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Abstract Background and Objective Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [14C]tinengotinib following a single oral dose in healthy subjects. Methods Six healthy male subjects received a single oral dose of [14C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism. Results Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (T max) of 1.0–4.0 h post-dose and a long terminal half-life (t ½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration–time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4. Conclusions Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent. Registration ChinadrugTrials.org.cn identifier: CTR20212852.

AimsTo investigate the prevalence and influencing factors of drug-related problems (DRPs) in inpatients with kidney disease to provide reference data for pharmaceutical care.MethodsThe basic information, diagnoses, and medication reconciliation (MR) of inpatients in the Department of Nephrology at our hospital between October 2020 and September 2021 were collected. The Chinese-modified DRP version based on the PCNE classification (Version 9.1) was used to assess, intervene and statistically analyze the results of the patients’ DRPs. The influence factor of DRPs in inpatients with kidney disease was analyzed by the multivariate binary logistic regression.ResultsOf 623 patients included in this study, 132 (21.80%) had DRPs. The prevalence of anemia was significantly higher in patients with DRPs than those without DRPs (43.18% vs. 28.72%, p < 0.05), the mean number of drug types consumed (7.25 ± 3.44 with DRPs vs. 5.93 ± 3.58 without DRPs, p < 0.05) and the proportion of ≥5 drugs (%) (79.55% with DRPs vs 58.04% without DRPs, p < 0.05) were significantly increased. In addition, the prevalence of hypertension (76.52% vs. 68.64%), diabetes (27.27% vs. 22.20%) and hyperuricemia (16.67% vs. 13.65%) in DRP patients were higher than those without DRPs, but there was no statistical difference (p > 0.05). The logistic regression analysis showed that patients with anemia (OR = 1.702, 95%CI: 1.146–2.529, p = 0.008), average number of medication types taken (OR = 1.089, 95%CI: 1.034–1.147, p = 0.001) significantly increased the risk of DRPs. The distribution of harm levels was as follows: 78 problems (59.09%) were level C, 29 (21.97%) were level B, 10 (7.58%) were level D, 7 (5.30%) were level A, 7 (5.30%) were level E, and 1 (0.76%) were level F. All DRPs were resolved after 128 interventions.ConclusionRenal anemia, the average number of drug varieties consumed, and the proportion of ≥5 drugs are associated with the occurrence of DRPs. Pharmacists conducting MR services can reduce DRPs of inpatients in the department of nephrology and ensure patient drug safety.

BackgroundAdalimumab induces the production of anti-drug antibodies (ADA) that may lead to reduced drug concentration and loss-of-response, posing significant clinical challenges. However, traditional immunoassays have limitations in terms of sensitivity and drug-tolerance, hindering the insights of ADA response.MethodsHerein, we developed an integrated immunoassay platform combining the electrochemiluminescence immunoassay with immunomagnetic separation strategy. A longitudinal cohort study involving 49 patients with ankylosing spondylitis was carried out to analyze the dynamic profiles of ADA and to investigate the impact of ADA on adalimumab pharmacokinetics using a population pharmacokinetic model. Additionally, cross-sectional data from 12 patients were collected to validate the correlation between ADA levels and disease relapse.ResultsThe ADA assay demonstrated high sensitivity (0.4 ng/mL) and drug-tolerance (100 μg/mL), while the neutralizing antibodies (NAB) assay showed a sensitivity of 100 ng/mL and drug-tolerance of 20 μg/mL. Analysis of the longitudinal cohort revealed that a majority of patients (44/49, 90%) developed persistent ADA within the first 24 weeks of treatment. ADA levels tended to plateau over time after an initial increase during the early immune response phase. Further, nearly all of the tested patients (26/27, 96%) were classified as NAB positive, with a strong correlation between ADA levels and neutralization capacity (R2 = 0.83, P < 0.001). Population pharmacokinetic modeling revealed a significant positive association between model-estimated individual clearance and observed ADA levels. Higher ADA levels were associated with adalimumab clearance and disease relapse in a cross-sectional cohort, suggesting a promising ADA threshold of 10 for potential clinical application. Moreover, the IgG class was the primary contributor to ADA against adalimumab and the apparent affinity exhibited an increasing trend over time, indicating a T-cell dependent mechanism for ADA elicitation by adalimumab.ConclusionIn summary, this integrated immunoassay platform shows promise for in-depth analysis of ADA against biologics, offering fresh insights into immunogenicity and its clinical implications.

AimsA strategy based on therapeutic drug monitoring and population pharmacokinetic (popPK) models would likely increase the rate of clinical remission (CR) after infliximab (IFX) induction in patients with Crohn’s disease (CD). This study aimed to evaluate the relationship between early IFX levels and antibodies to infliximab (ATI) and CR at week 14 and simulate the probability of attaining the identified exposure target.MethodsPatients with CD (n = 140) treated with IFX were enrolled to develop the popPK model. Of these, 43 moderate-to-severe patients with CD were followed up at week 14. Simulations were performed on patients with different dosage regimens and covariates.ResultsIFX levels >20.08 μg/mL at week 2, >18.44 μg/mL at week 6, and >3.08 μg/mL at week 14 were linked to CR. A one-compartment model fit the data best. The covariates influencing clearance were fat free mass, albumin and ATI levels. To achieve IFX levels >20.08 μg/mL at week 2, ≥400 mg IFX was predicted to be required in over 50% patients with 45–70 kg and 35–45 g/L albumin, except for patients with 70 kg and 30 g/L albumin.ConclusionIFX levels >20.08 μg/mL at week 2 and absence of ATI at week 14 are associated with CR. Optimising IFX induction dosing will be critical to achieve the target of early IFX levels associated with CR.

AimsPersistent uncertainties exist surrounding the therapeutic drug monitoring (TDM) of adalimumab in clinical settings. To address these issues, we conducted a systematic review to assess the current evidence regarding the benefits of TDM for adalimumab.MethodsPubMed, EMBASE, and Cochrane Databases were searched from inception to October 2022. The trials regarding to the list three key questions were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving adalimumab? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients with treatment failure to adalimumab? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with adalimumab? Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed to calculate the relative risk (RR) and 95% confidence interval (CI).ResultsA total of 9 studies was included in this review. For proactive TDM, meta-analysis indicated that proactive TDM (n = 163/257, 63.42%) showed no significant superiority over reactive TDM and/or conventional management (n = 336/606, 55.44%) in achieving and/or maintaining clinical remission by random effects model (RR: 1.24, 95% CI 0.98–1.58, I2 = 73%). There were three studies that supporting the reactive TDM, low drug levels in the absence of anti-drug antibodies (ADA) strongly indicate the need for dose intensification, and infliximab is a feasible choice for patients with low drug levels and ADA positivity. While swapping to another class should be considered in patients with adequate drug levels. In addition, TDM can help clinicians optimize dosing schedules and prevent overtreatment in patients who have achieved low disease activity and sufficient drug concentrations, with no predictive value for successful adalimumab discontinuation.ConclusionCurrent evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management. Reactive TDM can aid in understanding treatment failure and developing subsequent therapy. For patients reaching low disease activity and remission, TDM can help successful dose reduction, while it cannot inform the successful drug discontinuation. However, existing trials are limited, and more well-designed trials are necessary to clarify the role of TDM in adalimumab treatment.

B7 homolog 3 (B7-H3) has attracted much attention in glioblastoma (GBM) radioimmunotherapy (RIT) due to its abnormally high expression on tumor cells. In this study, we report that two specific humanized anti-human B7-H3 antibodies (hu4G4 and hu4H12) derived from mouse anti-human B7-H3 antibodies that were generated by computer-aided design and exclusively recognize membrane expression of B7-H3 by human glioma cells. Hu4G4 and hu4H12 were radiolabeled with 89Zr for RIT antibody screening. Micro-positron emission tomography (PET) imaging, biodistribution and pharmacokinetic (PK) analyses of 89Zr-labeled antibodies were performed in U87-xenografted models. 125I labelling of the antibodies for single-photon emission computed tomography (SPECT) imaging was also used to investigate the biological behavior of the antibodies in vivo. Furthermore, the pharmacodynamic (PD) of the 131I-labeled antibodies were evaluated in U87-xenografted mice and GL261 Red-FLuc-B7-H3 in situ glioma tumor models. Micro-PET imaging and biodistribution analysis with a gamma counter showed that 89Zr-deferoxamine (DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than 89Zr-DFO-(hu4H12, immunoglobulin G (IgG)). The biodistribution results of 125I-SPECT imaging were similar to those of 89Zr-PET imaging, though the biodistribution in long bone joints and the thyroid varied. The PD analysis results indicated that 131I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity. Interestingly, 131I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen type IV and platelet-derived growth factor receptor β (PDGFR-β) compared with control treatment, as determined by immunofluorescence (IF), which contributed to inhibiting tumor growth. Taken together, our data indicate that hu4G4 exhibits good tumor targeting and specificity, achieves low nonspecific concentrations in normal tissues, and has acceptable PK characteristics. 131I-hu4G4 also exerts effective antitumor effects with an ideal safety profile. Therefore, we expect hu4G4 to be an excellent antibody for the development of GBM RIT.

Background: Acute graft- versus -host disease (aGVHD) is a major complication following hematopoietic stem cell transplantation (HSCT). Objective: This study aimed to explore the risk factors for the incidence of aGVHD in patients post-HSCT. Design: This was a retrospective study. Methods: A total of 407 patients were enrolled. The patients’ data were recorded from the medical records. The exposure of cyclosporine was estimated based on a population pharmacokinetics model. The occurrence of aGVHD was clinically graded and staged in severity from grades I to IV. A proportional odds model that estimated the cumulative probabilities of aGVHD was used to analyze the data using a nonlinear mixed-effects model. Then, the model parameters and plausibility were evaluated by bootstrap and visual predictive checks. Results: The typical probabilities were 18.9% and 17.9% for grade II and grades III–IV, respectively. The incidence of grade II and grade III–IV aGVHD for human leukocyte antigen (HLA) haplo sibling donor patients was higher than that for HLA-matched donor patients. The incidence of grade II and grade III–IV aGVHD decreased with increasing early cyclosporine trough concentration; however, cyclosporine exposure was not associated with the incidence of aGVHD. Conclusion: HLA matching and early cyclosporine trough concentration were important factors for the occurrence of aGVHD.

Abstract Background To evaluate the safety and effectiveness of different dosages of intranasal Dexmedetomidine (DEX) in combination with oral midazolam for sedation of young children during brain MRI examination. Methods Included in this prospective single-blind randomized controlled trial were 156 children aged from 3 months to 6 years and weighing from 4 to 20 Kg with ASA I-II who underwent brain MRI examination between March 2021 and February 2022. Using the random number table method, they were divided into group A (using 3 ug/kg intranasal DEX plus 0.2 mg/Kg oral midazolam) and group B (using 2 ug/kg intranasal DEX plus 0.2 mg/Kg oral Midazolam). The one-time success rate of sedation, sedation onset time, recovery time, overall sedation time, and occurrence of adverse reactions during MRI examination were compared between the two groups. The heart rate (HR), mean arterial pressure (MAP), and percutaneous SpO2before and after drug administration were observed in both groups. Differences in sedation scores between the two groups were compared before intranasal drug administration (T0), 10 min after drug administration (T1), at the time of falling asleep (T2), at the end of examination (T3), and at the time of recovery (T4). Results The one-time success rate of sedation in group A and B was 88.31% and 79.75% respectively, showing no significant difference between the two groups (P>0.05). The sedation onset time in group A was 24.97±16.94 min versus 27.92±15.83 min in group B, and the recovery time was 61.88±22.18 min versus 61.16±28.16 min, both showing no significance difference between the two groups (P>0.05). Children in both groups exhibited good drug tolerance without presenting nausea and vomiting, hypoxia, or bradycardia and hypotension that needed clinical interventions. There was no significant difference in the occurrence of abnormal HR, MAP or other adverse reactions between the two groups (P>0.05). Conclusion 3 ug/kg or 2 ug/kg intranasal DEX in combination with 0.2 mg/kg oral Midazolam both are safe and effective for sedation of children undergoing MRI examination with the advantages of fast-acting and easy application. Trial registration It was registered at the Chinese Clinical Trial Registry ( ChiCTR1800015038 ) on 02/03/2018.

Understanding the factors that hamper immune therapy in breast cancer may increase the range of patients who benefit. Here authors show that breast cancer cells produce and subsequently transfer active TGF-β type II receptors to CD8 + T cells to render them exhausted, thus paralyzing the anti-tumor immune response.

SHR6390 (dalpiciclib) is a selective and effective cyclin-dependent kinase (CDK) 4/6 inhibitor and an effective cancer therapeutic agent. On 31 December 2021, the new drug application was approved by National Medical Product Administration (NMPA). The metabolism, mass balance, and pharmacokinetics of SHR6390 in 6 healthy Chinese male subjects after a single oral dose of 150 mg [14C]SHR6390 (150 µCi) in this research. The Tmax of SHR6390 was 3.00 h. In plasma, the t1/2 of SHR6390 and its relative components was approximately 17.50 h. The radioactivity B/P (blood-to-plasma) AUC0-t ratio was 1.81, indicating the preferential distribution of drug-related substances in blood cells. At 312 h after administration, the average cumulative excretion of radioactivity was 94.63% of the dose, including 22.69% in urine and 71.93% in stool. Thirteen metabolites were identified. In plasma, because of the low level of radioactivity, only SHR6390 was detected in pooled AUC0-24 h plasma. Stool SHR6390 was the main component in urine and stool. Five metabolites were identified in urine, and 12 metabolites were identified in stool. Overall, faecal clearance is the main method of excretion.

Aims: Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn’s disease (CD).Methods: CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated.Results: The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50 μg/mL, p < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48 μg/mL, p < .001) or those with low-titer ATI (1.15 vs. 2.95 μg/mL, p = .03). The HLA-DQA1*05 rs2097432 GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19–7.30, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24–6.96, p = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59–37.87, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18–7.88, p = .02). No association was found between other SNPs and ATI production.Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.

Background and aimsSurgical site infection is a common complication after surgery. Periprocedural antibiotics are necessary to prescribe for preventing or treating infections. The present study aimed to explore the effect of intravenous antibiotics on gut microbiota and menaquinone biosynthesis in patients, especially in elderly patients undergoing cardiac surgery.MethodsA total of 388 fecal samples were collected from 154 cardiac surgery patients. The V3–V4 hypervariable region of the bacterial 16S rRNA gene was amplified and sequenced on a MiSeq PE300. The gut microbiota diversity of samples was analyzed in terms of α- and β-diversity at the OTU level. The different groups were classified according to antibiotics in combinations and single antibiotics. PICRUSt2 was used for preliminary prediction of the gut microbiota function for menaquinone biosynthesis.ResultsThe intravenously administered antibiotics which are excreted via bile represents the main antibiotics that could disturb the gut microbiota’s composition in cardiac surgery patients, especially for elderly patients. The effect of antibiotics on gut microbiota is produced after antibiotics treatments over one week. The recovery of gut microbiota to the state of pre-antibiotics may require over two weeks of antibiotics withdrawal. Sex factor doesn’t represent as an influencer in gut microbiota composition. Long-term use of cefoperazone-sulbactam may affect coagulation function.ConclusionsThe composition of the gut microbiota had a significant change post-intravenous antibiotics treatment in cardiac surgery patients. The richness and diversity of gut microbiota are increased in elderly patients.

Aims: The aims of the study were to 1) establish a population pharmacokinetic (Pop-PK) model for busulfan in Chinese pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and then estimate busulfan exposure and 2) explore the association between busulfan exposure and clinical outcomes.Methods: A total of 128 patients with 467 busulfan concentrations were obtained for Pop-PK modeling using nonlinear mixed effect model (NONMEM) software. Sixty-three patients who received the 16-dose busulfan conditioning regimen were enrolled to explore the correlations between clinical outcomes and the busulfan area under the concentration–time curve (AUC) using the Cox proportional hazards regression model, Kaplan–Meier method and logistic regression.Results: The typical values for clearance (CL) and distribution volume (V) of busulfan were 7.71 L h−1 and 42.4 L, respectively. The allometric normal fat mass (NFM) and maturation function (Fmat) can be used to describe the variability in CL, and the fat-free mass (FFM) can be used to describe the variability in V. Patients with AUCs of 950–1,600 µM × min had 83.7% (95% CI: 73.3–95.5) event-free survival (EFS) compared with 55.0% (95% CI: 37.0–81.8) for patients with low or high exposure (p = 0.024). The logistic regression analysis results showed no association between transplant-related toxicities and the busulfan AUC (p > 0.05).Conclusions: The variability in busulfan CL was related to the NFM and Fmat, while busulfan V was related to the FFM. Preliminary analysis results suggested that a busulfan AUC of 950–1,600 µM × min was associated with better EFS in children receiving the 16-dose busulfan regimen.

This study aimed at exploring the concentration‐effect relationship of adalimumab and early adalimumab and anti‐adalimumab antibody (AAA) levels in predicting primary nonresponse in a real‐world pilot cohort of patients with ankylosing spondylitis. Thirty‐one patients were included. The Ankylosing Spondylitis Disease Activity Score improved with increasing adalimumab trough level at week 12 and reached a major improvement with levels between 8 and 12 μg/mL. Moreover, weeks 4 and 2 adalimumab levels below 4.28 and 3.37 μg/mL were predictive of primary nonresponse (area under the curve (AUC) = 0.89, 0.88; P = 0.0003, P = 0.034, respectively). Week 4 AAA signal‐to‐noise levels were significantly higher among primary nonresponders, and the cutoff for primary nonresponse prediction was above 5.31 (AUC = 0.81; P = 0.004). Adalimumab trough levels in a range of 8–12 μg/mL are optimum to reach major improvement, and lower adalimumab with higher AAA levels at the early stage (week 4) predict primary nonresponse by supporting proactive monitoring to optimize adalimumab therapy.

Abstract Introduction The B cell survival factor B lymphocyte stimulator (BLyS) is elevated in patients with systemic lupus erythematosus (SLE) and associated with disease activity. Belimumab, a monoclonal antibody specific for soluble BLyS, is approved for the treatment of adults with active, autoantibody-positive SLE receiving standard therapy. Ethnicity is one of the factors that can potentially affect the pharmacokinetics (PK) of therapeutic monoclonal antibodies, and therefore their efficacy and safety. Methods This phase 1, open-label study (200909) evaluated the pharmacokinetics (PK, primary objective), pharmacodynamics (PD), and safety (secondary objectives) of belimumab in Chinese patients with SLE (N = 20). Blood samples were taken up to 84 days after a single intravenous (IV) dose of belimumab 10 mg/kg. Results Peak serum concentrations of belimumab (C max) were obtained within the 1-h infusion. Geometric mean C max, area under the concentration–time curve (time 0 to last quantifiable concentration), terminal half-life, systemic clearance, and volume of distribution were 221 μg/mL, 2395 day·μg/mL, 14.6 days, 4.06 mL/day/kg, and 85.7 mL/kg, respectively. Decreases in CD20+, CD20+/CD27− naïve, CD20+/CD69+ active, CD20+/CD138+ plasmacytoid, CD19+/CD27BRIGHT/CD38BRIGHT SLE subset, and CD20−/CD138+ plasma B Cells post-dose were accompanied by an increase in CD20+/CD27+ memory B cells. Four cases of upper respiratory tract infection (three mild, one moderate) and one case of mild pharyngitis were possibly drug-related; all resolved during the study. Conclusion PK of a single belimumab 10 mg/kg IV dose in Chinese patients with SLE were similar to those observed previously in Japanese and American (white and African-American) patients with SLE. PD results were consistent with belimumab inhibiting BLyS, and belimumab was well tolerated. These data support the use of belimumab in Chinese patients with SLE. Trial Registration ClinicalTrials.gov identifier, NCT02880852.

Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation dynamic PET imaging in humanized transgenic animal models bearing MC38 tumors (knock-in of hCD47 and hPDL1). 89Zr-labeled IBI322 specifically accumulated in tumors with a tumor-to-muscle ratio of 12.37 ± 1.42 at 168 h (0.22 mg/kg) and the biodistribution of normal tissues from PET imaging could be used for preliminary safety prediction. According to the Pearson correlation analysis between the ELISA-quantified serum concentration and heart uptake (%ID/g) (r = 0.980), a modified Patlak model was proposed. The exploratory target-mediated 50% (0.38 mg/kg) and 90% (0.63 mg/kg) inhibitory mass doses were calculated with the current modified Patlak model. The preliminary pharmacodynamics (PD) study with 0.34 mg/kg revealed that the dose prediction was rational. In conclusion, dose escalation PET imaging with 89Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs.

Background. Inhalation therapy is the main treatment for asthma and chronic obstructive pulmonary disease (COPD) patients. Owing to the poor inhaler technique in using inhalers, we assessed the effect of a multidimensional pharmaceutical care on inhalation technique in patients with asthma and COPD. Materials and Methods. A 3-month controlled parallel-group study was undertaken in asthma and COPD patients using dry powder inhalers (DPIs). Patients in the intervention group received multidimensional pharmaceutical care, including establishment of a special dispensing window, face-to-face demonstration and education, brochure education, videos education, online consultation and education, and follow-up reeducation. Patients in the control group received usual pharmaceutical care. The inhaler technique score, correctness of inhaler usage, beliefs about medicines questionnaire (BMQ) score, asthma control test (ACT), and COPD assessment test (CAT) were measured pre- and postintervention. Quality of life improvement evaluated according to score changes of ACT in asthma and CAT in COPD and patient satisfaction were measured postintervention. Results. 259 patients finished the study with 133 in the intervention group and 126 in the control group. Compared to preintervention and control group postintervention, the inhaler technique score, correctness of inhaler usage, and ACT score significantly increased in the intervention group postintervention, while the BMQ score and CAT score decreased significantly P

The aim was to verify that dexmedetomidine (DEX) can attenuate CLP-induced intestinal injury via inhibition of inflammation. Male Sprague-Dawley (SD) rats were randomly allocated into Sham group and the other three CLP model groups, in terms of different treatments: placebo, DEX, and yohimbine plus DEX (DEX + YOH) groups. Pathology examination was conducted with HE stain. To identify differences among groups, the levels of DAO, and D-lactate in serum were measured by spectrophotometry, and the levels of TNF-α, IL-1β, and IL-6 in serum and organ were measured by ELISA. The expressions of occludin and TLR4 in tissue were detected by Western blot. The survival rate of an additional group of animals within 7 d was recorded. In DEX group, mortality was lower, histology change was minor, DAO, and D-lactate levels were reduced, and occludin expression was increased; the expressions of TNF-α, IL-1β, IL-6, and TLR4 were also decreased in DEX group. These results indicated that acute intestinal injury induced by CLP was mitigated by DEX treatment. However, these effects of DEX were significantly attenuated by yohimbine in DEX + YOH group. Our study indicated the protective effects of DEX on CLP-induced injury, which may be associated with the inhibition of inflammation via modulating TLR4 pathway and can be blocked by yohimbine.

This letter to the editor discusses a study comparing two different strategies for measuring adalimumab concentrations in human plasma. The authors analyze plasma samples from patients with ankylosing spondylitis and find that adalimumab concentrations measured using protein-A enrichment were higher than those obtained with TNF-α enrichment in ADA-positive samples. The article also introduces a method called immunocapture-LC-HRMS for measuring adalimumab concentrations and demonstrates its comparability to ELISA. The authors also discuss potential interference from anti-drug antibodies and suggest strategies to address this interference. [Extracted from the article]

Background and objectives: Due to the high individual variability of anticoagulant warfarin, this study aimed to investigate the effects of vitamin K concentration and gut microbiota on individual variability of warfarin in 246 cardiac surgery patients. Methods: The pharmacokinetics and pharmacodynamics (PKPD) model predicted international normalized ratio (INR) and warfarin concentration. Serum and fecal samples were collected to detect warfarin and vitamin K [VK1 and menaquinone-4 (MK4)] concentrations and gut microbiota diversity, respectively. In addition, the patient's medical records were reviewed for demographic characteristics, drug history, and CYP2C9, VKORC1, and CYP4F2 genotypes. Results: The PKPD model predicted ideal values of 62.7% for S-warfarin, 70.4% for R-warfarin, and 76.4% for INR. The normal VK1 level was 1.34 ± 1.12 nmol/ml (95% CI: 0.33-4.08 nmol/ml), and the normal MK4 level was 0.22 ± 0.18 nmol/ml (95% CI: 0.07-0.63 nmol/ml). The MK4 to total vitamin K ratio was 16.5 ± 9.8% (95% CI: 4.3-41.5%). The S-warfarin concentration of producing 50% of maximum anticoagulation and the half-life of prothrombin complex activity tended to increase with vitamin K. Further, Prevotella and Eubacterium of gut microbiota identified as the main bacteria associated with individual variability of warfarin. The results suggest that an increase in vitamin K concentration can decrease anticoagulation, and gut microbiota may influence warfarin anticoagulation through vitamin K2 synthesis. Conclusion: This study highlights the importance of considering vitamin K concentration and gut microbiota when prescribing warfarin. The findings may have significant implications for the personalized use of warfarin. Further research is needed to understand better the role of vitamin K and gut microbiota in warfarin anticoagulation. [ABSTRACT FROM AUTHOR]