Exosomes are nanovesicles secreted by cells to exchange materials and information. Recent studies have revealed that these modified nanovesicles can be powerful tools for the diagnosis and treatment of diseases. However, few studies have reported on the acquisition and application of these functionalized exosomes. Therefore, this study provides a systematic summary of the entire process of isolation, functionalization, modification, and application of enhanced exosomes and recent progress in this field. First, the process of exosome production and principles of disease treatment are elucidated. Thereafter, the methods of exosome isolation are summarized, with a focus on improved technology centered on aptamer technology and new technology represented by microfluidics. Next, the functional modifications of the exosomes are classified and summarized. Finally, new breakthroughs in the diagnostic and therapeutic capabilities of function-enhancing exosomes compared with those of traditional exosomes are summarized, especially in terms of how these exosomes can be used in bioimaging, photothermal therapy, and other means of achieving a quantum leap in detection and therapeutic efficacy. This paper summarizes the latest research findings on engineered exosomes, with a particular focus on emerging technologies such as microfluidics and aptamers that hold significant potential. It provides a thorough analysis of their respective advantages and limitations, aiming to offer actionable insights for the future advancement and more complex applications of exosomes.

Skin wounds that arise from diabetes and chronic wound conditions present significant challenges in clinical care. Microneedle patches can puncture the skin epidermis and deliver drugs directly to the injured tissue rendering them particularly effective for wound healing, while hydrogel offers a physical barrier, moisture retention, and oxygen permeability at wound sites. Therefore, in this study, a novel microneedle patch drug delivery system that employs methacrylated sericin and methacrylated hyaluronic acid as substrates was developed. Exosomes released from the tip portion are found to improve the proangiogenic, and reactive oxygen species and inflammation inhibitory properties of the microneedle patch. A zeolite imidazole framework-8 encapsulated in the backing portion of the microneedle to form a protective layer over the wound surface inhibits bacteria and prevents infection by foreign pathogens. The designed multifunctional microneedle patch accelerates the healing of diabetic wounds, offering a promising therapeutic approach.

Objective: Serum lactic acidosis has been reported as a serious adverse effect associated with linezolid. This study aims to explore the risk factors of linezolid‐induced lactic acidosis. Methods: Patients admitted to a 3600‐bed university hospital, who received linezolid treatment and had at least one steady‐state concentration of linezolid, were retrospectively reviewed to analyze the incidence of linezolid‐induced lactic acidosis. Meanwhile, univariate and multivariate logistic regression analyses were conducted to determine the risk factors of lactic acidosis. Results: A total of 95 adult patients were included in the study. 18.95% (18 out of 95) of patients developed lactic acidosis during linezolid treatment. Importantly, patients who concurrently used linezolid and metformin had a high risk of developing lactic acidosis (90.9%, 10 out of 11). After excluding these patients from the original database, 9.52% (8 out of the 84) of the patients developed lactic acidosis. In the population not receiving concurrent metformin treatment, univariate analysis showed that patients who developed lactic acidosis had higher linezolid C min and serum creatinine levels or lower creatinine clearance, and multivariate analysis showed that C min (OR: 1.114; 95% CI: 1.012–1.226; p = 0.027) was an independent risk factor for lactic acidosis. Conclusion: The concurrent use of linezolid and metformin raises the risk of lactic acidosis. Therapeutic drug monitoring of linezolid based on C min is recommended for decreasing the risk of lactic acidosis during linezolid treatment.

This study aimed to examine the potential drug-drug interaction (DDI) between vandetanib and luteolin in vivo and in vitro, with the objective of establishing a scientific foundation for their appropriate utilization in clinical settings. Sprague-Dawley (SD) rats were randomly divided into two groups: a control group (vandetanib administered by gavage alone) and an experimental group (vandetanib and luteolin administered together). A series of blood samples were collected at different time intervals. The plasma concentrations of vandetanib and its metabolite N-demethyl vandetanib in rats were determined using an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Incubation systems were set up with rat liver microsomes (RLM) and human liver microsomes (HLM) to measure the Michaelis-Menten constant (Km) and half-maximum inhibitory concentration (IC50) values. Additionally, the inhibitory mechanism of luteolin on vandetanib was also investigated. Ultimately, the molecular mechanism of inhibition was examined through the utilization of molecular docking techniques. In vivo animal experiment results showed that compared with the control group, the AUC(0-t) and Cmax of vandetanib in the experimental group were significantly increased. The findings from the in vitro experiments revealed that luteolin exhibited a moderate inhibitory effect on the metabolism of vandetanib. The IC50 values for RLM and HLM were determined to be 8.56 μM and 15.84 μM, respectively. The identified inhibition mechanism was classified as mixed. This study utilized molecular docking analysis to provide additional evidence supporting the competitive inhibition of luteolin on vandetanib in CYP3A4. The data presented in our study indicated a potential interaction between vandetanib and luteolin, which may necessitate the need for dose adjustment during their co-administration in clinical settings.

Background: Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma. Purpose: This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro. Methods: Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 mu m, 2.1 x 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows: m/z 422.01-*186.11 for givinostat, and m/z 405.40-*84.10 for IS, respectively. Results: In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (r2=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 mu L/min/mg protein with a half-life (t1/2) value of 92.87 min. Conclusion: Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.

Purpose:Zanubrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, has been demonstrated to treat multiple B-cell malignancies, which include Waldenström's macroglobulinemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma and mantle cell lymphoma (MCL). There have been very few studies of drug-drug interactions (DDI) between zanubrutinib and other medications. Methods:The current study validated a sensitive and reliable quantitative detection of zanubrutinib and posaconazole in rat plasma using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The plasma samples were prepared by protein precipitation with the addition of acetonitrile, using orelabrutinib and fluconazole as internal standards (IS). Fifteen male Sprague-Dawley (SD) rats were randomly and equally divided into three groups: posaconazole (40 mg/kg) administered orally alone, zanubrutinib (16 mg/kg) received orally alone, co-administered orally zanubrutinib (16 mg/kg) and posaconazole (40 mg/kg). Results:The methodology was validated, and the precision, stability, accuracy, matrix effect and extraction recovery were within the permissible values. This method was successfully applied to evaluate the potential DDI between zanubrutinib and posaconazole, and the results showed a significant 0.98-fold increase in both AUC0-t and AUC0-∞ of zanubrutinib when zanubrutinib was administered concomitantly with posaconazole. In addition, posaconazole significantly increased AUC0-t, AUC0-∞, Tmax, and Cmax of zanubrutinib by 2.31-, 4.78-, 2.93-, and 0.86-fold, respectively, while CLz/F significantly decreased by 83.5%. Conclusion:These data suggested that when zanubrutinib was co-administered with posaconazole, there are increased exposures to both zanubrutinib and posaconazole. The current results contributed to a better understanding of the metabolism and DDI of zanubrutinib and posaconazole, and it is necessary to further investigate and validate the results in humans.

ABSTRACT:Omadacycline is a novel aminomethylcycline antibiotic that retains its antibacterial activity against strain-specific efflux pumps and ribosomal protective protein mechanisms of tetracycline resistance. To determine the concentration of omadacycline in human plasma, an ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to provide a basis for therapeutic monitoring of omadacycline in clinical settings. The experimental approach involves using an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm), with a mobile phase of 0.1% aqueous formic acid:acetonitrile (90:10, vol/vol), a flow rate of 0.3 mL·min -1 , a column temperature of 40°C, and an injection volume of 0.1 μL. Protein precipitation was employed as pretreatment, using acetonitrile as the precipitant. Minocycline was used as an internal standard. Omadacycline and internal standard were monitored in positive ion mode with the following mass transition pairs: mass/charge (m/z) = 557.1→ 470.1 for omadacycline, and m/z = 458.3→ 440.9 for IS, respectively. The established method showed a good linearity in the range of 0.01-10 mcg/mL of omadacycline (Y = 0.4603X + 0.0452, r 2 = 0.999), with the lower limit of quantification of 0.01 mcg/mL. Method validation included accuracy, precision, matrix effect, recovery, carryover, dilution integrity, and stability, all of which met the requirements of the US Food and Drug Administration for the validation of bioanalytical methods. This method has been successfully applied to therapeutic drug monitoring in patients.

INTRODUCTION:This study aimed to reevaluate the clinical efficacy and safety of omadacycline in treating acute bacterial infections. METHODS:We searched PubMed, Embase, Cochrane Library, Web of Science, and Clinical Trials up to 1 January 2024, including only randomized controlled trials comparing OMC with other antibiotics in adults. Primary outcomes were clinical and microbiological responses; secondary outcomes included adverse events. RESULTS:Seven RCTs with 2957 patients met the inclusion criteria. OMC showed a slightly better clinical response at the post-therapy evaluation phase in the clinically evaluable population (RR = 1.03, 95% CI = 1.01-1.05, I2 = 0%). Microbial eradication rates for Gram-positive and Gram-negative infections showed no significant differences between OMC and comparators. Safety analysis revealed no significant differences in overall AEs, treatment-related AEs, serious AEs, or drug discontinuation due to AEs. However, OMC had a lower risk of diarrhea (RR: 0.48, 95% CI = 0.23-1.00, I2 = 65%). All-cause mortality did not differ significantly between OMC and comparators. CONCLUSIONS:OMC is a safe and effective treatment for acute bacterial infections, comparable to other antibiotics. REGISTRATION:This study has been registered in the online systematic review database (Prospective Register of Systematic Reviews [PROSPERO]), and the registration number is CRD42024575416.

This study aims to investigate the impact of therapeutic drug monitoring (TDM) on the microbiological eradication rate in patients with Staphylococcus aureus bacteremia. Demographic information and laboratory data were collected for patients who were diagnosed with Staphylococcus aureus bacteremia during their hospital stays from January 2021 to May 2024. A total of 105 patients were included in the TDM group and 208 patients in the non-TDM group. The Chi-squared test showed a significantly higher microbiological eradication rate in the TDM group compared to the non-TDM group before (p<0.001) and after (p=0.003) propensity score matching. Subgroup analysis showed that the eradication rate was significantly higher in the TDM group for patients with either methicillin-sensitive Staphylococcus aureus bacteremia (p<0.001) or methicillin-resistant Staphylococcus aureus bacteremia (p=0.007). Moreover, for patients with multi-site infections, the microbiological eradication rate was significantly higher in the TDM group for either methicillin-sensitive Staphylococcus aureus bacteremia (p<0.001) or methicillin-resistant Staphylococcus aureus bacteremia (p<0.001). Although the drugs undergoing TDM in this study-vancomycin, daptomycin, linezolid, and teicoplanin-are primarily used for treating methicillin-resistant Staphylococcus aureus bacteremia, TDM for these agents can also significantly improve the microbiological eradication rate in methicillin-sensitive Staphylococcus aureus bacteremia. Furthermore, multivariate logistic regression analysis confirmed that TDM is an independent protective factor for microbiological eradication rate (p<0.001). In conclusion, this study demonstrates that performing TDM in patients with Staphylococcus aureus bacteremia can indeed enhance the microbiological eradication rate, thereby improving patient outcomes.

Several mechanisms underlying nephrolithiasis, one of the most common urological diseases, involve calcium oxalate formation, including oxidative stress, inflammatory reactions, fibrosis, pyroptosis, and apoptosis. Although lycopene has strong antioxidant activity, its protective effects against CaOx-induced injury have not yet been reported. This study aimed to systematically investigate the protective effects of lycopene and explore its mechanisms and molecular targets. Crystal deposition, renal function, oxidative stress, inflammatory response, fibrosis, pyroptosis, and apoptosis were assessed to evaluate the renoprotective effects of lycopene against crystal formation in a CaOx rat model and oxalate-stimulated NRK-52E and HK-2 cells. Lycopene markedly ameliorated crystal deposition, restored renal function, and suppressed kidney injury by reducing oxidative stress, apoptosis, inflammation, fibrosis, and pyroptosis in the rats. In cell models, lycopene pretreatment reversed reactive oxygen species increase, apoptotic damage, intracellular lactate dehydrogenase release, cytotoxicity, pyroptosis, and extracellular matrix deposition. Network pharmacology and proteomic analyses were performed to identify lycopene target proteins under CaOx-exposed conditions, and the results showed that Trappc4 might be a pivotal target gene for lycopene, as identified by cellular thermal shift assay and surface plasmon resonance analyses. Based on molecular docking, molecular dynamics simulations, alanine scanning mutagenesis, and saturation mutagenesis, we observed that lycopene directly interacts with Trappc4 via hydrophobic bonds, which may be attributed to the PHE4 and PHE142 residues, preventing ERK1/2 or elevating AMPK signaling pathway phosphorylation events. In conclusion, lycopene might ameliorate oxalate-induced renal tubular epithelial cell injury via the Trappc4/ERK1/2/AMPK pathway, indicating its potential for the treatment of nephrolithiasis.

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Given that ponatinib can induce significant cardiotoxicity when taken, and that most Chinese medicines have cardioprotective effects, it is possible to administer them in combination in clinic to alleviate adverse effects. The quantitative determination of ponatinib and its metabolite N-desmethyl ponatinib was optimized and fully verified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). And the drug-drug interactions (DDI) of ponatinib with lycopene and shikonin, both in vivo and in vitro, were studied. The results of bioanalytical methodology showed that ponatinib and N-desmethyl ponatinib had good linearity in plasma samples, and their selectivity, accuracy, precision, stability, matrix effect and recovery were all satisfied with the need of quantitative analysis of samples. In animal experiments, compared with the control group, lycopene and shikonin significantly changed the pharmacokinetic parameters of ponatinib, including AUC(0-t), AUC(0-∞) and CLz/F, while having no effect on the pharmacokinetic parameters of N-desmethyl ponatinib. In vitro interaction studies indicated that lycopene showed mixed inhibition mechanism on ponatinib metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). And, shikonin displayed mixed inhibition mechanism in RLM and competitive inhibition mechanism in HLM, respectively. In summary, the UPLC-MS/MS method can accurately and sensitively quantify ponatinib and N-desmethyl ponatinib, and provide further reference for clinical drug combination between ponatinib and lycopene or shikonin.

Lacosamide, a third-generation novel antiepileptic drug, was first approved in 2008 as an adjunct to partial seizures. In 2014, the U.S. Food and Drug Administration (FDA) approved it as a single agent for partial seizures. Since epilepsy is a chronic condition, most patients need long-term antiepileptic medicinal products, so it is even more important to consider the drug-drug interactions (DDIs). For the purpose of this experiment, an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of lacosamide and O-Desmethyl-lacosamide (ODL), and DDIs between lacosamide and nisoldipine in vivo and in vitro was researched. The protein was precipitated with acetonitrile, the analytes were eluted with acetonitrile and a 0.1% formic acid solution in a gradient program, and lacosamide, ODL, and lamotrigine (Internal Standard, IS) were successfully separated by chromatography. The findings of the biological analysis revealed that the lower limit of quantification (LLOQ) for lacosamide in samples was 2 ng/mL and the linearity ranged from 2 to 10000 ng/mL. The LLOQ for ODL was 1 ng/mL, while the linearity range for this substance was 1–1,000 ng/mL. In rat liver microsomes (RLM), the LLOQ of ODL was 80 ng/mL and the linear range was 80–40000 ng/mL. The selectivity, stability, matrix effect and recovery rate were all satisfied with the need of quantitative analysis of samples. Then, the UPLC-MS/MS assay was employed successfully on the interactions of lacosamide and nisoldipine in vivo and in vitro. The half-maximal inhibitory concentration (IC50) was 3.412 μM in RLM, where nisoldipine inhibited the metabolism of lacosamide with a mixture of inhibition mechanism. In rat pharmacokinetic experiments, it was found that nisoldipine could significantly change the pharmacokinetic characteristics of lacosamide, including AUC(0-t), AUC(0-∞), Tmax, CLz/F and Cmax, but had no significant effect on ODL. In summary, the UPLC-MS/MS method could accurately and sensitively quantify lacosamide and ODL, and could be used for the interaction between nisoldipine and lacosamide in vivo and in vitro.

CONTEXT:Derazantinib-an orally bioavailable, ATP competitive, multikinase inhibitor-has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA). OBJECTIVE:This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo. MATERIALS AND METHODS:A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not). RESULTS:The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone. CONCLUSION:Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

Serum albumin, commonly recognized as a predominant major plasma protein, is ubiquitously distributed among vertebrates, demonstrating versatility and widespread accessibility. Numerous studies have discussed the composition and attributes of human and bovine serum albumin; nonetheless, few systematic and comprehensive summaries on human and bovine serum albumin exist. This paper reviews the applications of human and bovine serum albumin in biomedical engineering. First, we introduce the differences in the structure of human and bovine serum albumin. Next, we describe the extraction methods for human and bovine serum albumin (fractionation process separation, magnetic adsorption, reverse micellar (RM) extraction, and genetic engineering) and the advantages and disadvantages of recently developed extraction methods. The characteristics of different processing forms of human and bovine serum albumin are also discussed, concomitantly elucidating their intrinsic properties, functions, and applications in biomedicine. Notably, their pivotal functions as carriers for drugs and tissue-engineered scaffolds, as well as their contributions to cell reproduction and bioimaging, are critically examined. Finally, to provide guidance for researchers in their future work, this review summarizes the current state of human and bovine serum albumin research and outlines potential future research topics.

In this study, the effects of 17 CYP3A4 variants and drug-drug interactions (DDI) with its mechanism on alectinib metabolism were investigated. In vitro incubation systems of rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 variants were established. The formers were used to screen potential drugs that inhibited alectinib metabolism and study the underlying mechanism, and the latter was used to determine the dynamic characteristics of CYP3A4 variants. Alectinib and its main metabolite M4 were quantitatively determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results showed that compared with CYP3A4.1, only CYP3A4.29 showed higher catalytic activity, while the catalytic activity of CYP3A4.4, .7, .8, .12, .14, .16, .17, .18, .19, .20, .23, and .24 decreased significantly. Among them, the catalytic activity of CYP3A4.20 is the lowest, only 2.63% of that of CYP3A4.1. Based on the RLM incubation system in vitro, 81 drugs that may be combined with alectinib were screened, among which 18 drugs had an inhibition rate higher than 80%. In addition, nicardipine had an inhibition rate of 95.09% with a half-maximum inhibitory concentration (IC50) value of 3.54 ± 0.96 μM in RLM and 1.52 ± 0.038 μM in HLM, respectively. There was a mixture of non-competitive and anti-competitive inhibition of alectinib metabolism in both RLM and HLM. In vivo experiments of Sprague–Dawley (SD) rats, compared with the control group (30 mg/kg alectinib alone), the AUC(0–t), AUC(0–∞), Tmax and Cmax of alectinib administered in combination with 6 mg/kg nicardipine were significantly increased in the experimental group. In conclusion, the metabolism of alectinib was affected by polymorphisms of the CYP3A4 gene and nicardipine. This study provides reference data for clinical individualized administration of alectinib in the future.

AimsThis study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it.MethodsNonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function.ResultsA total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week.ConclusionsBoth loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week. image

Recently, the frequent emergence of multidrug-resistant gram-negative bacterial infections has forced colistin to be used as one of the last-line options for the treatment of these infections. This study aimed to establish and validate a simple, rapid, and reliable method for the quantitative determination of colistin in plasma and kidney homogenates by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of colistin sulfate in rats and the relationship between renal accumulation and time of administration in rats were estimated by measuring plasma and renal colistin concentrations. The colistin in the sample was precipitated by acetonitrile, followed by extraction with nitrogen blow-drying and reconstitution. The chromatographic separation of analytes was conducted on an C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Polymyxin B was used as an internal standard (IS). Colistin and IS were monitored in positive ion mode with the following mass transition pairs: m/z 585.6 -> m/z 101.4 for colistin A,m/z 578.6 -> m/z 101.4 for colistin B and m/z 595.6 -> m/z 227.2 for IS, respectively. The established method expressed good linearity in 50 - 20000 ng center dot mL-1 of colistin, with the lower limit of quantification (LLOQ) of 50 ng center dot mL-1. Methodology validations, including accuracy, precision, matrix effect, recovery, stability, and dilution integrity met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Noncompartmental pharmacokinetic parameters were obtained by the statistical moment theory. The estimates for the terminal half-life (t1/2), the peak time (Tmax), the peak concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), the volume of distribution (V), the total body clearance (CL) and the mean residence time (MRT0-t) were calculated to be 2.53 +/- 1.6 h, 2.17 +/- 1.57 h, 2913.01 +/- 644.89 ng center dot mL-1, 15153.46 +/- 3599.81 h center dot ng center dot mL-1, 0.98 +/- 0.56 L center dot kg- 1, 0.28 +/- 0.09 L center dot h- 1 center dot kg- 1 and 4.07 +/- 1.13 h, respectively. And the concentrations of colistin in rat kidney tissue after continuous administration for 1, 3, 5, 7 days were 1.49 +/- 0.35 mu g center dot g- 1, 2.88 +/- 0.74 mu g center dot g- 1, 3.40 +/- 0.25 mu g center dot g- 1 and 4.33 +/- 0.63 mu g center dot g- 1, respectively. The established method provided a convenient, rapid, stable, sensitive, accurate way for the determination of colistin concentration, which has been successfully used for the pharmacokinetic analysis of colistin sulfate in rat and to explore the relationship between the renal accumulation of colistin and the duration of dosing.

Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported. Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function. Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28–6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1–1.5 million IU/day, given in 2–3 doses, could attain PTA > 90% for MICs ≤ 0.5 μg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 μg/ml in renal healthy patients. Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 μg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 μg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.

Limited data are available for ceftazidime–avibactam (CZA) dosing in patients receiving renal replacement therapy, especially the data on the dosing in patients receiving intermittent hemodialysis (IHD). In this report, we firstly described a case in which CZA was administered as 2.5 g after each time of IHD, and a dose of 1.25 g was added on the 48th-hour for the 72-h interdialytic interval. Plasma concentrations of CZA measured at different time indicated that > 50

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency.Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model.Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25–21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan–Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30–60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min.Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.