Extraction, purification, structural characterization and immunomodulatory activity of a polysaccharide from Hirudo nipponica Whitman.

Hirudo nipponica Whitman has been utilized in traditional medicine for centuries for its bioactive components. In this study, a novel polysaccharide, which was called SZ, was isolated from H. nipponica Whitman through enzymatic hydrolysis, alkaline extraction, and chromatographic purification.

Quantification and discovery of quality control chemical markers for Shouhui Tongbian capsules by UPLC-MS/MS.

Guided by the principles of Analytical Quality by Design (AQbD), a highly selective and sensitive LC-MS/MS method was established for the simultaneous quantification of 15 compounds in Shouhui Tongbian capsules, enabling their effective quality control. The separation was carried out on a BEH C18 column (1.7 μm, 2.

The Application of Quantitative H-NMR for the Determination of Melatonin and Vitamin B6 in Commercial Melatonin Products.

Melatonin supplements have been widely used to improve sleep quality and overcome sleep disorders, with melatonin and vitamin B6 serving as the primary active ingredients. This study developed a novel analytical method for the simultaneous quantification of melatonin and vitamin B6 using H-NMR spectroscopy. The characteristic signals of melatonin and vitamin B6 hydrochloride at δ 7.

Population pharmacokinetic modeling of asciminib in support of exposure-response and ethnic sensitivity analyses in patients with chronic myeloid leukemia.

Background: The original population pharmacokinetics (popPK) model for asciminib in patients with chronic myeloid leukemia in chronic phase (CML-CP) was refined to address drug development needs in support of drug submission, namely, attainment of target drug exposure in specific patient populations, populating individual daily exposures for exposure-response analyses of key efficacy and safety endpoints, confirmation of comparability in exposure between 40 mg b.i.d.

The impact of aztreonam-clavulanic acid exposure on gene expression and mutant selection using a multidrug-resistant .

Multidrug-resistant poses a significant threat to the healthcare system by causing treatment failure in infected patients. The use of a beta-lactam in combination with a beta-lactamase inhibitor has been shown to be an effective strategy to solve this problem. antimicrobial susceptibility experiments have demonstrated the antimicrobial activity of aztreonam and clavulanate.

Population modelling of nilotinib exposure vs. longitudinal BCR::ABL1 response in patients with chronic phase chronic myeloid leukaemia using a semimechanistic disease model.

Aims: This study aims to evaluate the exposure-efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (CML-CP) and those who are imatinib-resistant or intolerant using a semimechanistic disease model.

Methods: The analysis included 489 CML-CP patients from 3 nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow-up ranging from 2 to 9 years. The semimechanistic disease model of CML-CP consisted of quiescent leukaemic stem cells, proliferating drug-susceptible and -resistant bone marrow cells.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%.

Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling.

Background: The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated synergy against multi-drug resistant .

Objectives: The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against .

Methods: A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances.

Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation.

Background And Objective: Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.

Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli.

Purpose: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-β-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate.

Methods: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E.

Utility and impact of quantitative pharmacology on dose selection and clinical development of immuno-oncology therapy.

Immuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20-40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process.

Simultaneous Determination of Levo-tetrahydropalmatine and Naltrexone in Rat Plasma by LC-MS/MS and its Application in a Pharmacokinetic Study.

Background: Levo-tetrahydropalmatine and low-dose naltrexone are used in association with reducing cocaine-related cravings, but there are no analytical methods for the quantitative simultaneous analysis of this drug combination.

Objective: A highly selective and sensitive LC-MS/MS assay was developed and validated to simultaneously quantify l-THP and naltrexone. The analytical method for l-THP offers improved sensitivity compared to previously published methods.

Comparative metabolomics reveal key pathways associated with the synergistic activities of aztreonam and clavulanate combination against multidrug-resistant .

Multidrug-resistant is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against .

Introduction: The emergence of multidrug-resistant (MDR) prompts clinicians to consider treating these infections with polymyxin combination.

Methods: Metabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L).

Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to major antibiotics such as penicillin, cephalosporin, fluoroquinolone and aminoglycoside, and has become a significant nosocomial pathogen. The efficacy of rifampicin and colistin combination against CRAB could be dependent on the administration routes and drug concentrations at the site of infection.

Objective: The objective is to predict drug disposition in biological tissues.

Physiologically based pharmacokinetic modelling to inform combination dosing regimens of ceftaroline and daptomycin in special populations.

Aims: The combination of daptomycin and ceftaroline used as salvage therapy is associated with higher survival and decreased clinical failure in complicated methicillin-resistant Staphylococcus aureus (MRSA) infections that are resistant to standard MRSA treatment. This study aimed to evaluate dosing regimens for coadministration of daptomycin and ceftaroline in special populations including paediatrics, renally impaired (RI), obese and geriatrics that generate sufficient coverage against daptomycin-resistant MRSA.

Methods: Physiologically based pharmacokinetic models were developed from pharmacokinetic studies of healthy adults, geriatric, paediatric, obese and RI patients.

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing and .

This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories.

Population Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Healthy Subjects and Patients with Sickle Cell Disease.

Background And Objectives: Crizanlizumab is a humanized monoclonal antibody against P-selectin for the prevention of vaso-occlusive crises in sickle cell disease (SCD). The objective of this study was to investigate crizanlizumab population pharmacokinetics (PK) and pharmacodynamics (PD), as well as influential covariates.

Methods: A population PK model for crizanlizumab was developed from healthy volunteer and SCD patient data, using a two-compartment intravenous infusion model utilizing a target-mediated drug disposition (TMDD) approach.

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant .

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B.

Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant .

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (T) and the fraction of time that the free drug concentration was above the MPC (T) from simulated pharmacokinetic profiles.

Metabolomic profiling of polymyxin-B in combination with meropenem and sulbactam against multi-drug resistant .

Empirical therapies using polymyxins combined with other antibiotics are recommended in the treatment of infections. In the present study, the synergistic activities of polymyxin-B, meropenem, and sulbactam as combination therapy were investigated using metabolomic analysis. The metabolome of was investigated after treatment with polymyxin-B alone (2 mg/l), meropenem (2 mg/l) alone, combination of polymyxin-B/meropenem at their clinical breakpoints, and triple-antibiotic combination of polymyxin-B/meropenem and 4 mg/l sulbactam.

Prediction of Tissue Exposures of Meropenem, Colistin, and Sulbactam in Pediatrics Using Physiologically Based Pharmacokinetic Modeling.

Background: The combination of polymyxins, meropenem, and sulbactam demonstrated efficacy against multi-drug-resistant bacillus Acinetobacter baumannii. These three antibiotics are commonly used against major blood, skin, lung, and heart muscle infections.

Objective: The objective of this study was to predict drug disposition and extrapolate the efficacy in these tissues using a physiologically based pharmacokinetic modeling approach that linked drug exposures to their target pharmacodynamic indices associated with antimicrobial activities against A.