[Effects of Straw Returning with Lime on SOC and Carbon Pool Management in Acidic Paddy Soil].

Soil acidification and low SOC are the main limiting factors in acidic paddy soils. Straw returning with lime is an effective measure to alleviate soil acidification and improve soil fertility; however, its interaction effects on SOC and carbon pool management are still unclear. To investigate the impact of straw returning with lime on the organic carbon pool of acidic paddy soil, field experiments were conducted on acidic paddy soil in Baiyun District and Huiyang District of Guangdong Province. The changes in soil total organic carbon (TOC), water-soluble organic carbon (DOC), active organic carbon (LOC), particulate organic carbon (POC), microbial biomass carbon (MBC), carbon pool index (CPI), stable organic carbon (IOC), carbon pool activity (L), carbon pool activity index (CPAI), and carbon pool management index (CPMI) were analyzed under three treatments (CK, conventional fertilization; RS, straw returning+conventional fertilization; RS+L straw returning with lime+conventional fertilization). The results demonstrated that compared with that in CK, the TOC, LOC, POC, and MBC in the RS+L treatment were significantly increased by 10.24%-17.79%, 34.49%-44.37%, 19.27%-23.59%, and 33.36%-43.26%, respectively (P<0.05). Compared with that in CK, the RS+L treatment significantly increased the DOC content during the early growth stage (15-45 days after transplanting) of rice (P<0.05) but had no significant influence on the DOC content during the late growth stage of rice. Compared with that in RS, the TOC, LOC, POC, and MBC in the RS+L treatment were increased by 2.15%-6.95%, 1.17%-17.90%, 4.27%-8.65%, and 12.99%-14.53%, respectively. Compared with that in CK, the RS+L treatment significantly increased IOC and CPI by 8.32%-15.57% and 14.00%-20.00%, respectively (P<0.05). Compared with that in the CK treatment, the RS treatment significantly increased CPI by 14.00%-18.00% (P<0.05). No significant differences in L, CPAI, or CPMI were detected among the different treatments. The soil pH in the RS+L treatment was significantly higher than that in the CK treatment (P<0.05). No significant differences in rice yield were detected among the different treatments. Principal component analysis demonstrated that rice yield was primarily correlated with DOC, LOC, CPAI, and CPMI but its contribution to SOC and carbon pool management index was low. Principal component analysis also indicated that straw returning with lime could improve soil pH and nutrient contents of acidic paddy soil, driving the formation and accumulation of organic carbon fraction such as MBC and POC, thus boosting the increase in SOC. In conclusion, straw returning with lime is beneficial to the accumulation of MBC, POC, LOC, and IOC in acidic paddy soil to improve the content and stability of soil total organic carbon, which is an effective way to improve the carbon sequestration of acidic paddy soil.

S-propargyl-cysteine promotes the stability of atherosclerotic plaque via maintaining vascular muscle contractile phenotype.

Introduction: Plaque rupture in atherosclerosis contributes to various acute cardiovascular events. As a new sulfide-containing donor, S-propargyl-cysteine (SPRC) has been reported to play a beneficial role in cardioprotection, potentially through its anti-inflammatory, anti-oxidative and anti-atherogenic activities. Our previous study observed an increase in eNOS phosphorylation in endothelial cells. However, it remains unclear whether SPRC influences vascular smooth muscle cells (VSMCs) within the plaque and if this effect contributes to plaque stabilization. Methods: An atherosclerotic unstable plaque mouse model was established by subjecting ApoE-/- mice to tandem stenosis of the right carotid artery along with a Western diet. Daily SPRC administration was conducted for 13 weeks. Plaque morphology and stability were assessed using MRI scanning and histopathological staining. In our in vitro studies, we stimulated human artery vascular smooth muscle cells (HAVSMCs) with platelet-derived growth factor-BB (PDGF-BB), both with and without 100 µM SPRC treatment. Cell phenotype was assessed using both Western blot and Real-time PCR. Cell proliferation was assessed using the BrdU cell proliferation kit and immunofluorescence of Ki-67, while cell migration was measured using scratch wound healing and transwell assay. MiR-143-3p overexpression and knockdown experiments were used to investigate whether it mediates the effect of SPRC on VSMC phenotype. Results and Discussion: SPRC treatment reduced plasma lipid levels, increased collagen content and decreased cell apoptosis in atherosclerotic plaques, indicating improved plaque stability. Both in vivo and in vitro studies elucidated the role of SPRC in preserving the contractile phenotype of VSMCs through up-regulation of miR-143-3p expression. Furthermore, SPRC suppressed the pro-proliferation and pro-migration effects of PDGF-BB on HAVSMCs. Overall, these findings suggest that the inhibitory effect of SPRC on phenotype switch from contractile to synthetic VSMCs may contribute to its beneficial role in enhancing plaque stability.

[Rapid screening of 84 pesticide residues in dendrobium by Sin-QuEChERS Nano purification column with gas chromatography-tandem mass spectrometry].

A rapid screening method for 84 pesticide residues in dendrobium perfringens parent material with different polarities was developed using a Sin-QuEChERS Nano clean-up column combined with gas chromatography-tandem mass spectrometry (GC-MS/MS). The differences in extraction efficiency of the targets were compared with different extraction solvents (acetonitrile containing 1% acetic acid, acetone) and methods (immersion with or without water). The purification effect and extraction recoveries of Sin-QuEChERS Nano method and classical dispersive solid-phase extraction (dSPE), solid-phase extraction (SPE) and QuEChERS were systematically compared using Dendrobium nobile samples. The differences in matrix effects between the Sin-QuEChERS Nano method, which was more effective in purification, and the dSPE method were also analyzed. The purification effects of three commercially available Sin-QuEChERS Nano purification columns (simple matrix purification column, complex matrix purification column and herbal purification column) were compared. The applicability of the purification methods were also verified by using different parts of Dendrobium nobile samples (stems, leaves and flowers). From the results, it could be concluded that weighing 2.00 g and the samples in 5 mL of water for 20 min, followed by extraction with acetonitrile containing 1% acetic acid was more effective. The average extraction recovery of the target components by Sin-QuEChERS Nano purification method was 90.5%, which further identified Sin-QuEChERS Nano-Chinese medicine purification column as the preferred purification column for dendrobium purification. The target components were separated by a DB-1701MS quartz capillary column (30 m×0.25 mm×0.25 µm) with programmed temperature rise, detected by multiple reaction monitoring (MRM) mode, and quantified by matrix-matched solution external standard method. The GC-MS/MS assay was used for the methodological validation of the 84 representative pesticides within Dendrobium officinale and Dendrobium nobile was carried out by GC-MS/MS detection method. The results indicated that the targets showed excellent linear correlation in different scopes with correlation coefficients (r2) >0. 990. The limits of detection (LODs, S/N=3) of the method were 1.5 to 5.8 µg/kg, and the limits of quantification (LOQs, S/N=10) ranged from 5.0 to 15.0 µg/kg. The spiked recoveries of the target pesticides under different spiked levels were 68.7%-116.2%, and the relative standard deviations (RSDs, n=6) were less than 15%. Compared to other typical pretreatment methods, the Sin-QuEChERS Nano method provided better performance in terms of purification. The method not only effectively removed pigments, organic acids, and alkaline interferents, but also saved preparation time. Losses due to solvent transfer were also avoided and no further vortexing or centrifugation was required, making it a simplified and effective extraction and purification procedure. The method was sensitive, rapid, simple and reliable. It effectively improved the detection efficiency during the rapid screening of pesticides in dendrobium and presented a strong practical application value. In addition, the developed method could further expand the types of target pesticides and could be used to detect more pesticide residues in foods and Chinese herbal medicine. The established Sin-QuEChERS Nano method was used for the analysis of authentic samples. The applicability of the method was evaluated by analyzing a total of 80 samples collected from Anlong, Libo, Dushan, and Yanhe County in Guizhou Province. The types of samples included dendrobium maple, Dendrobium nobile (flowers, stems, leaves) and Dendrobium officinale (flowers, stems, leaves, powder, tablets). At least one pesticide residue was detected in 12 samples, with a detection rate of 15%. The five pesticides with higher detection rates and residues were chlorpyrifos (0.08-0.5 mg/kg), chlorothalonil (0.06-3.2 mg/kg), propanil zinc (0.03-0.15 mg/kg), methyl parathion (0.04-0.23 mg/kg) and cyhalothrin (0.10-2.68 mg/kg). Except for the pesticides in maximum residue limits (MRLs), the pesticide residues detected from dendrobium samples were below the limits set by Chinese national standard (GB 2763-2021) and local standard DBS 52/048-2020.

Meroterpenoids containing benzopyran or benzofuran motif from Ganoderma cochlear.

Five undescribed benzopyran containing meroterpenoids, ganodercins Q－U, two undescribed benzofuran containing meroterpenoids, ganodercins V and W, and two known meroterpenoids were isolated from Ganoderma cochlear. Their structures were elucidated by using HRESIMS, NMR spectroscopy and computational methods. The results of biochemical studies using a palmitic acid (PA) induced insulin resistance (IR) model show that (-)-ganodercin Q, (+)-ganodercins R and W activate phospho-AKT (p-AKT) at 20 µM and improve glucose uptake in a concentration dependent manner. The results of renoprotection studies show that (+)-ganodercin S, cochlearol F, (+)- and (-)-ganodercins V reduce the expression of collagen I.

Sibling relationships and civic engagement: A longitudinal study of Chinese young adults.

This study examined the longitudinal associations of sibling intimacy and conflict with civic attitudes and behaviours among Chinese young adults. At two time points separated by about 12 months, questionnaire data were collected from 272 Chinese college students (mean age at Time 1 = 19.68 years; 69% female), students who studied in Hong Kong and had at least one sibling. Students rated their intimacy and conflict with their siblings and their parents at Time 1, and their civic attitudes and behaviours at both time points. Hierarchical regression revealed that, controlling for demographic characteristics and parent-child intimacy and conflict, sibling intimacy predicted increases in both civic attitudes and behaviours. Sibling conflict was a non-significant predictor, however. Findings highlighted the roles of siblings in understanding civic development in young adulthood and the utility of targeting sibling intimacy as means to foster young adults' positive attitudes to and active participation in civic activities.

The lived experiences of patients undergoing acellular porcine corneal stroma transplantation.

To explore the lived experiences of patients undergoing acellular porcine corneal stroma (APCS) transplantation, a descriptive, qualitative design was performed. A purposive sample of 13 patients who underwent APCS transplantation to treat progressive infectious keratitis were enrolled in the semi-structured, open-ended interviews. The taped and transcribed interviews were analyzed using a thematic analysis approach. Alterations in the transparency of APCS grafts were accompanied by a gradual improved visual acuity (before surgery: 1.38± 0.91 logMAR; 3mo postoperatively: 0.40±0.24 logMAR, respectively). Accordingly, in terms of lived experiences, the patients generally reported "negative" experiences before the operation and during the early postoperative period, but this was greatly improved 3mo after surgery. Four main themes were derived: anxiety and fear, stigma, lifestyle change, and gratitude and insights. Conclusively, health care professionals should provide holistic care for patients, proactively promoting patients' physical and mental health.

The molecular genetic background leading to the formation of the human erythroid-specific Xga/CD99 blood groups.

The Xga and CD99 antigens of the human Xg blood group system show a unique and sex-specific phenotypic relationship. The phenotypic relationship is believed to result from transcriptional coregulation of the XG and CD99 genes, which span the pseudoautosomal boundary of the X and Y chromosomes. However, the molecular genetic background responsible for these blood groups has remained undetermined. During the present investigation, we initially conducted a pilot study aimed at individuals with different Xga/CD99 phenotypes; this used targeted next-generation sequencing of the genomic areas relevant to XG and CD99 This was followed by a large-scale association study that demonstrated a definite association between a single nucleotide polymorphism (SNP) rs311103 and the Xga/CD99 blood groups. The G and C genotypes of SNP rs311103 were associated with the Xg(a+)/CD99H and Xg(a-)/CD99L phenotypes, respectively. The rs311103 genomic region with the G genotype was found to have stronger transcription-enhancing activity by reporter assay, and this occurred specifically with erythroid-lineage cells. Such activity was absent when the same region with the C genotype was investigated. In silico analysis of the polymorphic rs311103 genomic regions revealed that a binding motif for members of the GATA transcription factor family was present in the rs311103[G] region. Follow-up investigations showed that the erythroid GATA1 factor is able to bind specifically to the rs311103[G] region and markedly stimulates the transcriptional activity of the rs311103[G] segment. The present findings identify the genetic basis of the erythroid-specific Xga/CD99 blood group phenotypes and reveal the molecular background of their formation.

Safety of antivascular endothelial growth factor administration in the ocular anterior segment in pterygium and neovascular glaucoma treatment: Systematic review and meta-analysis.

BACKGROUND: Anti-VEGF agents has been widely used in ocular diseases, but its safety for treating anterior segment disorders, the conclusions are controversial. METHODS: Several major databases, including CENTRAL, MEDLINE, and EMBASE, were searched. Safety data from 18 randomized controlled trials (RCTs) were used to compare anti-VEGF treatment in the ocular anterior segment in pterygium and neovascular glaucoma treatment with placebo/sham treatment for eye diseases. A meta-analysis for adverse events was performed. RESULTS: Eighteen RCT studies with 955 eyes were included in the meta-analysis. Significant difference in conjunctival disorders (OR: 1.62; 95% CI, 1.01-2.59; P = .05) was noted among the included studies, but not in ocular intolerance (odds ratio [OR]: 0.75; 95% CI, 0.34-1.62; P = .46), corneal disorders (OR: 0.71; 95% CI, 0.37-1.37; P = .31), or the subgroup analysis of conjunctival disorders. CONCLUSIONS: The administration of anti-VEGF agents in the ocular anterior segment for patients with pterygium and glaucoma was tolerable in tolerance and cornea, but was the risk factor of conjunctival disorders. The healing of corneal epithelium may be delayed in patients with primary corneal epithelial defects after anti-VEGF application. However, due to the limited evidence, further research should be performed on the safety of anti-VEGF administration in patients with different corneal disorders.

Analgesic effect of AG490, a Janus kinase inhibitor, on oxaliplatin-induced acute neuropathic pain.

Neuropathic pain often occurs during chemotherapy with oxaliplatin. AG490 has been shown to exert an antagonistic effect on inflammatory pain, but its effect on oxaliplatin-induced neuropathic pain remains poorly understood. This study sought to observe the analgesic effect of AG490 on acute neuropathic pain induced by a single oxaliplatin treatment and to address the possible mechanism. In this study, we established a model of oxaliplatin-induced acute neuropathic pain by intraperitoneal injection of 6 mg/kg oxaliplatin. On day 2 after injection, models were intraperitoneally injected with 1, 5, or 10 mg/kg AG490. Paw withdrawal threshold to mechanical stimuli and tail withdrawal latency to cold stimuli were determined. Western blot assay was performed to detect the expression of spinal phosphorylated signal transducer and activator of transcription 3 (p-STAT3). Immunohistochemistry was used to determine the immunoreactivity of p-STAT3 and interleukin-6. Results demonstrated that paw withdrawal threshold and tail withdrawal latency were significantly increased by the treatment of AG490 in rats. There was no significant difference in the effect among the different doses of AG490. AG490 10 mg/kg decreased the expression of p-STAT3, the immunoreactivity of p-STAT3 and interleukin-6 in spinal cord of acute neuropathic pain rats. These findings confirm that AG490 can attenuate oxaliplatin-induced acute neuropathic pain and is associated with the inhibition in the JAK/STAT3 signaling pathway.

Cloning, purification and biochemical characterisation of a GH35 beta-1,3/beta-1,6-galactosidase from the mucin-degrading gut bacterium Akkermansia muciniphila.

A putative GH35 ß-galactosidase gene from the mucin-degrading bacterium Akkermansia muciniphila was successfully cloned and further investigated. The recombinant enzyme with the molecular mass of 74 kDa was purified to homogeneity and biochemically characterised. The optimum temperature of the enzyme was 42 °C, and the optimum pH was determined to be pH 3.5. The addition of sodium dodecyl sulphate (SDS) reduced the enzyme's activity significantly. The addition of Mg2+-ions decreased the activity of the ß-galactosidase, whereas other metal ions or EDTA showed no inhibitory effect. The enzyme catalysed the hydrolysis of ß1,3- and ß1,6- linked galactose residues from various substrates, whereas only negligible amounts of ß1,4-galactose were hydrolysed. The present study describes the first functional characterisation of a ß-galactosidase from this human gut symbiont.

Rolling adhesion of HL-60 cells treated with all-trans retinoic acid on E-selectin / 中国组织工程研究

BACKGROUND: All-trans retinoic acid (ATRA) is an ideal therapy for acute promyelocytic leukemia, which can induce promyelocytes to differentiate to mature granulocytes. However, differentiation syndrome is still a high risk for the patients undergoing ATRA therapy. Occurrence of this complication is closely related with cellular morphology change and expression and function of cellular adhesion molecules, especially selectin and integrin families. OBJECTIVE: To reveal rolling adhesion behavior and mechanical mechanism of ATRA treated HL-60 cells on the substrate coated with E-selectin under different fluid shear forces. METHODS: Using the equipment of parallel plate flow chamber, untreated and ATRA treated HL-60 cells were driven to roll on E-selectin-coated substrate. The mean rolling velocity and mean stop time were calculated. Here, the HL-60 cells were incubated in the medium containing 1×10-6mol/L ATRA for 0, 48, 72, 96 hours. The substrates were captured with 40 μg/L E-selectin overnight and the shear stresses were set to 0.02, 0.04, 0.06 Pa. RESULTS AND CONCLUSION: The velocity of untreated/treated HL-60 cells decreased firstly and then increased with monotonously increasing shear stress. On the contrary, the mean stop time and factional stop time increased firstly and then decreased. Therefore, we deduced that the flow enhanced rolling adhesion was regulated by the catch bond for the HL-60 cells rolling on E-selectin under flow. On the other side, rolling velocities decreased under the same shear stress even if treated with or without ATRA, and the mean stop time and factional stop time increased inversely, which further illustrate the rolling velocity is mainly regulated by stop time.

Population pharmacokinetic study of cyclosporine in the hematopoietic stem cell transplant recipients.

OBJECTIVES: The aim of this study is to investigate the population pharmacokinetics (PopPK) of cyclosporine (CsA) in the Chinese hematopoietic stem cell transplantation (HSCT) recipients for promoting the individualization of CsA administration. METHODS: A total of 887 retrospective drug monitoring data points were collected from 58 HSCT recipients. Whole blood samples were collected at predose (C0) and 2 hours (C2) post dose. The administration of CsA was intermittent intravenous infusion, continuous intravenous infusion and oral. Population modeling was performed using the NONMEM (nonlinear mixedeffect modeling) program. A one compartment pharmacokinetic model was used to fit the data. RESULTS: Body surface area (BSA), administration route and postoperative days were identified as significant covariates for clearance (CL) according to the final model: CL = 31.0 × (BSA/1.59)0.761 × (ROUT) × (POD), where ROUT was 1.91 if the administration route was intravenous infusion, otherwise it is equal to 1. The POD was 0.818, 0.753, 0.539, and 0.509 for posttransplant Days 0 - 10, 11 - 20, 21 - 30 and more than 30 days, respectively. Administration route was a significant covariate for volume (V) according to the final model: V = 192 × (ROUT), where ROUT was 4.10, 3.63 and 1 when the administration route was continuous intravenous infusion, intermittent intravenous infusion and oral. The other covariates were not identified as a significant effect on CsA pharmacokinetic parameters. CONCLUSION: Body surface area, administration route and postoperative days should be considered in individual pharmacotherapy of cyclosporine for HSCT patient to achieve the desired therapeutic target.

12P-conjugated PEG-modified gold nanorods combined with near-infrared laser for tumor targeting and photothermal therapy.

Gold nanorods have been reported as potential tumor photothermal therapy in vivo and in vitro. However, development of the safe and efficient tumor-targeting gold nanorods for in vivo localized tumor therapy is still a challenge. In our present study, we synthesized the PEG modified gold nanorods and demonstrated its negligible cytotoxicity in vitro. These nanorods also have been demonstrated to efficiently ablate the different kinds of tumor cells in vitro after exposure to the near-infrared laser. When the PEG modified gold nanorods conjugated with the 12P (sequence: TACHQHVRMVRP), this conjugate showed great tumor-targeting and hyperthermia effects on the human liver cancer cell line HepG2 in vitro when coupled with the near-infrared laser treatment. To determine the potential hyperthermia effect of PEG modified gold nanorods or 12P conjugate on tumor cells in vivo, the mice hepatic cancer cells were used to induce the subcutaneous tumor-bearing model in ICR mice. The significant inhibition effects of near-infrared laser mediated PEG modified gold nanorods or 12P conjugate on the tumor growth were observed. These composite results suggest that the 12P-conjugated PEG modified gold nanorods exhibit great biocompatible, particular tumor-targeting and effective photothermal ablation of tumor cells, which warrant the potential therapeutic value of this conjugate for further application in in vivo localized tumor therapy.

Response surface analysis of sevoflurane-remifentanil interactions on consciousness during anesthesia.

BACKGROUND: Recently, the combination of sevoflurane and remifentanil has been widely used in general anesthesia. In this study, we investigated the sevoflurane-remifentanil pharmacodynamic interactions at clinical concentrations using the observer's assessment of alertness/sedation (OAA/S) and the bispectral index (BIS) by response surface analysis. METHODS: Totally 65 American Society of Anesthesiologists (ASA) I patients age 20 to 50 years old were included in this study. Patients were randomly assigned to be anesthetized with different target end-tidal sevoflurane concentrations that ranged from 0.2% to 3.4% in increments of 0.2%. The end-tidal sevoflurane concentration was maintained constant throughout the study. Remifentanil was infused with a target controlled infusion (TCI) system at increasing step-wise concentrations from 1 ng/ml to 10 ng/ml. The values of OAA/S and BIS at different sevoflurane-remifentanil concentration combinations were measured. The pharmacodynamic interactions between sevoflurane and remifentanil were analyzed by a response surface method. The three-dimensional response surfaces were constructed with Minitab Software. Model parameters were estimated with NONMEM program. RESULTS: Sevoflurane and remifentanil acted synergistically on OAA/S. Sevoflurane alone could produce OAA/S ≤ 1 at a minimal alveolar concentration (MAC) of 0.93%. When used in combination with remifentanil at 1, 3, 6, and 10 ng/ml, the corresponding sevoflurane MACs were reduced to 0.79%, 0.58%, 0.48%, and 0.38%, with reductions of 17.2%, 37.6%, 48.4%, and 62.0% from baseline, respectively. In patients administered remifentanil alone, the OAA/S score was ≥ 3 even when the remifentanil concentration reached 10 ng/ml. BIS was closely associated with the sevoflurane concentration and the remifentanil concentration did not noticeably influence the relationship between the sevoflurane concentration and BIS. A sevoflurane concentration of (1.04 ± 0.19)% to (1.81 ± 0.21)% could maintain a BIS between 60 and 40. CONCLUSIONS: The response surface method can analyze the pharmacodynamic interactions between remifentanil and sevoflurane qualitatively and quantitatively. Within the range of our study (remifentanil ≤ 10 ng/ml, sevoflurane ≤ 3.4%), the two drugs produced synergistic effects on OAA/S but had no interactive effect on BIS. A guideline of BIS between 40 and 60 may cause excessive anesthesia when opioids are used to maintain anesthesia.

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats.

AIM: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. METHODS: A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h post-treatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NONMEM version 7.1.2. RESULTS: A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg(-1)·h(-1), 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29- and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. CONCLUSION: A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug- and system-specific PK/PD parameters for the course of induction.

[The therapeutic drug monitoring network server of tacrolimus for Chinese renal transplant patients].

This study is to develop a therapeutic drug monitoring (TDM) network server of tacrolimus for Chinese renal transplant patients, which can facilitate doctor to manage patients' information and provide three levels of predictions. Database management system MySQL was employed to build and manage the database of patients and doctors' information, and hypertext mark-up language (HTML) and Java server pages (JSP) technology were employed to construct network server for database management. Based on the population pharmacokinetic model of tacrolimus for Chinese renal transplant patients, above program languages were used to construct the population prediction and subpopulation prediction modules. Based on Bayesian principle and maximization of the posterior probability function, an objective function was established, and minimized by an optimization algorithm to estimate patient's individual pharmacokinetic parameters. It is proved that the network server has the basic functions for database management and three levels of prediction to aid doctor to optimize the regimen of tacrolimus for Chinese renal transplant patients.

Population pharmacokinetics of rocuronium delivered by target-controlled infusion in adult patients.

BACKGROUND: Target-controlled infusion (TCI) has been recently developed and successfully implemented in clinical practice. The current study was to estimate the population pharmacokinetics of rocuronium TCI in adult patients using nonlinear mixed-effects model (NONMEM), and to investigate the influence of relevant factors in adult patients. METHODS: Fourteen ASA I-II patients undergoing elective laparoscopy operation with general anesthesia were included. After induction, all patients received rocuronium by TCI system. The beginning target plasma concentration (Cpt) was 2.0 µg/ml, then increased Cpt according to the neuromuscular transmission monitoring. The endpoint of Cpt was determined when the T1 scale was blocked by 90% - 95%. TCI rocuronium was stopped 30 minutes before the end of the operation. Arterial blood was drawn before anesthesia at 0, 2, 4, 6, 8, 10, 15, 20, 30, 45, 60, 120, 180, 240 and 360 minutes after the infusion of rocuronium was stopped for the analysis of plasma concentrations of rocuronium by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The population pharmacokinetics analysis was performed using NONMEM program. RESULTS: The pharmacokinetics of TCI rocuronium in adult patients was best described by a three-compartment model. Pharmacokinetic parameters were clearance (CL)1 = 0.205 L/min, CL2 = 0.324 L/min, CL3 = 0.0292 L/min, volumes of distribution (V)1 = 4.00 L, V2 = 2.28 L, V3 = 4.26 L, Vdss = 10.54 L. Both age and weight as covariates affected the pharmacokinetic parameters. V1 and CL1 were negatively correlated with patient age. CL1 was positively correlated with weight. CONCLUSIONS: No pharmacokinetic change was noted when rocuronium was administered via TCI. Both age and weight as covariates affected the pharmacokinetic parameters.

[Pharmacodynamic interaction between propofol and remifentanil on the tolerance response to electrical tetanus stimuli].

OBJECTIVE: To describe the pharmacodynamic interaction between propofol and remifentanil in suppressing somatic and hemodynamic responses to electrical tetanus stimuli (ETS) during induction of intravenous anesthesia with response surface method. METHODS: Seventy patients of ASA I or II, aged 18-65 years, scheduled for elective surgery were anesthetized by propofol and remifentanil. Propofol was administered with a target-controlled infusion (TCI) device at a target concentration that remained constant throughout the study, and remifentanil was administered with a TCI device at increasing staircase target concentrations. The somatic and hemodynamic responses to electrical tetanus stimuli were assessed multiple times after allowing for plasma effect site equilibration. The pharmacodynamic interaction between propofol and remifentanil was analyzed by response surface method. The three-dimensional response surfaces were constructed with Minitab Software. Model parameters were estimated with NONMEM. RESULTS: Response surface method characterized the pharmacodynamic interactions between propofol (0-9 mg/L) and remifentanil (0-10 µg/L) qualitatively and quantitatively. The three-dimensional response surfaces showed considerable synergy between propofol and remifentani for blunting somatic and hemodynamic responses to ETS. When the target concentration of remifentani was 1 µg/L, 2 µg/L and 3 µg/L, the C50 of propofol for blunting somatic responses to ETS decreased by 40.1%, 71.5% and 82.1% respectively; and the C50 of propofol for blunting hemodynamic responses to ETS decreased by 45.0%, 72.8% and 83.7% respectively. However, further increases in remifentanil only modestly reduced the C50 of propofol associated with loss of response to ETS. Ceiling effect was seen. CONCLUSION: Response surface method can analyze the pharmacodynamic interactions qualitatively and quantitatively. The response surface models revealed the significant synergy between propofol (≤9 mg/L) and remifentanil (≤10 µg/L) for blunting somatic and hemodynamic responses to electrical tetanus stimuli. The ceiling effects of remifentanil were demonstrated in the reduction of propofol C50 regarding tolerance of responses to ETS.

Population pharmacokinetics of remifentanil in patients undergoing orthotopic liver transplantation.

BACKGROUND: Little is known about the influence of liver transplantation on the pharmacokinetics of most anesthetic drugs. The goal of this study was to study the population pharmacokinetics of remifentanil in the different phases of orthotopic liver transplantation (OLT) and the influence of relevant factors. METHODS: Thirteen adult patients undergoing OLT were enrolled. A single bolus infusion of remifentanil 5 microg/kg was administered during the preanhepatic, anhepatic and neohepatic phases of OLT. Arterial blood samples of 1.5 ml were collected at 0 (baseline), 1, 2, 3, 5, 7, 10, 15, 20, 25, 30, 45, 60 and 90 minutes after drug administration. Remifentanil concentration was assayed by high-performance liquid chromatography/mass spectrometry/mass spectrometry (HPLC/MS/MS). Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling (NONMEM). RESULTS: The pharmacokinetics of remifentanil in patients undergoing OLT was best described by a two-compartment open model. The pharmacokinetic parameters were not influenced by age, gender, operative phase, blood temperature, rehydration volume, or blood loss volume during sampling. The volume of distribution in the central compartment (V(1)) and the volume of distribution in the peripheral compartment (V(2)) were influenced by body weight. CONCLUSIONS: The population pharmacokinetics of remifentanil in patients undergoing OLT can be well described by a two-compartment open model. The functional status of the liver does not significantly affect the pharmacokinetics of remifentanil, but the body weight is an influential factor of V(1) and V(2).

[Population pharmacokinetics of tacrolimus in Chinese renal transplant patients].

The goal of this study is to investigate the population pharmacokinetics of oral tacrolimus in Chinese renal transplant patients and to identify possible relationship between covariates and population parameters. Details of drug dosage history, sampling time and concentration of 802 data points in 58 patients were collected retrospectively. Before analysis, the 58 patients were randomly allocated to either the model building group (n=41) or the validation group (n=17). Population pharmacokinetic data analysis was performed using the nonlinear mixed-effects model (NONMEM) program on the model building group. The pharmacokinetics of tacrolimus was best described by a one compartment model with first-order absorption and elimination. Typical values of apparent clearance (CL/F), apparent volume of distribution (V/F) were estimated. A number of covariates including demographic index, clinical index and coadministration of other drugs were evaluated statistically for their influence on these parameters. The final population model related clearance with POD (post operative days), HCT (haematocrit), AST (aspartate aminotransferase) and coadministration of nicardipine and diltiazem. Predictive performance of the final model evaluated with the validation group showed insignificant bias between observed and model predicted concentrations. Typical value of CL/F and V/F was 21.7 L x h(-1) and 241 L, inter-patient variability (RSD) in CL/F and V/F was 41.6% and 49.7%, respectively. The residual variability (SD) between observed and model-predicted concentrations was 2.19 microg x L(-1). The population pharmacokinetic model of tacrolimus in Chinese renal transplant patients was established and significant covariates on the tacrolimus model were identified.