetate PET/CT cardiac imaging at Peking Union Medical College Hospital (from a clinical study assessing myocardial tissue and metabolic characteristics in men with alcohol consumption) were included. Each subject was injected with 740 MBq 11C-acetate before a 40-minute PET/CT scan, and time-activity curve in the left ventricle was collected as input function. Pharmacokinetic parameters (K1 and k2) calculated from the 40-minute dynamic data (53 frames) was regarded as the reference standard. The number of included dynamic image frames was sequentially reduced from the last frame, and the corresponding pharmacokinetic parameters of 11C-acetate were calculated. Correlation, consistent analysis of trends and the relative differences on pharmacokinetic parameters between shortened data and reference standard were evaluated. The shortest acceptable scan time was determined based on the criterion that the R2 of linear regression models was higher than 0.9 in all myocardial segments. Results The R2 between 11C-acetate pharmacokinetic parameters and the reference standard was higher than 0.9 in all myocardial segments at scan time ≥17 min (37 frames) for both K1 and k2. The regression coefficients of K1 values calculated from the shortened data and the reference standard in myocardium were distributed in the range of 0.982-1.007, and the regression coefficients of k2 values calculated from the shortened data and the reference standard were distributed in the range of 0.783-1.000. When the scan time was reduced to 17 min (37 frames), the K1 and k2 values of left anterior descending branch, right coronary artery and left circumflex branch perfusion regions were significantly different from the reference standard (all P < 0.05). Left anterior descending branch perfusion region had the highest relative difference (RD) [K1: (3.93±1.98)%; k2: (13.79±6.40)%], while right coronary perfusion region had the lowest RD [K1: (2.84±1.89)%; k2: (9.74±5.62)%]. Conclusions For the male population with alcohol consumption or are healthy, shortening the scan time to 17 min (37 frames) during dynamic 11C-acetate PET/CT cardiac imaging can obtain tracer pharmacokinetic parameters consistent with the reference standard, which can provide references for optimizing clinical image acquisition time.

Therapeutic monoclonal antibodies (mAbs), which are developed to treat many pathologies, including cancer, autoimmune and infectious diseases, are one of the fastest growing classes of medicinal products. Given the large number of mAbs in the pipeline and continued interest from pharmaceutical companies, the mAb market is expected to continue to grow in the coming years. To maximise both the therapeutic benefit and the safety of medicinal products in this class, it is essential that their pharmacological properties be carefully characterised and understood.The aim of the study was to analyse literature data on approaches to studying the pharmacokinetics of mAbs. This review presents data on the main physicochemical and pharmacological properties of mAbs and compares them with small molecules. The article describes the influence of various factors on mAb pharmacokinetics.For example, such factors include the method of administration, hydrophilicity, and charge of the mAb, individual characteristics of the patient (body weight, plasma albumin levels, genetic characteristics, etc.), and concurrent administration of other medicinal products. The authors evaluated the role of intra- and inter-individual variability of pharmacokinetic parameters. The rapid development of this group of medicinal products and the emergence of new promising molecules are indicative of the need to study the pharmacokinetics and pharmacodynamics of mAbs in detail and to maximise both the therapeutic benefit and the safety of the medicinal products in this class.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and remains a significant global public health concern, with many new cases reported annually. Despite advancements in TB treatment and control, the emergence of drug-resistant strains has presented a considerable challenge to eradication efforts. One crucial area that necessitates further research in antituberculosis is the development of effective treatments for drug-resistant strains, particularly multidrug resistance tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), and totally drug–resistant tuberculosis (TDR-TB). The limited and often unsatisfactory treatment options available for drug-resistant strains require the exploration of novel drugs and treatment regimens to combat this escalating issue. This study focuses on designing and developing a series of new 1,8-naphthyridine derivatives for their potential antitubercular activity. The compounds were designed and evaluated through in-silico screening using Molinspiration Cheminformatics, Osiris Property Explorer, AdmetSAR, and SwissADME. The initial filtering process identified the top 16 hybrids, which were then subjected to docking using the AutoDock tool. These compounds' binding energies were higher than the standard drug isoniazid, indicating a potentially more substantial interaction with the target. Based on the promising in silico and docking results, further investigations were conducted on the top 3 compounds, namely ST03, ST09, and ST14. To assess the stability and binding energies observed during the initial docking process, molecular dynamics simulations were performed over a 100 ns period. Both the docking and simulation studies consistently demonstrated that the 1,8-naphthyridine hybrid ST09 exhibited stable and efficient binding energies, suggesting its potential as an effective antituberculosis agent.

Purpose: The current research focuses on enhancement of in vitro dissolution and in vivo bioavailability characteristics of iloperidone (IP) by formulation, optimization of L-SNEDDS using Box-Behnken design (BBD), and desirability function. L-SNEDDS were transformed into free-flowing powders by adsorption onto Neusilin US2 carrier. Methods: The excipients for formulation of SNEDDS (oils, surfactants, and co-surfactants) were selected based on drug solubility and their emulsification ability. For optimization of the formulation, four response variables such as globule size (nm), percentage transmittance (%), self-emulsification time (sec), and percent drug released in 15 min were considered. The 2D contour plots and 3D response surface plots were constructed using Design Expert software. Optimized formulation by adsorption method was converted to S-SNEDDS that were characterized by FTIR, DSC, SEM, and PXRD analyses. They were evaluated for particle size, polydispersity index, (PDI) and zeta potential. Results: The developed optimal L-SNEDDS of IP through BBD approach resulted in improvement of solubility and dissolution rate as compared with the pure drug. The characterization studies revealed droplet size to be 21.80 ± 2.41 nm, 99.584 ± 0.65% transmittance, 24.43 ± 2.12-sec emulsification time, and 95.31 ± 1.57% cumulative drug release in 15 min. The in vivo pharmacokinetic studies revealed that the optimized formulation showed an improvement in bioavailability when studied in Wistar rats in comparison with oral suspension of drug. Solid state characterization studies concluded lack of any significant interactions of drug with the lipid excipients and porous carriers. Accelerated stability studies emphasized stability of the product. Conclusion: The results conclude the potentiality of optimization of L-SNEDDS by application of BBD and desirability function and improvement in bioavailability by S-SNEDDS on oral administration. [ABSTRACT FROM AUTHOR]

Context: Pharmacokinetic studies play a fundamental role in making informed decisions during the drug development stage and fulfilling regulatory agencies’ requirements for drug approval. Disposition profiles of plasma drug concentrations over time can be characterized by using non-compartmental analysis, compartmental and physiological-based modeling. These models allow us to determine the pharmacokinetic parameters that best describe the absorption, distribution, metabolism, and excretion (ADME) processes. Aims: To develop a conceptual and practical guide for the classroom on the most relevant pharmacokinetic parameters and their applications. Results: The apparent volume of distribution (Vd), systemic drug clearance (CL), bioavailability (F) and elimination half-life (t1/2) are among the most relevant pharmacokinetic parameters discussed in this article. The Vd describes the relationship at equilibrium between the amount of drug in the body and its plasma concentrations after distribution, used to calculate the initial dose to reach the target drug concentration. The CL describes the relationship between plasma drug concentrations and the rate of elimination from the body, allowing calculation of a maintenance dosing rate to maintain an average target concentration at steady-state. The t1/2 is the time required to halve the plasma drug concentration, whereas F is critical to understand the biological performance of the drug formulation. Conclusions: In this teacher’s topic text, we emphasize the importance of these parameters for optimizing strategies of model-informed dose individualization. Indeed, they are crucial for predicting systemic drug exposures and how long the drug will last in the body, as well as time to steady state after multiple-dosing regimens.

Abstract Background Tanreqing capsules (TRQCs) and Tanreqing injections (TRQIs) are widely used in the treatment of respiratory diseases. In this study, a simple, rapid, and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for simultaneous quantification of the main components of Tanreqing, which include chlorogenic acid, ursodeoxycholic acid, chenodeoxycholic acid, and baicalin, in beagle dog plasma to compare their pharmacokinetic parameters. Methods Plasma samples were pretreated with protein precipitation. Chromatographic separation was performed on Waters Acquity UPLC HSS T3 (2.1 mm × 100 mm, 1.8 μm) column using a gradient elution with (A) 0.1% (v/v) formic acid aqueous solution and (B) acetonitrile. Six healthy beagles were divided into two groups, and a crossover, comparative pharmacokinetic study of TRQC (0.09 g/kg) and TRQI (0.5 mL/kg) after a single-dose administration or daily doses over 7 days was carried out. One group was administrated a single dose of TRQC and followed continuously for 7 days, whereas the other group was treated with TRQI in the same way. Results The calibration curves were linear over the ranges of 2.00–1000.00 ng/mL for baicalin, 10.00–5000.00 ng/mL for ursodeoxycholic acid, 1.00–500.00 ng/mLfor chenodeoxycholic acid and chlorogenic acid, respectively. The relative standard deviation of both intra-day and inter-day accuracy is less than 11.23%. The average extraction recovery of all compounds was greater than 82.21%. The major pharmacokinetic parameters of the four compounds were not significantly different between the two formulations (P > 0.05). Conclusions The measured levels of the four major components of TRQCs and TRQIs were comparable in these dogs, providing a reference for the clinical application of TRQCs instead of TRQIs.

Glimepiride (GM) is a hydrophobic drug that dissolves slowly and yields inconsistent clinical responses after oral administration. Transdermal drug delivery (TDD) is an appropriate alternative to oral administration. Microneedles (MNs) offer a promising delivery system that penetrates the skin, while polymeric micelles can enhance the solubility; hence, the combination of both results in high drug bioavailability. This study aims to improve glimepiride's solubility, dissolution rate, and bioavailability by incorporating nanomicelles into MNs for TDD. The nanomicelles formulated with 10% Soluplus® (SP) and 40% GM had a mean particle size of 82.6 ± 0.54, PDI of 0.1 ± 0.01, −16.2 ± 0.18 zeta potential, and achieved a 250-fold increase in solubility. The fabricated pyramid shaped GM-dissolving MNs were thermally stable and had no formulation incompatibility, as confirmed by thermal and FTIR analysis. The in vitro dissolution profile revealed that the GM release from nanomicelles and nanomicelle-loaded DMN was concentration-independent following non-Fickian transport mechanism. Improved pharmacokinetic parameters were obtained with dose of 240 µg as compared to 1 mg of GM oral tablet, in healthy human volunteers. The observed Cmax, Tmax and MRT were 1.56 μg/mL ± 0.06, 4 h, and 40.04 h ± 3.37, respectively. The safety profile assessment indicated that microneedles are safe with no adverse effects on skin or health. This study provides an alternative delivery system for the administration of glimepiride, resulting in improved bioavailability, enhanced patient compliance, and reduced dosing frequency. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The whole concept of NAFLD has now moved into metabolic dysfunction-associated fatty liver disease (MAFLD) to emphasize the strong metabolic derangement as the basis of the disease. Several studies have suggested that hepatic gene expression was altered in NAFLD and NAFLD-related metabolic comorbidities, particularly mRNA and protein expression of phase I and II drug metabolism enzymes (DMEs). NAFLD may affect the pharmacokinetic parameters. However, there were a limited number of pharmacokinetic studies on NAFLD at present. Determining the pharmacokinetic variation in patients with NAFLD remains challenging. Common modalities for modeling NAFLD included: dietary induction, chemical induction, or genetic models. The altered expression of DMEs has been found in rodent and human samples with NAFLD and NAFLD-related metabolic comorbidities. We summarized the pharmacokinetic changes of clozapine (CYP1A2 substrate), caffeine (CYP1A2 substrate), omeprazole (Cyp2c29/CYP2C19 substrate), chlorzoxazone (CYP2E1 substrate), midazolam (Cyp3a11/CYP3A4 substrate) in NAFLD. These results led us to wonder whether current drug dosage recommendations may need to be reevaluated. More objective and rigorous studies are required to confirm these pharmacokinetic changes. We have also summarized the substrates of the DMEs aforementioned. In conclusion, DMEs play an important role in the metabolism of drugs. We hope that future investigations should focus on the effect and alteration of DMEs and pharmacokinetic parameters in this special patient population with NAFLD. [ABSTRACT FROM AUTHOR]

Malaria is one of the major public health challenges in Nigeria. Treatment failure as a result of drug interaction is a major problem. A study of the effect of ascorbic acid on the antiplasmodial activity of artemether has been reported. This study was carried out to determine the effect of ascorbic acid on the pharmacokinetic profile of artemether. Fourteen male rabbits weighing between 2.0 - 2.5 kg were used in this study. Four of the rabbits were used for determination of the efficiency, recovery studies and calibration curve while ten rabbits were randomly selected into Group A and B consisting of five rabbits each were used for the pharmacokinetic studies. Group A was administered a single dose of 10 mg/kg artemether while Group B was co-administered a single dose of 10 mg/kg artemeter and10 mg/kg ascorbic acid intramuscularly. The dihydroartemisinin in the plasma was analysed using High Performance Liquid Chromatography. The results showed that ascorbic acid affect the pharmacokinetic parameters of artemether. The time to reach maximum concentration (Tmax) increase from 30.00 min to 42.00 min while the maximum concentration (Cmax) and Area-under the Concentration Curve (AUC) decrease from 1461.9 (ng/mL) and 6566.7 (ng hr/mL) to 1331.1 (ng/mL) and 6105.8 (ng hr/mL), respectively. Ascorbic acid altered the pharmacokinetic profile of artemether. In clinical practice patients should be adviced not to co-administer ascorbic acid with artemether. [ABSTRACT FROM AUTHOR]

The present study aims to explore the anti-inflammatory potential activity of the hexane extract from branches (HEB) of Endlicheria paniculata (Lauraceae) and its main compound, methyldehydrodieugenol B, in the inflammatory response induced by a murine implant sponge model. HPLC-ESI/MS analysis of HEB led to the identification of six chemically related neolignans, with methyldehydrodieugenol B as the main compound. An in silico analysis of the pharmacokinetic parameters of the identified compounds suggested moderate solubility but good absorption and biodistribution in vivo. Thus, the treatment of mice with HEB using in vivo assays indicated that HEB promoted pro-inflammatory, antiangiogenic, and antifibrogenic effects, whereas treatment with methyldehydrodieugenol B caused anti-inflammatory, antifibrogenic, and antiangiogenic effects. The obtained results shown the therapeutic potential of HEB and methyldehydrodieugenol B in the treatment of pathologies associated with inflammation and angiogenesis, including chronic wounds. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer (HNC) is the sixth most prevalent cancer worldwide. Dynamic contrast‐enhanced MRI (DCE‐MRI) helps in diagnosis and prognosis. Quantitative DCE‐MRI requires an arterial input function (AIF), which affects the values of pharmacokinetic parameters (PKP). Purpose: To evaluate influence of four individual AIF measurement methods on quantitative DCE‐MRI parameters values (Ktrans, ve, kep, and vp), for HNC and muscle. Study Type: Prospective. Population: A total of 34 HNC patients (23 males, 11 females, age range 24–91) Field Strength/Sequence: A 3 T; 3D SPGR gradient echo sequence with partial saturation of inflowing spins. Assessment: Four AIF methods were applied: automatic AIF (AIFa) with up to 50 voxels selected from the whole FOV, manual AIF (AIFm) with four voxels selected from the internal carotid artery, both conditions without (Mc−) or with (Mc+) motion correction. Comparison endpoints were peak AIF values, PKP values in tumor and muscle, and tumor/muscle PKP ratios. Statistical Tests: Nonparametric Friedman test for multiple comparisons. Nonparametric Wilcoxon test, without and with Benjamini Hochberg correction, for pairwise comparison of AIF peak values and PKP values for tumor, muscle and tumor/muscle ratio, P value ≤ 0.05 was considered statistically significant. Results: Peak AIF values differed significantly for all AIF methods, with mean AIFmMc+ peaks being up to 66.4% higher than those for AIFaMc+. Almost all PKP values were significantly higher for AIFa in both, tumor and muscle, up to 76% for mean Ktrans values. Motion correction effect was smaller. Considering tumor/muscle parameter ratios, most differences were not significant (0.068 ≤ Wilcoxon P value ≤ 0.8). Data Conclusion: We observed important differences in PKP values when using either AIFa or AIFm, consequently choice of a standardized AIF method is mandatory for DCE‐MRI on HNC. From the study findings, AIFm and inflow compensation are recommended. The use of the tumor/muscle PKP ratio should be of interest for multicenter studies. Evidence Level: 2 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

The in vivo anticancer potential of vincristine (VC) loaded, thiolated chitosan-based nanoformulation (NFs) with an outer hyaluronic acid (VC-loaded in TCs-HA) coating was studied in prostate cancer (PC) xenograft in the immunosuppressed rat model induced by PC3 cell lines. Our previous study has already reported the in vitro efficacy of the said NFs. The ADMET Predictor (TM) Cloud version 10.4.0.5, 64-bit, was used to simulate VC's physicochemical and pharmacokinetic parameters. The percentage of encapsulation efficiency of VC by direct and indirect methods was 81.5 and 90%, respectively. Plasma samples from healthy rats showed improved pharmacokinetic and bioavailability profiles of NFs compared to VC injection via HPLC. The haemolytic analysis of NFs showed two times lesser toxicity to red blood cells. Xenograft rats showed maximum tumour volume up to 235 ± 0.02 mm3 with increased body weight, and it was reduced by 56 ± 0.01 to 107.3 ± 0.03 mm3 during the whole treatment by NFs compared to pure VC. The histopathology of the NFs group showed less malignancy with angiogenesis and significantly less metastasis to the liver and kidney. ELISA showed high expression of apoptotic biomarkers, including Bax, cleaved Caspase 3, and cleaved PARP, while the expression of BCL2, Caspase 3, COX-II, NFκB, and TNF-α was reduced. Immunohistochemical analysis also revealed that post-NF administration, cytoplasmic expressions of TNF-α and COX-II were reduced, as were nuclear expressions of NFκB. Thus, the prepared chemotherapeutic NFs were a comparatively potent oncolytic agent, safe with lesser off-target toxicity, and had an improved pharmacokinetic and bioavailability profile. [ABSTRACT FROM AUTHOR]

Malaria is one of the major public health challenges in Nigeria. Treatment failure as a result of drug interaction is a major problem. A study of the effect of ascorbic acid on the antiplasmodial activity of artemether has been reported. This study was carried out to determine the effect of ascorbic acid on the pharmacokinetic profile of artemether. Fourteen male rabbits weighing between 2.0 – 2.5 kg were used in this study. Four of the rabbits were used for determination of the efficiency, recovery studies and calibration curve while ten rabbits were randomly selected into Group A and B consisting of five rabbits each were used for the pharmacokinetic studies. Group A was administered a single dose of 10 mg/kg artemether while Group B was co-administered a single dose of 10 mg/kg artemeter and10 mg/kg ascorbic acid intramuscularly. The dihydroartemisinin in the plasma was analysed using High Performance Liquid Chromatography. The results showed that ascorbic acid affect the pharmacokinetic parameters of artemether. The time to reach maximum concentration (Tmax) increase from 30.00 min to 42.00 min while the maximum concentration (Cmax) and Area-under the Concentration Curve (AUC) decrease from 1461.9 (ng/mL) and 6566.7 (ng hr/mL) to 1331.1 (ng/mL) and 6105.8 (ng hr/mL), respectively. Ascorbic acid altered the pharmacokinetic profile of artemether. In clinical practice patients should be adviced not to co-administer ascorbic acid with artemether.

Microneedles have recently emerged as a promising platform for delivering therapeutic agents by disrupting the skin, resulting in improved and high drug delivery via this route. Ibuprofen is widely used topically and orally for chronic pain conditions; to avoid untoward gastric effects, topical application is preferred over the oral route. This study aimed to enhance the solubility of the poorly water-soluble ibuprofen using Soluplus (SP) as a solubilizer and to fabricate dissolving microneedle patches of the drug. The fabricated patches were compared with marketed oral and topical formulations of ibuprofen. A 432-fold increase was observed in the solubility of the drug at 8% SP. The FTIR studies revealed that the drug and polymers were compatible. MNs were of uniform morphology and released the drug in a predictable manner. The in vivo analysis on healthy human volunteers revealed a Cmax of 28.7 µg/mL ± 0.5 with a Tmax of 24 h and a MRT of 19.5 h, which was significantly higher than that observed for commercially available topical formulations. The prepared ibuprofen microneedles have higher bioavailability and MRT at a lower dose (165 µg) as compared to tablet and cream doses (200 mg). [ABSTRACT FROM AUTHOR]

In this study, a new stereospecific strategy for the preparation of C 8 N aminocyclohexenols such as C 7 N, validamine analogs were developed from starting compound 4 via intramolecular aza -michael β -amination reaction between α , β -unsaturated ketones and ammonia in methanol. The strategy was to produce C 8 N derivatives such as validamine C 7 N via Kornblum-DeLaMare rearrangement, which involves stereocontrolled amination of a double bond, esterification, carbonyl group reduction, benzofuran ring opening, ammonolysis of acetate groups. The mechanism of target molecules is discussed. Pseudosugars with different configurations containing an amino group at the anomeric position were tested against α -glucosidase, β -glucosidase, and α -amylase. Among these compounds, compound 12 against α -glucosidase, compound 14 against β -glucosidase, and compound 21 against α -amylase exhibited the best activity compared to acarbose. Moreover, enzyme kinetic studies to understand the enzyme inhibition mechanism and DFT studies to investigate binding interactions with enzyme active sites were performed on these compounds (12 , 14 , and 21). Additionally, the pharmacokinetic parameters (ADME) were examined using the QikProp module to determine their potential as drug candidates. [Display omitted] • Catalyst-free C–N bond production by β -Michael addition. • Compared to acarbose, compounds 12 and 14 exhibited the best activity against (α-, β-) glucosidase, and 21 against α-amylase. • Compounds 12 and 14 meet the parameters specified in Lipinski's rule of five. [ABSTRACT FROM AUTHOR]

In order to better promote the application of the polymeric mixed micelles (PMMs) in oral delivery, in addition to focusing on the improvement of micellar structural stability, it is necessary to obtain the absorption characteristics of the intact micellar particles. In this work, the transport behavior across Caco-2 cells of FS/PMMs composed of Pluronic F127 and Solutol HS15 was tracked by encapsulating an environment-responsive probe into the particles. The specific property of the probe is the water-initiated aggregation-caused quenching (ACQ) ability, by which integral particles can be identified accurately. The influence of polymeric ratios (FS) on the transcellular behavior of FS/PMMs was explored and the single pass intestinal perfusion experiment was used to further illustrate it. Moreover, pharmacokinetics parameters were detected to analyze the relationship among FS ratios, transport behavior, and pharmacokinetic parameters. FS ratios were found to hardly affect the endocytosis pathways and intracellular itinerary of FS/PMMs, but do affect the proportion of each path. FS/PMMs with high HS15 content, namely System-I, were found to primarily undergo receptor-mediated endocytosis pathway and be less susceptible to lysosomal degradation, which would lead to more absorption and higher Cmax and AUC than drug suspension. In contrast, despite System-II with high F127 content cannot contribute to drug plasma concentration, it can prolong the in vivo retention time. These findings provided evidence for the role of polymeric ratios in modulating the transcellular absorption and pharmacokinetic parameters of the drug-loaded PMMs, and would be a step forward in helping PMMs' design to enhance oral drug delivery. [ABSTRACT FROM AUTHOR]

Background: Tanreqing capsules (TRQCs) and Tanreqing injections (TRQIs) are widely used in the treatment of respiratory diseases. In this study, a simple, rapid, and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for simultaneous quantification of the main components of Tanreqing, which include chlorogenic acid, ursodeoxycholic acid, chenodeoxycholic acid, and baicalin, in beagle dog plasma to compare their pharmacokinetic parameters. Methods: Plasma samples were pretreated with protein precipitation. Chromatographic separation was performed on Waters Acquity UPLC HSS T3 (2.1 mm × 100 mm, 1.8 μm) column using a gradient elution with (A) 0.1% (v/v) formic acid aqueous solution and (B) acetonitrile. Six healthy beagles were divided into two groups, and a crossover, comparative pharmacokinetic study of TRQC (0.09 g/kg) and TRQI (0.5 mL/kg) after a single-dose administration or daily doses over 7 days was carried out. One group was administrated a single dose of TRQC and followed continuously for 7 days, whereas the other group was treated with TRQI in the same way. Results: The calibration curves were linear over the ranges of 2.00–1000.00 ng/mL for baicalin, 10.00–5000.00 ng/mL for ursodeoxycholic acid, 1.00–500.00 ng/mLfor chenodeoxycholic acid and chlorogenic acid, respectively. The relative standard deviation of both intra-day and inter-day accuracy is less than 11.23%. The average extraction recovery of all compounds was greater than 82.21%. The major pharmacokinetic parameters of the four compounds were not significantly different between the two formulations (P > 0.05). Conclusions: The measured levels of the four major components of TRQCs and TRQIs were comparable in these dogs, providing a reference for the clinical application of TRQCs instead of TRQIs. [ABSTRACT FROM AUTHOR]

Purpose: To quantitatively evaluate the performance of two types of recurrent neural networks (RNNs), long short-term memory (LSTM) and gated recurrent units (GRU), using Monte Carlo dropout (MCD) to predict pharmacokinetic (PK) parameters from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data., Methods: DCE-MRI data for simulation studies were synthesized using the extended Tofts model and a population-averaged arterial input function (AIF). The ranges of PK parameters for training the RNNs were determined from data of patients with brain tumors. The effects of the number of training samples, number of hidden units, dropout rate (DR), and bolus arrival time delay and dispersion in AIF on the accuracy of the PK parameters were investigated, and the uncertainties for different DRs and peak signal-to-noise ratios (PSNRs) were quantified. For comparison, PK parameters were estimated using the nonlinear least-squares method. In the clinical studies, the PK parameter and uncertainty images were generated by applying the trained RNNs to DCE-MRI data., Results: Compared with GRU, the computational cost for training the LSTM was significantly higher. The prediction accuracy of GRU decreased with decreasing numbers of training samples and hidden units, whereas the performance of LSTM remained stable. Despite an increased computational cost, MCD reduced the prediction error at low PSNR and improved the quality of PK parameter images. The simulation results recommended using a DR of 0.25-0.5 at low PSNR and ≤ 0.25 for other PSNRs. The clinical studies recommended using a DR of 0.25 and 0.5 for LSTM and GRU, respectively., Conclusions: MCD is effective in quantifying uncertainty in PK parameter prediction from DCE-MRI data and improves their performance, particularly at low PSNR; however, at the expense of increased computational cost. This study helps deepen our understanding of RNNs with MCD and select suitable hyperparameters for creating an RNN architecture for DCE-MRI studies., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Insulin aspart, a rapid-acting analog, achieves faster subcutaneous absorption than regular insulin. This study aimed to demonstrate equivalence in the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of Recombinant Human Insulin Aspart from BioGenomics Limited (as test) and Novo-Nordisk (as reference) in healthy adult males. This was a double-blind, randomized, cross-over study, assessing PK and PD parameters under fasting conditions. Participants received either 0.2 U/kg of test or reference product via a subcutaneous route in the abdominal area. PK parameters included maximum serum concentration (C max ), area under the curve [(AUC [0-t] ) and (AUC [0-∞] )], time to maximum serum concentration (T max ), and half-life (t ½ ). PD parameters included amount of glucose infused (G tot ), maximum glucose infusion rate (R max ), time of R max (tR max ), late time of half-maximal glucose infusion rate (tR max50 ), time of first measured glucose infusion rate (t onset ), and cessation of glucose infusion/clamp (tR last ). Seventy subjects between 18 and 45 years of age and body mass index between 18 and 27 kg/m 2 were enrolled. The 90% confidence intervals (CIs) for C max , AUC [0-t] , AUC [0-∞] for insulin, and the 95% CIs for G tot , R max for glucose were within 80%-125% as required to assess test-reference bioequivalence. No serious adverse events were observed. Both the preparations showed bioequivalence under fasting conditions with a similar safety profile., (© 2025, The American College of Clinical Pharmacology.)

Pharmacokinetic (PK) properties of a drug are vital attributes influencing its therapeutic effectiveness, playing an important role in the drug development process. Focusing on the difficult task of predicting PK parameters, we compiled an extensive data set comprising parameters across multiple species. Building upon this groundwork, we introduced the PKStack ensemble model to predict PK parameters across diverse species. PKStack integrates a variety of base models and includes uncertainty in its predictions. We also manually collected PK data from animals as an external test set. We predicted a total of 45 tasks for nine PK parameters in five species, and in general, the prediction accuracy was better for intravenous injections, including parameters such as human V d (R 2 = 0.72, RMSE = 0.31), human CL (R 2 = 0.52, RMSE = 0.32), and others. In addition to predictive accuracy, we also considered the interpretability of the results and the definition of the model's application domain. Based on the findings, our model has great potential for practical applications in drug discovery.

Nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid, can have a dose-dependent nephrotoxic effect. The study of the pharmacokinetics of acetylsalicylic acid products will contribute to timely detection and correction of side effects caused by this medicinal product.The aim of the study was to evaluate potential nephrotoxic effects following a single oral administration of 75 mg of acetylsalicylic acid, based on the analysis of the pharmacokinetic parameters.Materials and methods: the study involved 24 healthy volunteers who received 75 mg of acetylsalicylic acid (tablets) once orally. The measurement of the active metabolite of acetylsalicylic acid—salicylic acid—in blood plasma was performed by HPLC/MS using an Agilent 1200 liquid chromatography system coupled to an Agilent 6140 tandem mass spectrometer. Agilent Eclipse XDB-C18 column (4.6 mm×150 mm; 5.0 μm) was used for chromatographic separation. The test procedure used in the study was validated. The results obtained were used to calculate the pharmacokinetic parameters: Cmax (maximum concentration), Tmax (time to maximum concentration), T1/2 (half-life of the drug), AUC0-t (area under the pharmacokinetic curve from 0 to the last time point of the curve), AUC0-∞ (total area under the pharmacokinetic curve from 0 to ∞), MRT (mean residence time of the drug in the blood), Kel (elimination rate constant), Cl/F (total clearance), Vd/F (apparent volume of distribution). The Statistics (22.0.0.0) software was used for statistical processing of the results.Results: T1/2 of salicylic acid in blood plasma was determined to be 1.6 ± 0.5 h, Cmax was 4523.0 ± 725.0 ng/mL, and Tmax was 0.98 ± 0.4 h. AUC0–t was equal to 16183.0 ± 3823.0 ng×h/m, Vd/F was 12.0 ± 3.1 L/kg, and MRT was 2.9 ± 0.6 h.Conclusions: the analysis of the pharmacokinetic parameters demonstrated a high absorption rate, intensive distribution, and moderate elimination rate of salicylic acid (the main metabolite of acetylsalicylic acid), indicating a low risk of nephrotoxic effects associated with the studied dose of the drug.

ABSTRACT: Background: Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objectives: These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (ViagraⓇ; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods: Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. Forty-two and 80 healthy male volunteers were recruited in the first and second study, respectively. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results: In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the ViagraⓇ FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91–108.78) and area under the plasma concentration-time curve: 1.09 (104.49–113.21) for sildenafil citrate ODF administered with water vs ViagraⓇ FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also showed bioequivalence for sildenafil citrate ODF (without water) compared with ViagraⓇ FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47–109.36) and area under the plasma concentration-time curve: 1.06 (103.42–108.40) for sildenafil citrate ODF administered without water vs ViagraⓇ FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity. Conclusions: These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with ViagraⓇ FCT administered with water under fasted conditions in healthy adult male volunteers. The new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form.

Simple Summary: This study was designed to assess the effect of metronomic cyclophosphamide on carboplatin's tolerability, efficacy, and pharmacokinetics in female dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were treated with 300 mg/m2 intravenous (i.v.) carboplatin therapy (n = 8) or 300 mg/m2 i.v. carboplatin which was associated with 12.5 mg/m2/day oral cyclophosphamide (n = 8). A non-compartmental analysis was applied to calculate the PK parameters of carboplatin in the second and fourth chemotherapy cycles. The carboplatin pharmacokinetics showed high interindividual variability with 10-fold variation in the area under the plasma concentration–time curve (AUC) in the animals receiving carboplatin only. The systemic plasma exposure (AUC and Cmax) to carboplatin was equivalent in both of the treatments (carboplatin alone and carboplatin + cyclophosphamide). Carboplatin + metronomic cyclophosphamide was well-tolerated by all of the animals. Our results demonstrated that adding low daily doses of cyclophosphamide to the carboplatin therapy increased the survival rate of the female dogs with mammary cancer. This prospective study aimed to evaluate the effect of metronomic cyclophosphamide on carboplatin's tolerability, efficacy, and pharmacokinetics in dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were divided into groups: 300 mg/m2 intravenous (i.v.) carboplatin therapy (G1 = 8) or 300 mg/m2 i.v. carboplatin which was associated with 12.5 mg/m2 oral cyclophosphamide in a metronomic regimen (G2 = 8). The investigated animals underwent a clinical evaluation, a mastectomy, a carboplatin chemotherapy, and serial blood sampling for the pharmacokinetic analysis. The adverse events and survival rates were monitored. A non-compartmental analysis was applied to calculate the pharmacokinetic parameters of carboplatin in the 2nd and 4th chemotherapy cycles. Carboplatin PK showed high interindividual variability with a 10-fold variation in the area under the plasma concentration–time curve (AUC) in G1. The systemic plasma exposure to carboplatin was equivalent in both of the treatments considering the AUC and maximum plasma concentration (Cmax) values. Although the red blood cells (p < 0.0001), platelets (p = 0.0005), total leukocytes (p = 0.0002), and segmented neutrophils (p = 0.0007) were reduced in G2, the survival rate increased (p = 0.0044) when it was compared to G1. In conclusion, adding low daily doses of cyclophosphamide to a carboplatin therapy showed promising outcomes in female dogs with mammary tumors. [ABSTRACT FROM AUTHOR]

Ondansetron has been widely applied as an antiemetic drug in the treatment or prevention of nausea and vomiting caused by emetic cancer chemotherapy. Fast-release films have the advantages of rapid drug release and improved patient compliance, especially for the disabled bedridden, elderly, or pediatric patients. The basic film-forming materials were studied through single-factor tests and the crystal inhibitors were optimized using the solid dispersion technique. The ratio of drug and polymers was optimized by X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) which revealed there was no presence of crystal in the optimized solid dispersion. The final film was a white thin film and was smooth on the surface without obvious bubbles or cracks. The mean weight of each film was 40 ~ 50 mg. The mean thickness was 60 ~ 70 µm. The surface pH was 6.4 ~ 6.6. The films could release 85% of the drug within 1.5 min in 0.1 mol/L HCl and within 30 min in pH 6.8 PBS. The pharmacokinetic experiment of Ondansetron Hydrochloric solution, marketed films Zuplenz® and the preparation were carried out in rats. As a result, the films of Ondansetron Hydrochloric containing ondansetron solid dispersion had the advantages of fast drug release, improved patient compliance, and higher bioavailability compared to oral solution and the marketed films. [ABSTRACT FROM AUTHOR]

This paper aims to solve the arterial input function (AIF) determination in dynamic contrast-enhanced MRI (DCE-MRI), an important linear ill-posed inverse problem, using the maximum entropy technique (MET) and regularization functionals. In addition, estimating the pharmacokinetic parameters from a DCE-MR image investigations is an urgent need to obtain the precise information about the AIF–the concentration of the contrast agent on the left ventricular blood pool measured over time. For this reason, the main idea is to show how to find a unique solution of linear system of equations generally in the form of y = A x + b , named an ill-conditioned linear system of equations after discretization of the integral equations, which appear in different tomographic image restoration and reconstruction issues. Here, a new algorithm is described to estimate an appropriate probability distribution function for AIF according to the MET and regularization functionals for the contrast agent concentration when applying Bayesian estimation approach to estimate two different pharmacokinetic parameters. Moreover, by using the proposed approach when analyzing simulated and real datasets of the breast tumors according to pharmacokinetic factors, it indicates that using Bayesian inference—that infer the uncertainties of the computed solutions, and specific knowledge of the noise and errors—combined with the regularization functional of the maximum entropy problem, improved the convergence behavior and led to more consistent morphological and functional statistics and results. Finally, in comparison to the proposed exponential distribution based on MET and Newton's method, or Weibull distribution via the MET and teaching–learning-based optimization (MET/TLBO) in the previous studies, the family of Gamma and Erlang distributions estimated by the new algorithm are more appropriate and robust AIFs. [ABSTRACT FROM AUTHOR]

In this study, the effectiveness of the combination therapy of 1,8-cineole with amoxicillin (AMX) and clavulanic acid (Clav) was investigated. For this, the pharmacokinetic behaviors of AMX in rabbits were studied after a single oral dose. The animals were divided randomly into two groups: the reference group (received AMX/Clav (50/12.5 mg/kg)) and the test group (received AMX/Clav/1,8-cineole (50/12.5/10 mg/kg)). Blood samples were collected prior to administration and after T1h, T2h, T3h, and T6h post-administration. Plasma concentrations of AMX were quantified using a validated HPLC method. The antibacterial activity of plasma and cerebrospinal fluid (CSF) of treated rabbits was tested against Escherichia coli ESBL-producing a strain by microdilution method. The obtained results showed significant differences in pharmacokinetic parameters between the two groups. The resulting AUC0–6h and Cmax mean values of the AMX reference group were 14.74 µg.h/mL and 3.49 µg/mL, respectively. However, those of the AMX test group were 22.30 µg.h/mL and 5.79 µg/mL, respectively. The results showed that the antibacterial activity of the plasma and CSF test group was significantly higher than that of the reference group. The effectiveness of this combination (Olipen: AMX/Clav/1,8-cineole) was demonstrated by increasing the level of the antibiotic and by improving the bioavailability. [ABSTRACT FROM AUTHOR]

Serum kinetics of diminazene aceturate following intramuscular (IM) administration of diminazene aceturate alone at 3.5 mg/kg and its combination with oxytetracycline at 20 mg/kg were evaluated in 6 healthy male Sahel goats to ascertain the effect of oxytetracycline on serum concentration and pharmacokinetic parameters of diminazene aceturate. Two groups (A and B) of three goats each were used, and oxytetracycline was administered 30 minutes prior to diminazene aceturate administration. Blood samples were collected at various intervals (0.17 h -- 72 h) post- drug administration, and diminazene serum concentrations were measured using the method of Klatt and Hadju. Kinetic determinants were calculated employing a two- compartment open model. Mean serum concentrations of diminazene aceturate of 2.43 ± 0.95 µg/ml and 1.73 ± 0.44 µg/ml at 0.17 h were measured in groups A and B, respectively. These serum concentrations were found to increase until a peak concentration of 6.91 ± 0.59 µg/ml and 7.55 ± 1.20 µg/ml were reached at 2.0 h in groups A and B, respectively. The peak concentrations subsequently decreased at 72 h post diminazene aceturate administration with serum concentrations of 0.00 ± 0.00 and 0.32 ± 0.28 µg/ml in groups A and B, respectively. Pharmacokinetics parameters like the volume of distribution (Vd), elimination half-life (T½β), concentration maximum (Cmax), absorption rate constant (α), and area under the curve from 0 to 72 h (AUC0 - 72) were significantly higher in goats treated with diminazene aceturate and oxytetracycline combination while total body clearance (Cl), and elimination rate constant (β), were significantly higher in goats treated with diminazene aceturate alone. The mean residence time (MRT) of diminazene aceturate increased from 19.70 ± 2.53 h in diminazene aceturate treatment to 25.11 ± 1.81 h in diminazene aceturate and oxytetracycline treatment. Oxytetracycline was therefore found to alter the elimination pattern of diminazene aceturate in oxytetracycline pre-treated goats. [ABSTRACT FROM AUTHOR]