Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity.Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity.Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2 g every 24 h is lower than the accumulation of 1 g every 12 h dosing regimen.Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment

Pharmacological Potential of Hippophae rhamnoides L. Nano-Emulsion for Management of Polycystic Ovarian Syndrome in Animals’ Model: In Vitro and In Vivo Studies

The most common female endocrinopathy, polycystic ovarian syndrome (PCOS), generally affects women of childbearing age. Hippophae rhamnoides L. has been traditionally used to improve menstrual cyclicity. Gas chromatography by flame ionization detection analysis showed that it contained various phytoconstituents such as omega-3 fatty acid, phytosterols, palmitic acid, oleic acid, and linoleic acid. H. rhamnoides L. (HR) nano-emulsion was also formulated. HR and its encapsulated nano-emulsion (HRNE) were evaluated for the treatment of PCOS. Thirty-five healthy female adult albino rats were acquired and divided into seven groups (n = 5). Letrozole (1 mg/kg) was used for 5 weeks to induce the disease. To confirm disease (PCOS) induction, the animals were weighed weekly and their vaginal smears were analyzed daily under a microscope. After PCOS induction, animals were treated with metformin, HR, and HRNE with two different doses (0.5/kg and 1 g/kg, p.o.) for 5 weeks. At the end of the treatment, animals were euthanized, and blood was collected for hormonal assessment, lipid profiling, and liver functioning test assessment. Both the ovaries were preserved for histopathology and liver for the purpose of assessment of antioxidant potential. The results revealed that HR and HRNE at both doses improved the hormonal imbalance; follicle-stimulating hormone, estrogen, and progesterone levels are increased, while luteinizing hormone surge and testosterone level are controlled. Insulin sensitivity is improved. Ovarian histopathology showed that normal ovarian echotexture is restored with corpus luteum and mature and developing follicles. HR and HRNE also improved the lipid profile and decreased lipid peroxidation (MDA) with improved antioxidant markers (SOD, CAT, and GSH). Results were statistically analyzed by one-way analysis of variance and were considered significant only if p < 0.05. In conclusion, it can be postulated that H. rhamnoides L. proved effective in the management of PCOS and its nano-emulsion effects were statistically more significant, which might be due to better bioavailability

A pH-responsive bi-MIL-88B MOF coated with folic acid-conjugated chitosan as a promising nanocarrier for targeted drug delivery of 5-Fluorouracil

Cancer has remained one of the leading causes of death worldwide, with a lack of effective treatment. The intrinsic shortcomings of conventional therapeutics regarding tumor specificity and non-specific toxicity prompt us to look for alternative therapeutics to mitigate these limitations. In this regard, we developed multifunctional bimetallic (FeCo) bi-MIL-88B-FC MOFs modified with folic acid—conjugated chitosan (FC) as drug delivery systems (DDS) for targeted delivery of 5-Fluorouracil (5-FU). The bi-MIL-88B nanocarriers were characterized through various techniques, including powder X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Interestingly, 5-FU@bi-MIL-88B-FC showed slower release of 5-FU due to a gated effect phenomenon endowed by FC surface coating compared to un-modified 5-FU@bi-MIL-88B. The pH-responsive drug release was observed, with 58% of the loaded 5-FU released in cancer cells mimicking pH (5.2) compared to only 24.9% released under physiological pH (5.4). The in vitro cytotoxicity and cellular internalization experiments revealed the superiority of 5-FU@bi-MIL-88B-FC as a highly potent targeted DDS against folate receptor (FR) positive SW480 cancer cells. Moreover, due to the presence of Fe and Co in the structure, bi-MIL-88B exhibited peroxidase-like activity for chemodynamic therapy. Based on the results, 5-FU@bi-MIL-88B-FC could serve as promising candidate for smart DDS by sustained drug release and selective targeting

Comparative genomics of food-derived probiotic Lactiplantibacillus plantarum K25 reveals its hidden potential, compactness, and efficiency

This study aimed to investigate the intricate genetic makeup of the Lactiplantibacillus plantarum K25 strain by conducting a comprehensive analysis of comparative genomics. The results of our study demonstrate that the genome exhibits a high-level efficiency and compactness, comprising a total of 3,199 genes that encode proteins and a GC content of 43.38%. The present study elucidates the evolutionary lineage of Lactiplantibacillus plantarum strains through an analysis of the degree of gene order conservation and synteny across a range of strains, thereby underscoring their closely interrelated evolutionary trajectories. The identification of various genetic components in the K25 strain, such as bacteriocin gene clusters and prophage regions, highlights its potential utility in diverse domains, such as biotechnology and medicine. The distinctive genetic elements possess the potential to unveil innovative therapeutic and biotechnological remedies in future. This study provides a comprehensive analysis of the L. plantarum K25 strain, revealing its remarkable genomic potential and presenting novel prospects for utilizing its unique genetic features in diverse scientific fields. The present study contributes to the existing literature on Lactiplantibacillus plantarum and sets the stage for prospective investigations and practical implementations that leverage the exceptional genetic characteristics of this adap organism

Assessment of anticancer properties of cumin seed (Cuminum cyminum) against bone cancer

IntroductionEarly-life osteosarcoma is associated with severe morbidity and mortality, particularly affecting young children and adults. The present cancer treatment regimen is exceedingly costly, and medications like ifosfamide, doxorubicin, and cisplatin have unneeded negative effects on the body. With the introduction of hyphenated technology to create medications based on plant molecules, the application of ayurvedic medicine as a new dimension (formulation, active ingredients, and nanoparticles) in the modern period is rapidly growing. The primary source of lead compounds for the development of medications for avariety of ailments is plants and their products. Traditionally, Cuminum cyminum (cumin) has been used as medication to treat a variety of illnesses and conditions.MethodsThe cumin seed was successfully extracted with solvents Hexane, Chloroform, Methanol, Ethanol and Acetone. Following the solvent extraction, the extract residue was assayed in MG63 cells for their anti-proliferative properties. ResultsFirst, we used the [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] (MTT) assay to test the extracted residue’s cytotoxicity. The results show that hexane extract Half-maximal inhibitory concentration (IC50 86 µG/mL) effciently inhibits cells by causing programmed cell death. Furthermore, using the Acridine orange/ethidium bromide (AO/EB) staining method, the lactate dehydrogenase assay, and the reactive oxygen species assay using the Dichloro-dihydro-fluorescein diacetate (DCHFDA) staining method, we have demonstrated that the hexane extract causes apoptosis in MG63 cells. Furthermore, flow cytometry research revealed that the hexane extract stops the cell cycle in the S phase. In addition, the hexane extract limits colony formation and the migration potential as shown by the scratch wound healing assay. Furthermore, the extract from cumin seeds exhibits remarkable bactericidal properties against infections that are resistant to drugs. Gas chromatography analysis was used to quantitatively determine the hexane and methanolic extract based on the experimental data. The primary chemical components of the extract are revealed by the study, and these help the malignant cells heal. The present study finds that there is scientific validity in using cumin seeds as a novel method of anticancer therapy after undergoing both intrinsic and extrinsic research

GC–MS profiling of Bacillus spp. metabolites with an in vitro biological activity assessment and computational analysis of their impact on epithelial glioblastoma cancer genes

Background: Bacterial metabolites play a crucial role in human health and have proven effective in treating various diseases. In this study, the 16S rRNA method and streaking were employed to isolate and molecularly identify a bacterial strain, with the goal of characterizing bioactive volatile metabolites extracted using nonpolar and polar solvents.Methods: Gas chromatography–mass spectrometry (GC–MS) analysis was conducted to identify 29 compounds in the bacterial metabolites, including key compounds associated with Bacillus spp. The main compounds identified included 2-propanone, 4,4-ethylenedioxy-1-pentylamine, 1,2-benzenedicarboxylic acid, 1,1-butoxy-1-isobutoxy-butane, and 3,3-ethoxycarbonyl-5-hydroxytetrahydropyran-2-one.Results: The literature indicates the diverse biological and pharmacological applications of these compounds. Different concentrations of the metabolites from Bacillus species were tested for biological activities, revealing significant inhibitory effects on anti-diabetic activity (84.66%), anti-inflammatory activity (99%), antioxidant activity (99.8%), and anti-hemolytic activity (90%). Disc diffusion method testing also demonstrated a noteworthy inhibitory effect against tested strains.Conclusion:In silico screening revealed that 1,2-benzenedicarboxylic acid exhibited anticancer activity and promising drug-designing properties against epithelial glioblastoma cancer genes. The study highlights the potential of Bacillus spp. as a valuable target for drug research, emphasizing the significance of bacterial metabolites in the production of biological antibacterial agents

The therapeutic potential of skin mucus from Asian swamp eel (Monopterus albus): In vivo evaluation and histological evidence

Objectives The Asian swamp eel (Monopterus albus), is commonly distributed in Asian countries. However, its therapeutic potential has not been thoroughly investigated yet. The current study aimed to evaluate the in-vivo therapeutic properties of the skin mucus of this fish. Methods The eel mucus was collected fleshly and topical gel with carbopol 934 was formulated to study the antibacterial activity on the infected skin of the rats. Sprague Dawley rats were used in the study and divided into 4 groups negative, positive, normal control, and treated groups. Results Intracutaneous injections of pathogenic bacteria (Streptococcus pyogenes, Staphylococcus aureus) and fungi (Microsporum gypseum, Candida albicans) were injected into the rats. The development of tinea capitis, impetigo, and cutaneous candidiasis in the animal model was confirmed based on clinical and histopathological observations. To treat the infected rats, a formulated gel of eel skin mucus was applied on the infected rat’s skins topically. The histological analysis confirms a complete recovery in the skin tissues similar to commercial antifungal and antibacterial agents used in the positive control groups. Conclusion The present novel eel skin mucus is an efficient therapeutic candidate in treating skin infections associated with pathogenic microbes

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting Haloperidol Exposure in Healthy and Disease Populations

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly used in the management of several medical conditions, including psychotic disorders. Due to the large interindividual variability among patients taking haloperidol, it is very likely for them to experience either toxic or subtherapeutic effects. We intend to develop a haloperidol PBPK model for identifying the potential sources of pharmacokinetic (PK) variability after intravenous and oral administration by using the population-based simulator, PK-Sim. The model was initially developed and evaluated to predict the PK of haloperidol and its reduced metabolite in adult healthy population after intravenous and oral administration. After evaluating the developed PBPK model in healthy adults, it was used to predict haloperidol&ndash;rifampicin drug&ndash;drug interaction and was extended to tuberculosis patients. The model evaluation was performed using visual assessments, prediction error, and mean fold error of the ratio of the observed-to-predicted values of the PK parameters. The predicted PK values were in good agreement with the corresponding reported values. The effects of the pathophysiological changes and enzyme induction associated with tuberculosis and its treatment, respectively, on haloperidol PK, have been predicted precisely. For all clinical scenarios that were evaluated, the predicted values were within the acceptable two-fold error range

Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer’s disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes