The Impact of Baohuoside I on the Metabolism of Tofacitinib in Rats.

Purpose: To study the potential drug-drug interactions between tofacitinib and baohuoside I and to provide the scientific basis for rational use of them in clinical practice. Methods: A total of eighteen Sprague-Dawley rats were randomly divided into three groups: control group, single-dose group (receiving a single dose of 20 mg/kg of baohuoside I), and multi-dose group (receiving multiple doses of baohuoside I for 7 days). On the seventh day, each rat was orally administered with 10 mg/kg of tofacitinib 30 minutes after giving baohuoside I or vehicle. Blood samples were collected and determined using UPLC-MS/MS. In vitro effects of baohuoside I on tofacitinib was investigated in rat liver microsomes (RLMs), as well as the underlying mechanism of inhibition. The semi-inhibitory concentration value (IC50) of baohuoside I was subsequently determined and its inhibitory mechanism against tofacitinib was analyzed. Furthermore, the interactions between baohuoside I, tofacitinib and CYP3A4 were explored using Pymol molecular docking simulation. Results: The administration of baohuoside I orally has been observed to enhance the area under the concentration-time curve (AUC) of tofacitinib and decrease the clearance (CL). The observed disparity between the single-dose and multi-dose groups was statistically significant. Furthermore, our findings suggest that the impact of baohuoside I on tofacitinib metabolism may be a mixture of non-competitive and competitive inhibition. Baohuoside I exhibit an interaction with arginine (ARG) at position 106 of the CYP3A4 enzyme through hydrogen bonding, positioning itself closer to the site of action compared to tofacitinib. Conclusion: Our study has demonstrated the presence of drug-drug interactions between baohuoside I and tofacitinib, which may arise upon pre-administration of tofacitinib. Altogether, our data indicated that an interaction existed between tofacitinib and baohuoside I and additional cares might be taken when they were co-administrated in clinic.

Application of machine learning combined with population pharmacokinetics to improve individual prediction of vancomycin clearance in simulated adult patients.

Background and aim: Vancomycin, a glycopeptide antimicrobial drug. PPK has problems such as difficulty in accurately reflecting inter-individual differences, and the PPK model may not be accurate enough to predict individual pharmacokinetic parameters. Therefore, the aim of this study is to investigate whether the application of machine learning combined with the PPK method can improve the prediction of vancomycin CL in adult Chinese patients. Methods: In the first step, a vancomycin CL prediction model for Chinese adult patients is given by PPK and Hamilton Monte Carlo sampling is used to obtain the reference CL of 1,000 patients; the second step is to obtain the final prediction model by machine learning using an appropriate model for the predictive factor and the reference CL; and the third step is to randomly select, in the simulated data, a total of 250 patients for prediction effect evaluation. Results: XGBoost model is selected as final machine learning model. More than four-fifths of the subjects' predictive values regarding vancomycin CL are improved by machine learning combined with PPK. Machine learning combined with PPK models is more stable in performance than the PPK method alone for predicting models. Conclusion: The first combination of PPK and machine learning for predictive modeling of vancomycin clearance in adult patients. It provides a reference for clinical pharmacists or clinicians to optimize the initial dosage given to ensure the effectiveness and safety of drug therapy for each patient.

AS1411 aptamer/RGD dual functionalized theranostic chitosan-PLGA nanoparticles for brain cancer treatment and imaging.

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies.

Development of a generalized pharmacokinetic model to characterize clinical pharmacokinetics of monomethyl auristatin E-based antibody-drug conjugates.

AIMS: This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic. METHODS: A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max $$ {\mathrm{C}}_{\mathrm{max}} $$ and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs. RESULTS: A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs. CONCLUSIONS: This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs.

Therapeutic effects of tetrandrine in inflammatory diseases: a comprehensive review.

Inflammation can be triggered by any factor. The primary pathological manifestations can be summarized as the deterioration, exudation, and proliferation of local tissues, which can cause systemic damage in severe cases. Inflammatory lesions are primarily localized but may interact with body systems to cause provocative storms, parenchymal organ lesions, vascular and central nervous system necrosis, and other pathologic responses. Tetrandrine (TET) is a bisbenzylquinoline alkaloid extracted from the traditional Chinese herbal medicine Stephania tetrandra, which has been shown to have significant efficacy in inflammatory conditions such as rheumatoid arthritis, hepatitis, nephritis, etc., through NF-κB, MAPK, ERK, and STAT3 signaling pathways. TET can regulate the body's imbalanced metabolic pathways, reverse the inflammatory process, reduce other pathological damage caused by inflammation, and prevent the vicious cycle. More importantly, TET does not disrupt body's normal immune function while clearing the body's inflammatory state. Therefore, it is necessary to pay attention to its dosage and duration during treatment to avoid unexpected side effects caused by a long half-life. In summary, TET has a promising future in treating inflammatory diseases. The author reviews current therapeutic studies of TET in inflammatory conditions to provide some ideas for subsequent anti-inflammatory studies of TET.

Analysis of Vancomycin Dosage and Plasma Levels in Critically Ill Adult Patients Requiring Extracorporeal Membrane Oxygenation (ECMO).

Introduction: Critically ill patients undergoing extracorporeal membrane oxygenation (ECMO) exhibit unique pharmacokinetics. This study aimed to assess the achievement of vancomycin therapeutic targets in these patients. Methods: This retrospective cohort study included patients on ECMO treated with vancomycin between January 2010 and December 2018. Ninety patients were analyzed based on ECMO connection modality, baseline creatinine levels, estimated glomerular filtration rate (eGFR), renal replacement therapy (RRT) requirements, and vancomycin loading dose administration. Results: Twenty-three percent of the patients achieved the therapeutic range defined by baseline levels. No significant differences in meeting the therapeutic goal were found in multivariate analysis considering ECMO cannulation modality, initial creatinine level, initial eGFR, RRT requirement, or loading dose use. All trough levels between 15 and 20 mcg/mL achieved an estimated area under the curve/minimum inhibitory concentration (AUC/MIC) between 400 and 600, almost all trough levels over 10 mcg/mL predicted an AUC/MIC >400. Discussion: Achieving therapeutic plasma levels in these patients remains challenging, potentially due to factors such as individual pharmacokinetics and pathophysiology. A trough plasma level between 12 and 20 estimated the therapeutic AUC/MIC for all models, proposing a possible lower target, maintaining exposure, and potentially avoiding adverse effects. Despite being one of the largest cohorts of vancomycin use in ECMO patients studied, its retrospective nature and single-center focus limits its broad applicability.

In-vitro antioxidant and anti-inflammatory potential along with p.o. pharmacokinetic profile of key bioactive phytocompounds of Snow Mountain Garlic: a comparative analysis vis-à-vis normal garlic.

Snow mountain garlic (SMG) is a trans-Himalayan medicinal plant used in the traditional medicine system for several ailments, including inflammatory arthritis. Research studies are insufficient to validate its folk medicinal applications. In the present study, the comparative abundance of its key bioactive phytocompounds, viz., S-allyl-L-cysteine (SAC), alliin, and S-methyl-L-cysteine (SMC) against normal garlic were assessed using the LC-MS/MS-MRM method. In addition, the study also explored the antioxidant and anti-inflammatory potency of crude extract of SMG and purified signature phytocompounds (i.e., SMC, SAC, and alliin) in comparison with normal garlic and dexamethasone in LPS-stimulated RAW264.7 macrophage cells. The LC-MS/MS-MRM study revealed significant differences among SMG and normal garlic, viz., alliin 22.8-fold higher in SMG, and SMC could be detected only in SMG. In the bioassays, SMG extract and purified signature phytocompounds significantly downregulated oxidative damage in activated macrophages, boosting endogenous antioxidants' activity. SMG extract-treated macrophages significantly suppressed NF-κB expression and related inflammatory indicators such as cytokines, COX-2, iNOS, and NO. Notably, the observed anti-inflammatory and antioxidant bioactivities of SMG extract were comparable to signature phytocompounds and dexamethasone. In addition, SAC being uniformly found in SMG and normal garlic, its comparative pharmacokinetics was studied to validate the pharmacodynamic superiority of SMG over normal garlic. Significantly higher plasma concentrations (Cmax), half-life (t1/2), and area under curve (AUC) of SAC following SMG extract administration than normal garlic validated the proposed hypothesis. Thus, the abundance of bioactive phytocompounds and their better pharmacokinetics in SMG extract might be underlying its medicinal merits over normal garlic.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimen to prevent antagonistic effects. Thus, this work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Superior bioavailability of the calcium salt form of ß-hydroxy-ß-methylbutyrate compared with the free acid form.

We investigated the bioavailability of the calcium salt (HMB-Ca) and the free acid (HMB-FA) forms of ß-hydroxy-ß-methylbutyrate (HMB). Sixteen young individuals received the following treatments on three different occasions in a counterbalanced crossover fashion: (1) HMB-FA in clear capsules; (2) HMB-Ca in gelatine capsules; (3) HMB-Ca dissolved in water. All treatments provided 1 g of HMB. Blood samples were taken before and on multiple time points following ingestion. The following parameters were calculated: peak plasma (Cmax), time to peak (Tmax), slope of HMB appearance in blood, area under the curve (AUC), half-life time (t1/2) and relative bioavailability (HMB-Ca in water set as reference). All treatments led to rapid and large increases in plasma HMB. HMB-Ca in capsules and in water showed similar plasma HMB values across time (p = 0.438). HMB-FA resulted in lower concentrations vs. the other treatments (both p < 0.001). AUC (HMB-Ca in capsules: 50,078 ± 10,507; HMB-Ca in water: 47,871 ± 10,783; HMB-FA: 29,130 ± 12,946 µmol L-1 × 720 min), Cmax (HMB-Ca in capsules: 229.2 ± 65.9; HMB-Ca in water: 249.7 ± 49.7; HMB-FA: 139.1 ± 67.2 µmol L-1) and relative bioavailability (HMB-Ca in capsules: 104.8 ± 14.9%; HMB-FA: 61.5 ± 17.0%) were lower in HMB-FA vs. HMB-Ca (all p < 0.001). HMB-Ca in water resulted in the fastest Tmax (43 ± 22 min) compared to HMB-Ca in capsules (79 ± 40 min) and HMB-FA (78 ± 21 min) (all p < 0.05), while t1/2 was similar between treatments. To conclude, HMB-Ca exhibited superior bioavailability compared to HMB-FA, with HMB-Ca in water showing faster absorption. Elimination kinetics were similar across all forms, suggesting that the pharmaceutical form of HMB affects the absorption rates, but not its distribution or elimination.

Novel protocol for multiple-dose oral administration of the L-type Ca2+ channel blocker isradipine in mice: A dose-finding pharmacokinetic study.

Studies in genetically modified animals and human genetics have recently provided new insight into the role of voltage-gated L-type Ca2+ channels in human disease. Therefore, the inhibition of L-type Ca2+ channels in vivo in wildtype and mutant mice by potent dihydropyridine (DHP) Ca2+ channel blockers serves as an important pharmacological tool. These drugs have a short plasma half-life in humans and especially in rodents and show high first-pass metabolism upon oral application. In the vast majority of in vivo studies, they have therefore been delivered through parenteral routes, mostly subcutaneously or intraperitoneally. High peak plasma concentrations of DHPs cause side effects, evident as DHP-induced aversive behaviors confounding the interpretation of behavioral readouts. Nevertheless, pharmacokinetic data measuring the exposure achieved with these applications are sparse. Moreover, parenteral injections require animal handling and can be associated with pain, discomfort and stress which could influence a variety of physiological processes, behavioral and other functional readouts. Here, we describe a noninvasive oral application of the DHP isradipine by training mice to quickly consume small volumes of flavored yogurt that can serve as drug vehicle. This procedure does not require animal handling, allows repeated drug application over several days and reproducibly achieves peak plasma concentrations over a wide range previously shown to be well-tolerated in humans. This protocol should facilitate ongoing nonclinical studies in mice exploring new indications for DHP Ca2+ channel blockers.

The pharmacokinetics and pharmacodynamics of fentanyl administered via transdermal patch in horses.

Introduction: Understanding the pharmacokinetics and pharmacodynamics of fentanyl in horses is crucial for optimizing pain management strategies in veterinary medicine. Methods: Six adult horses were enrolled in a randomized crossover design. Treatments included: placebo, two 100 mcg/h patches (LDF), four 100 mcg/h patches (MDF), and six 100 mcg/h patches (HDF). Patches were in place for 72 h. Blood was obtained for fentanyl plasma concentration determination, thermal threshold, mechanical threshold, heart rate, respiratory rate, and rectal temperature were obtained prior patch placement and at multiple time points following patch placement for the following 96 h. Fentanyl plasma concentration was determined using LC-MS/MS. Data were analyzed using a generalized mixed effects model. Results: Mean (range) maximum plasma concentration (Cmax), time to Cmax, and area under the curve extrapolated to infinity were 1.39 (0.82-1.82), 2.64 (1.21-4.42), 4.11 (2.78-7.12) ng/ml, 12.7 (8.0-16.0), 12.7 (8.0-16.0), 12 (8.0-16.0) h, 42.37 (27.59-55.56), 77.24 (45.62-115.06), 120.34 (100.66-150.55) h ng/ml for LDF, MDF, and HDF, respectively. There was no significant effect of treatment or time on thermal threshold, mechanical threshold, respiratory rate, or temperature (p > 0.063). There was no significant effect of treatment on heart rate (p = 0.364). There was a significant effect of time (p = 0.003) on heart rate with overall heart rates being less than baseline at 64 h. Conclusions: Fentanyl administered via transdermal patch is well absorbed and well tolerated but does not result in an anti-nociceptive effect as measured by thermal and mechanical threshold at the doses studied.

Nanoparticle-based optical interfaces for retinal neuromodulation: a review.

Degeneration of photoreceptors in the retina is a leading cause of blindness, but commonly leaves the retinal ganglion cells (RGCs) and/or bipolar cells extant. Consequently, these cells are an attractive target for the invasive electrical implants colloquially known as "bionic eyes." However, after more than two decades of concerted effort, interfaces based on conventional electrical stimulation approaches have delivered limited efficacy, primarily due to the current spread in retinal tissue, which precludes high-acuity vision. The ideal prosthetic solution would be less invasive, provide single-cell resolution and an ability to differentiate between different cell types. Nanoparticle-mediated approaches can address some of these requirements, with particular attention being directed at light-sensitive nanoparticles that can be accessed via the intrinsic optics of the eye. Here we survey the available known nanoparticle-based optical transduction mechanisms that can be exploited for neuromodulation. We review the rapid progress in the field, together with outstanding challenges that must be addressed to translate these techniques to clinical practice. In particular, successful translation will likely require efficient delivery of nanoparticles to stable and precisely defined locations in the retinal tissues. Therefore, we also emphasize the current literature relating to the pharmacokinetics of nanoparticles in the eye. While considerable challenges remain to be overcome, progress to date shows great potential for nanoparticle-based interfaces to revolutionize the field of visual prostheses.

Impact of Dietary Fat and Oral Delivery System on Cannabigerol Pharmacokinetics in Adults.

Background and Aims: Cannabigerol (CBG) is a nonintoxicating cannabinoid synthesized in the Cannabis sativa plant that is incorporated into dietary supplements. This study investigated the influence of dietary fat and an emulsified delivery vehicle on CBG pharmacokinetics (PKs) after oral ingestion by adults. Materials and Methods: Consented participants were enrolled in a double-crossover pilot study and were blinded to the delivery vehicle type (isolate or emulsification) and isocaloric meal condition (low-fat=<5 g fat/meal or high-fat [HF]=>30 g fat/meal). The concentration of CBG in human plasma was measured after a single 25 mg dose of CBG using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using noncompartmental analysis. Results: The PKs of the two delivery systems (emulsified vs. non-emulsified) were significantly impacted by the HF meal condition. Participants in the HF meal group exhibited significantly higher area under the plasma concentration time curve from time 0 to last quantifiable value, maximum concentration, and terminal half-life. Participants in the HF meal group also had a significantly lower terminal elimination rate constant and time to maximum concentration (Tmax), in addition to decreased Tmax variation. The threshold for bioequivalence between conditions was not met. An exploratory aim correlated anthropometric measures and previous day's dietary intake on PK parameters which yielded inconsistent results across dietary fat conditions. Conclusions: In aggregate, dietary fat had a greater effect on CBG PKs than the emulsified delivery vehicle. This supports accounting for dietary intake in development of therapeutics and administration guidelines for orally delivered CBG.

Role for Carboxylic Acid Moiety in NSAIDs: Favoring the Binding at Site II of Bovine Serum Albumin.

The molecular structures of nonsteroidal anti-inflammatory drugs (NSAIDs) vary, but most contain a carboxylic acid functional group (RCOOH). This functional group is known to be related to the mechanism of cyclooxygenase inhibition and also causes side effects, such as gastrointestinal bleeding. This study proposes a new role for RCOOH in NSAIDs: facilitating the interaction at the binding site II of serum albumins. We used bovine serum albumin (BSA) as a model to investigate the interactions with ligands at site II. Using dansyl-proline (DP) as a fluorescent site II marker, we demonstrated that only negatively charged NSAIDs such as ibuprofen (IBP), naproxen (NPX), diflunisal (DFS), and ketoprofen (KTP) can efficiently displace DP from the albumin binding site. We confirmed the importance of RCOO by neutralizing IBP and NPX through esterification, which reduced the displacement of DP. The competition was also monitored by stopped-flow experiments. While IBP and NPX displaced DP in less than 1 s, the ester derivatives were ineffective. We also observed a higher affinity of negatively charged NSAIDs using DFS as a probe and ultrafiltration experiments. Molecular docking simulations showed an essential salt bridge between the positively charged residues Arg409 and Lys413 with RCOO-, consistent with the experimental findings. We performed a ligand dissociation pathway and corresponding energy analysis by applying molecular dynamics. The dissociation of NPX showed a higher free energy barrier than its ester. Apart from BSA, we conducted some experimental studies with human serum albumin, and similar results were obtained, suggesting a general effect for other mammalian serum albumins. Our findings support that the RCOOH moiety affects not only the mechanism of action and side effects but also the pharmacokinetics of NSAIDs.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Population pharmacokinetics of gentamicin in acute lymphoblastic leukemia pediatric patients compared to non-oncology patients.

Understanding the pharmacokinetics of gentamicin is essential in special populations, such as pediatric patients with acute lymphoblastic leukemia (ALL), in light of previous studies indicating that ALL patients have a lower volume of distribution than non-ALL patients. Furthermore, validation of such results is needed to ensure their clinical application. Accordingly, this single-center, retrospective, cross-sectional study compares the pharmacokinetic parameters of volume of distribution and clearance (Cl) of gentamicin between ALL and non-ALL patients. Inclusion criteria were pediatric patients aged between 1 and 14 years with or without ALL and receiving intravenous gentamicin for treatment courses > 72 h. Patients' characteristics, such as age, sex, height, serum albumin, diagnosis, serum creatinine (Scr) concentration, dosing, and pharmacokinetic information, including peak and trough concentrations, were retrieved. The study scrutinized a total of 115 pediatric patients, comprising toddlers (15.7 %), children (76.5 %), and adolescents (7.8 %). All patients received gentamicin every 8 h, with an average dose of 2.50 (0.64) mg/kg. Patients were divided into two groups based on disease state, with 45.2 % (n = 52) in the non-ALL group and 54.8 % (n = 63) in the ALL group. Both groups had similar characteristics in terms of gender, weight, body surface area, and dose. The only significant covariates identified were weight and creatinine clearance (Clcr) for volume of distribution (Vd). A significant difference was found in Scr, Clcr, and blood urea nitrogen (BUN); however, no significant difference between ALL and non-ALL patients emerged in the volume of distribution or Cl. In conclusion, the study findings indicate that dosing requirements were similar between the two groups. Further prospective studies with larger sample sizes are warranted.

Simultaneous assessment of absorption and pharmacokinetic characteristics of four active flavonoids from Chimonanthus nitens Leaf Granules using LC-MS determination: in vivo and in vitro.

A sensitive UPLC-HRMS method was developed and validated for simultaneous quantification of four active flavonoids from Chimonanthus nitens Leaf Granules (CNLG) in biological matrix. The method was utilized in pharmacokinetic study of the four flavonoids in rats as well as other evaluation assays in vitro. It was revealed that rutin, nicotiflorin, and astragalin had poor oral bioavailability in rats possibly due to low intestinal permeability and metabolism in intestinal flora. Kaempferol underwent rapid glucuronidation and sulphation in rat plasma with medium permeability coefficient. The results provided valuable data for future research and development of CNLG flavonoids.

Pharmacokinetics of tilmicosin in plasma, urine and feces after a single intragastric administration in donkey (Equus asinus).

Tilmicosin, a macrolide antibiotic, has the potential to treat bacterial infections in donkeys. However, the pharmacokinetics of tilmicosin in donkeys have not been reported. The aim of this study was to investigate the pharmacokinetics of tilmicosin in donkey plasma, urine, and feces after a single intragastric administration to determine the suitability of tilmicosin for donkeys. A total of 5 healthy male donkeys with similar body weights were selected. The donkeys were administered a single dose of 10 mg · kg-1 body weight (BW) tilmicosin by gavage. The concentrations of tilmicosin in plasma, urine, and feces were determined. The results showed that after a single intragastric administration of 10 mg · kg-1 body weight, tilmicosin in donkey plasma reached a maximum concentration of 11.23 ± 5.37 mg · L-1 at 0.80 ± 0.10 h, with a half-life of 14.49 ± 7.13 h, a mean residence time of 28.05 ± 3.05 h, a Cl/F of 0.48 ± 0.18 L · kg-1 · h-1, and a Vd/F of 9.28 ± 2.63 Lkg-1. The percentage of tilmicosin excreted through the urine of donkeys is 2.47%, and the percentage excreted through the feces is 66.43%. Our study provides data to inform the use of tilmicosin in donkeys.

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of PA9159 Nasal Spray, a Highly Potent Glucocorticoid in Healthy Chinese Volunteers.

OBJECTIVE: PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated. METHODS: This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10-80 µg and 20-40 µg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated. RESULTS: A total of 60 participants completed the study. PA9159 doses of up to 80 µg in the SAD and up to 40 µg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8% (368/880) of the samples in all treatment groups, including 25.2% (105/416) of the SAD and 56.7% (263/464) of the MAD. The majority (>80.0%) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t1/2) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUCss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median Tmax was approximately 6 hours in both the SAD and MAD cohorts. CONCLUSIONS: The PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis.

Saliva monitoring of prednisolone in children with first onset steroid-sensitive nephrotic syndrome: Is it possible?

AIMS: Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS). METHODS: Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8 weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. RESULTS: From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h-1 70 kg-1 and 158 (7%) L 70 kg-1, respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. CONCLUSION: Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions.